Review ArticleProspective of 68Ga Radionuclide Contribution to theDevelopment of Imaging Agents for Infection and Inflammation
Irina Velikyan 123
1Section of Nuclear Medicine and PET Department of Surgical Sciences Uppsala University Uppsala Sweden2Preclinical PET Platform Department of Medicinal Chemistry Uppsala University Uppsala Sweden3PET Centre Centre for Medical Imaging Uppsala University Hospital 75185 Uppsala Sweden
Correspondence should be addressed to Irina Velikyan irinavelikyanakademiskase
Received 17 September 2017 Revised 19 November 2017 Accepted 10 December 2017 Published 4 January 2018
Academic Editor Xiang-Guo Li
Copyright copy 2018 IrinaVelikyanThis is an open access article distributed under the Creative CommonsAttribution License whichpermits unrestricted use distribution and reproduction in any medium provided the original work is properly cited
During the last decade the utilization of 68Ga for the development of imaging agents has increased considerably with the leadingposition in the oncology The imaging of infection and inflammation is lagging despite strong unmet medical needs This reviewpresents the potential routes for the development of 68Ga-based agents for the imaging and quantification of infection andinflammation in various diseases and connection of the diagnosis to the treatment for the individualized patient management
1 Introduction
The blossom of 68Ga utilization is reflected in the con-tinuous rapid growth of the number of basic and clinicalresearch publications as well as clinical trials and clinicalpractice [1ndash3] The potential scope of 68Ga-based imagingagents is rather extensive including ligands specifically tar-geting receptors enzymes and antigens hapten and effectormolecules involved in pretargeted imaging small moleculeswith biological function to monitor glycolysis hypoxia cellproliferation and angiogenesis nontargeting particles ofvarious sizes for imaging of ventilation and perfusion [4]The leading clinical application area is oncologywith targetedimaging of somatostatin receptors (SSTR) prostate specificmembrane antigen (PSMA) integrin receptors glucagon-like peptide 1 receptors (GLP1R) gastrin-releasing peptidereceptors (GRPR) human epidermal growth factor receptorfamily (HER2) and pretargeted imaging of carcinoembry-onic antigen (CEA) [1 3 5]
The scope of 68Ga-based imaging agents for inflammationand infection is rather limited despite disease diversity andmagnitude and strong unmet medical need [1 4 6] How-ever the research and development of 68Ga-based tracersfor the diagnosis and discrimination of inflammation andinfection accelerated during last five years [7ndash19] Such 68Ga-based tracers with specific action could also considerably
contribute to drug development Unfortunately the failurerate of new therapeutic drugs in general is rather highand it is a costly process PET offers advantages such aspossibility of quantifying the target occupancy by the drugvery early in the development in vivo in humans due tothe microdosing concept thus facilitating stratification ofcandidate therapeutic drugs
This review presents the status of the 68Ga-based imagingagents for inflammation and infection and discusses thepotential routes for the development of the agents and theirconnection to the treatment for the individualized patientmanagement
2 Infection and Inflammation
Infection is caused by the invasion of such pathogens as bac-teria virus fungi parasite or prion It is a significant causeof morbidity and mortality globally especially in childrencausing more death than any other disease Tuberculosismalaria and AIDS stand for about 50 of all lethal casesclaiming 5 million lives and causing 300 million illnesseseach year Bacterial infection for example tuberculosisand multidrug resistant bacteria presents diagnostic andtherapeutic challenges [20 21] Inflammation is immuneresponse to microbial invasion or an injury and can either be
HindawiContrast Media amp Molecular ImagingVolume 2018 Article ID 9713691 24 pageshttpsdoiorg10115520189713691
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related to the pathogens or be sterile It can be classified asacute or chronic and the latter has been investigated as themajor cause of inflammatory autoimmune cardiovascularneurological and cancerous diseases
In order to control infectious diseases and provide effi-cient treatment early diagnosis as well as discriminationbetween bacterial and sterile inflammation is crucial Thedisease specificity of the diagnostic tools is a desirablecharacteristic Currently available diagnostic means presentsome disadvantages Clinical laboratory tests such as whiteblood cell (WBC) counts and C-reactive protein (CRP)cannot unambiguously distinguish between bacterial andviral infection and may result in unnecessary treatmentwith antibiotics [22] Radiological imaging techniques suchas magnetic resonance imaging (MRI) X-ray computedtomography (CT) and ultrasound are morphological andrely on the anatomical changes that occur at later stage ofthe disease Moreover these methods are not specific toneither inflammation nor infection type Detection of viralinfection is even more challenging since it does not produceanatomic changes as bacterial infection does even when theviral infection is severe
In contrast to morphological imaging techniques func-tional methods such as gamma scintigraphy (Single Pho-ton Emission Computed Tomography (SPECT) and planargamma imaging) and Positron Emission Tomography (PET)provide fast whole-body and noninvasive real time evalu-ation of physiology and pathology on molecular level earlyin disease processes before noticeable changes in anatomicalstructure occur The whole-body examination might be ofgreat importance especially in cases of occult infection [23]The respective examinations can be repeated in order tomonitor the treatment outcome resulting in personalizedmedicine approach [24ndash27] The advantages of PET overSPECT are intrinsic to the technology and are presented withhigher examination throughput considerably higher sensi-tivity possibility of detection and quantification of tracerpicomolar amounts as well as tracer uptake kinetics recordingand dynamic image reconstruction [28] In recent years thestand-alone PET scanners have been substituted with hybridPET-CT scanners that offer both high sensitivity of functionalPET and temporalspatial resolution of morphological CT inone examination The hybrid PET-MRI scanners have alsoentered market providing advantages of MRI over CT inhigher soft tissue contrast and absence of radiation dose tothe patient PET has demonstrated efficiency and profitabilityin individualized patient diagnostics especially in oncologyand its impact on patient management has been recognizedby Medicare and Medicaid Services [29]
21 Common Clinical Imaging Agents for Inflammation andInfection There are a few radiopharmaceuticals used inclinical routine and they are nonspecific in their action 67Ga-Citrate 99mTc111In-white blood cells (WBC) and [18F]-fluo-rodeoxyglucose ([18F]FDG) [30] They target components ofinflammatory response to injury and infection and accumu-late in the lesions as a result of an increased blood flow andenhanced vascular permeability 67Ga-Citrate presumably
transfers 67Ga to transferrin and lactoferrin that accumulateat the inflammation site on the cells such as leukocytes and B-lymphocytes expressing respective receptors [31] Moreover67Ga can be accumulated in the macrophages bacteria andfungi via siderophores Radiolabelled WBCs accumulate inthe sites of leukocyte infiltration and do not discriminateinfective from sterile inflammation [32] [18F]FDG accumu-lates in leukocytes macrophages monocytes lymphocytesand giant cells due to upregulation of glucose transporters[33]67Ga-Citrate has been in clinical use for imaging of infec-
tion and inflammation for over 40 years It is applicable forexample for the diagnosis of lung infections acutechronicosteomyelitis tuberculosis sarcoidosis and retroperitonealfibrosis [34] However the specificity of the agent is subopti-mal with accumulation inmalignancies and bone remodelingsites as well as bowel excretion pathway Moreover radiationdoses to the healthy organs and tissues are unfavorableand the examination requires several visits to the hospitalwith an interval of 1ndash3 days between radiopharmaceuticaladministration and examination
Radiolabelled autologous WBCs have been used for awide range of infections such as peripheral osteomyelitispostoperative infection joint prosthesis infection diabeticfoot infection cardiovascular infection fever of unknownorigin (FUO) opportunistic infection central nervous sys-tem infection musculoskeletal infection and inflammatorybowel disease for over three decades Various labelling tech-niques using 111In-oxine 99mTc-sulfur colloids and 99mTc-exametazime (HMPAO) have been developed however theradiopharmaceutical preparation procedure is complicatedand potentially hazardous for both personnel and patient [2130]Moreover the examination process is very demanding onthe patient [35]
Most nuclear medicine applications worldwide (90)stand for diagnostics with leading position for 99mTc-basedradiopharmaceuticals especially in cardiology [36]Themostessential contribution to the improvement of the patientmanagement in oncology has been presented by [18F]-fluorodeoxyglucose ([18F]FDG)PET-CT reflecting the ele-vation of glucose transporter expression in tumour cellsand providing nearly universal application in the evalua-tion of various fast growing cancer types [18F]FDGPET-CT stands for over 90 of all PET-CT examinations [3738] [18F]FDGPET is an established diagnostic means alsoin infection and inflammation and the major indicationsfor it are FUO sarcoidosis peripheral bone osteomyelitissuspected spinal infection metastatic infection bacteremiaand vasculitis [33] However demand for the imaging agentstowards disease specific targets in cancer and inflamma-tioninfection is growing [39 40] since [18F]FDG fails todetect slowly growing tumours and to discriminate malig-nancy from sterile inflammation infection wound healingtuberculosis sarcoidosis and reactive lymph nodes [41 42]Another disadvantage is high accumulation of [18F]FDG inhealthy organs such as brain and gut resulting in suboptimalimage contrast and consequently potential risk for lesiondetection failure
Contrast Media amp Molecular Imaging 3
Table 1 Positron-emitting gamma-emitting and therapeutic radionuclides their physical characteristics and production mode Adaptedfrom [4]
18F 110min 634 120573+ (97) Accelerator64Cu 128 h 656 120573+ (19) Accelerator68Ga 676min 1899 770 120573+ (89) Generator89Zr 784 h 900 120573+ (23) Accelerator124I 417 d 2100 120573+ (23) Accelerator
Gamma emitters67Ga 7826 h 91 93 185 296 388 120574 Accelerator99mTc 60 h 141 120574 Generator111In 679 h 245 172 (05ndash25) 120574 Auger electrons Accelerator123I 133 h 159 120574 Accelerator
Therapeutic radionuclides177Lu 671 d 113 2084 (598) 120574 (120573minus) Reactor
22 Unmet Medical Need Noninvasive and specific diag-nosis of many inflammatory diseases such as sarcoidosisosteomyelitis inflammatory bowel disease and rheumatoidarthritis as well as early and accurate diagnosis of deep-seated infectious diseases such as septic arthritis abscessesendocarditis and infections of prosthetics and implantswould benefit patients [20] Introduction of specific imagingagents disclosing cellular mechanisms of various diseaseson molecular level would allow improvement in patientmanagement and treatment outcome There is a strong needfor specific imaging agents not only for the accurate andquantitative diagnosis but also for the prognosis treatmentselection planning and adjustment as well as response mon-itoring as for example requirement for a certain antibioticand treatment duration Moreover the imaging could guidesurgical procedures and monitor implants of medical devicesor transplanted organs [43] Such imaging guided treatmentwould decrease the cost side effects and overtreatmentavoiding immune suppression effects in inflammation andpossibly reducing the problem of antimicrobial resistance bythe termination of an accomplished successful treatment asearly as possible There are potential challenges in targetingboth components of inflammatory response and microbesspecifically discrimination between infectious and sterileinflammation discrimination between acute and chronicinflammation discrimination between various infectiousmicroorganisms discrimination between pathogenic bac-teria and microbiota targeting specific types of bacteriadifficulty of accessing bacteria aggregated in a biofilm andquantification of reproducing bacteria
Health care requires further improvement of efficiencysafety and quality of treatment with patient personalizedapproach that would allow early diagnosis which is a crucialfactor in the reduction of mortality and patient managementcost [81] The concept of individualized patient managementon molecular level with regard to both diagnostics andtherapy is based on discoveries and success in genomicsproteomics and biotechnology Those achievements alsoaccelerate the development of various imaging agents and
the application of molecular imaging diagnostic techniquesis expanding very fast globally contributing considerably tothe realization of personalized medicine
3 Advantages of 68Ga NuclideProperties and Chemistry
Such radionuclides as 11C 18F 64Cu 68Ga 89Zr 99mTc 111Inand 124I are used in various radiopharmaceuticals for diag-nostic imaging with PET and SPECT (Table 1) With regardto PET 18F stands for 41 11C stands for 31 and 64Cu 68Ga89Zr and 124I stand for 28 of the radiopharmaceuticals [82]With regard to SPECT 99mTc and 111In stand respectivelyfor 42 and 29 of the radiopharmaceuticals As mentionedabove in the field of inflammation and infection gammaemitting 67Ga 99mTc 111In and positron-emitting 18F arecommonly in use The choice of a radionuclide depends onvarious aspects of production and application availabilityproduction mode and cost of the radionuclide nuclearcharacteristics and decay mode of the radionuclide labellingchemistry pathways and duration radiation dose to subjectsrelevance of the physical half-life of the radionuclide to thepharmacokinetic time frame of the imaging agentWithin thegroup of gamma emitters used for SPECT the productionvia generator system is an advantage that contributes to theleading position of 99mTc due to ready accessibility and lowercost Moreover the single and lower gamma energy of 99mTcresults in higher image resolution as compared to 67Ga and111In and shorter half-life of 99mTc reduces radiation dose tothe patient (Table 2)
The advantages of PET such as higher spatial resolutionsensitivity and accurate signal quantification are crucialespecially in the case of small size lesions Furthermoredynamic scanning allows modeling and investigation of themechanism of the interaction between the imaging agentand target Even though 68Ga has a relatively high positronenergy the resolution of the images is comparable to thatof 18F since it is the scanner detector resolution (4ndash6mm)
4 Contrast Media amp Molecular Imaging
Table 2 Effective doses for some PET and SPECT imaging agents Reproduced from [6]
Agent Examination time Effective dose [mSv][111In]In-DTPA-octreotideSPECT 24ndash48 h 108[68Ga]Ga-DOTA-TOCPET 30ndash60min 23[18F]FDGPET 60ndash120min 56[99mTc]-BPAMDSPECT 2ndash6 h 6[99mTc]-MDPSPECT 2ndash6 h 3-4[68Ga]Ga-BPAMDPET 30ndash60min 3-4
which is the limiting factor [4 83 84]The 68-min half-life of68Ga is not compatiblewith ligands of slowpharmacokineticsfor example antibodies Thus other positron emitters suchas 124I 89Zr and 64Cu with longer half-lives allowing 2ndash4days required for the clearance of the agent for the bloodcirculation and washout for the nontarget tissue are morerelevantThe relatively short half-life of 68Ga presents advan-tage in cases when repetitive examinations on the same dayare of interest [85] The high fraction of positron emission isanother advantage of 68Ga (89) as compared to 64Cu (19)and 124I (23) Comparison of some clinically used imagingagents demonstrates the lower effective dose that patient isexposed to when using 68Ga-based agent as compared tothe agents comprising 18F 99mTc and 111In (Table 2) [686 87] Moreover the duration of patient examinations isshorter for 68Ga-agents than that for SPECT agents and tosome extend for [18F]FDG In summary the use of 68Gawould be beneficial in terms of accessibility high sensitivityand resolution quantification dynamic scanning fast scan-ning protocol repetitive examinations and low radiationburden
The chemical form in aqueous solution is Ga(III)cation which provides robust coordination chemistry 68Ga-labelling can be direct or chelator mediated The directlabelling utilizes the chelating ability of macromolecules forexample lactoferrin and transferrin comprising Tyr His andAsp AA residues that can chelate Ga(III) in the presence ofsynergetic bicarbonate ion Lowmolecular weight ligands canform stable complexes of variable lipophilicity and charge fornontargeting imaging The chelator mediated 68Ga-labellingrequires presence of a bifunctional chelator (BFC) for the sub-sequent straightforward and side specific coordination withGa(III) Considerable number of chelators was successfullydeveloped [4 6 88ndash95]Themost commonly used are DOTAand NOTA based chelators The former requires heatingunder over 60∘C for the complexation with 68Ga while thelatter can chelate 68Ga at ambient temperature which mightbe crucial in case of temperature sensitive ligands and italso allows for cold kit type radiopharmaceutical prepara-tion under radiopharmacy practice [96] DOTA presents anadvantage in the context of radiotheranostics since it canform stable complexes with 68Ga for PET diagnostics and177Lu for radiotherapy
The chelator or prosthetic group mediated labellingmost commonly results in agents comprising biologicallyactive vectormolecule chelatorprosthetic groupmoiety and
radionuclide Very often pharmacokinetic modifiers (PKM)are incorporated in order to modulate pharmacokinetics andagent organ distribution and improve in vivo stability as wellas separate the binding site from the bulky chelatorprostheticgroup moiety which may deteriorate the biological activityof the vector molecule Considerable number of publicationsreveal strong influence of even slight modifications in any ofthe agent structural components and the accurate predictionof pharmacokinetics and pharmacodynamics of a new agentis not straightforward [97] Nevertheless vast experience andknowledge have been intensively gathered during last twodecades providing possibility for more efficient and effectivedevelopment The labelling chemistry of 68Ga is well charac-terized and is relevant to small molecules macromoleculesand particles
Ga(III) as a chemical element presents a unique advan-tage over other radionuclides as it has properties closelyresembling those of Fe(III) which is involved in manybiochemical processes including inflammation MoreoverFe(III) is an essential nutrient and limiting factor ofmicrobiallife [98] Stable Ga(III) has been used in treatment of variousdiseases including cancer infection and inflammation [99ndash101] The ability of Ga(III) to bind iron proteins for examplelactoferrin and transferrin as well as siderophores andenzymes can be utilized in the imaging agent development
4 Biomarkers andRadiopharmaceutical Development
The development of imaging agents relies strongly on theadvances experience and knowledge of the research ofbiomarkers for example receptors and antigens transportsystems substances involved in angiogenesis glycolysishypoxia proliferation and apoptosis and enzyme activityTargeting biomarkers that are specific for a given diseaseis one the major aims of an agent development for bothdiagnostic imaging and therapy The knowledge and accessto respective vector molecules have considerably expandeddue to the achievements in proteomics and genomics Infec-tion inflammation and fibrosis are closely interrelated pro-cesses and corresponding biomarkers might present practicalinterest in developing respective imaging agents Favorablecharacteristics of a target in general include expressionupregulation absence of expression in normal tissue andinternalization or stable binding of the respective ligand forthe longitudinal accumulation of the latter [102]
Contrast Media amp Molecular Imaging 5
5 Imaging Inflammation
Inflammatory response is a complex process involvingimmune system cells (T- and B-lymphocytes NK cellsmacrophages monocytes neutrophils eosinophils andmastcells) and products of their (patho)physiological activity forexample cytokines involved in the cell signaling Variousfunctions of the cells and their products as well as theirreceptors provide a broad range of potential imaging targets[103ndash107] Targeting the white blood cells of the immunesystem such as macrophages monocytes lymphocytes andneutrophils for the detection of their upregulation and traf-ficking secretion of cytokines and chemokines and phago-cytosis has been investigated both clinically and preclinicallyReceptors such as SSTRNCA-90 integrins folate bombesinvascular cell adhesion protein-1 and interleukins expressedby activated T-cells CXCR2 expressed on neutrophils andCXCR4 overexpressed by leukocytes have demonstratedpotential for in vivo targeted imaging [108] Respectiveligands and substrates can be considered for radiolabellingCytokines including interferons lymphokines interleukinsand chemokines bind to various receptors for example IL1and IL2 receptor types IFN CD40 CD37 CD30 CD4CCR5 and IL1-17R receptor family Folate CD64 NCA90and CD15 receptors expressed on macrophages leukocytesand granulocytes can serve as targets Not only do moleculesof such super families as chemokine integrin selectin andimmunoglobulin participate in the cell emigration cascadebut also enzymes on the surface of endothelia cells andleukocytes contribute to the leukocyte extravasation [109]Receptors on the endothelial wall for example for bindingof IL1 and TNF120572 are another category of the targets Theseare only few examples of targets for potential imaging agentdevelopment (Table 3) Many targets were utilized in oncol-ogy [28] and their translation to inflammation is feasible
51 Targeting Cell Receptors with Antibodies Radiolabelled(99mTc 111In and 123I) anti-CD2 anti-CD5 anti-CD25 anti-CD45 antibodies and their fragments were used for the imag-ing of T-lymphocyte infiltration in various inflammatorydiseases [110] Typically for antibody slow pharmacokineticsthe time delay between the administration and examina-tion stretches up to 24 hours Interleukin-8 labelled with99mTc was studied in rabbits with induced acute pyogenicosteomyelitis [111] and induced acute colitis [112] The agentwas found suitable for the scintigraphic evaluation of therespective diseases CD163 receptor expressed in monocytesand activated macrophages was targeted with an anti-CD163antibody labelled with 68Ga in rats with acute collagen-induced arthritis [45]The agent demonstrated specific bind-ing and thus potential for studies of inflammatory diseases
52 Targeting Angiogenesis Angiogenesis plays an importantrole in wound healing chronic inflammation and tumourgrowth [113] The family of vascular endothelial growthfactors (VEGF) and integrins play crucial role in the angio-genesis cascade Integrin receptors are overexpressed on thesurface of vascular endothelial cells during angiogenesis inmalignances tissue healing and inflammation The largest
group is radiolabelled peptide ligands comprising arginine-glycine-aspartic acid (RGD) sequence and peptidomimeticstargeting 120572v1205733 integrin receptors Various analogues weredeveloped introducing cyclization andmultimerization vari-ety of chelatecoligand moieties PKM such as carbohy-drate and polyethylene glycol chains [114ndash121] Various RGDanalogues labelled with 18F 68Ga and 99mTc were usedin oncological clinical trials [122] The majority of themcomprised 18F however advantages of 68Ga such as accessi-bility of the radionuclide more straightforward and efficientlabelling chemistry lower radiation dose and better imagecontrast renderedmore extensive development of 68Ga-basedanalogues [123ndash127]
The imaging agents tested in cancer systems can berelevant for the imaging of inflammation related diseasesTheimaging and evaluation of synovial angiogenesis in patientswith rheumatoid arthritis was accomplished using [68Ga]Ga-PRGD2 [46] The elevated agent uptake was detected inthe sites of active inflammation rich neovasculature andphysiological integrin receptor expression while no traceraccumulationwas detected in axillary lymphnodeswith reac-tive hyperplasia and strenuous skeletal muscles [68Ga]Ga-PRGD2PET-CT was found useful for the evaluation of syn-ovial angiogenesis and follow-up of the treatment response
[68Ga]Ga-NOTA-c(RGDyK)was developed for the imag-ing of myocardial infarction (MI) and follow-up of theresponse to the therapeutic intervention and demonstratedpromising results preclinically [47] The uptake in the MIlesions was enhanced and correlated with the vascularendothelial growth factor expression Dynamic [68Ga]Ga-NOTA-c(RGDyK)PET scanning with subsequent kineticmodeling studies in rats with forelimb ischemia showedhigher uptake and distribution volume in the ischemicarea as compared to that of sham operation and controlregions [48] Monitoring myocardial repair and angiogenesisafter ischemic injury was found plausible using [68Ga]Ga-NODAGA-RGD and [68Ga]Ga-TRAP-(RGD)3 in rat model[49] Elevated uptake of [68Ga]Ga-DOTA-E-[c(RGDfK)]2was observed in the infarcted area while no accumulationwas detected in the noninfarcted myocardium of the samerats [50]The uptake of [68Ga]Ga-DOTA-RGD in atheroscle-rotic plaques was studied in vivo in atherosclerotic micewith promising results [52] Elevated uptake of [68Ga]Ga-NODAGA-RGD in injured myocardium as compared toviable ischemic areas in pig model presumably indicatedincreased expression of 120572V1205733 receptors associated with injuryrepair in the presence of coronary stenosis [51]
Although targeting VEGF receptors were studied in thecontext of cancerous diseases chronic inflammation can alsobe considered A ligand consisting of a single chain (scVEGF3ndash112 amino acids of human VEGF121) [128 129] was labelledwith 68Ga and the resulting agent showed distinct uptake inthe tumour xenografts in mice however high kidney uptakeneeded to be addressed [130 131]
53 Targeting Selectins P-selectin is expressed on the activeendothelium surface and platelets and operates the migra-tion of leukocytes in response to inflammatory cytokines
6 Contrast Media amp Molecular Imaging
Table 3 68Ga-based imaging agents for inflammation and infection investigated preclinically and clinically
E-selectin binding peptide labelled with 99mTc accumu-lated in acute osteomyelitic lesions in rats presumably byinteraction with activated vascular endothelium [132] Ananalogue of P-selectin natural ligand fucoidan labelled with68Ga could discriminate active and inactive atheroschleroticplaques in mice [44]
54 Targeting Vascular Adhesion Protein-1 Vascular adhe-sion protein-1 (VAP-1) and CD73 are endothelial surfaceenzymes involved in the recruitment of leukocytes and theirmovement from the blood into the tissue [109] Endothelialactivation that takes place during inflammation can be uti-lized for specific targeting imaging Several peptide analogues
Contrast Media amp Molecular Imaging 7
300
250
200
150
100
50
0
(kBq
ml)
Inflammation
Kidneys
Muscle
Inflammation
Kidneys
Muscle
Figure 1 PET images of the distribution of [68Ga]Ga-DOTAVAP-P1 [68Ga]Ga-DOTAVAP-PEG-P1 and [68Ga]Ga-DOTA-Siglec-9 inturpentine-induced rat model of sterile inflammation All three peptide analogues showed target-to-nontarget ratio above 6 with rapidaccumulation in the inflammation site and renal clearance Adapted from [57]
labelledwith 68Gawere designed for the visualization ofVAP-1 and showed promising results in animals with inducedinfection and sterile inflammation [7ndash13 133] The bindingwas proven specific and it was possible to differentiate inflam-mation from infection [68Ga]Ga-Siglec targeting VAP-1demonstrated preclinical potential for imaging of synovialinflammation in patients with rheumatic diseases [53] Thesame agent was utilized for respiratory distress syndrome(ARDS an inflammatory lung injury) imaging in a porcinemodel [54] Imaging VAP-1 with [68Ga]Ga-Siglec was foundpromising also for the detection of inflamed atheroscle-rotic lesions [55] and inflammatory response induced bycatheter implantation and staphylococcal infection [56]68Ga-Siglec and two more peptide analogues with affinityto VAP-1 ([68Ga]Ga-DOTAVAP-P1 [68Ga]Ga-DOTAVAP-PEG-P1 and [68Ga]Ga-DOTA-Siglec-9) were investigated inrat model of sterile skinmuscle inflammation (Figure 1) [57]They showed distinct uptake in the affected sites
55 Targeting Chemokines Cytokines are produced bymacrophages B-lymphocytes T-lymphocytes and mast cellsand act through receptors modulating for example immuneresponse to infection and inflammation Cytokines includechemokines interleukins interferons and lymphokines thatcan be classified in broad families exhibiting diverse func-tions for example IL-1 and IL-6 superfamilies and TNFTNFreceptor superfamily Therapeutics targeting cytokines are inclinical use for example inhibiting TNF or IL-6 in rheumaticdiseases
Chemokine receptors are physiologically expressed onB-lymphocytes T-lymphocytes macrophages neutrophilseosinophils monocytes and hematopoietic stem cells [134]Imaging agents targeting CXCR4 are based on inhibitors(AMD3100) or small peptides (NFB T140 pentixafor andTN14003) and comprise 18F 67Ga 68Ga or 64Cu [135ndash148] They were developed and studied for the imaging of
various cancerous diseases lung breast prostate cancersacute myeloid leukemia and glioblastoma
The application of CXCR4 targeting agents was extendedbeyond oncology Clinical caseimage reports [149 150]were published on the utilization of [68Ga]Ga-pentixafor fordetection and quantification of CXCR4 receptor density inischemic heart diseases reflecting the role of the receptorin inflammatory and progenitor cell recruitment [58 59]The same agent was successfully used in the assessment ofmacrophage infiltration in atherosclerotic plaques in rabbitdisease model [151]
56 Targeting Folate Receptors Folate receptors (FRs) areoverexpressed on a variety of cancer cells and activatedmacrophages but not on normal cells [152 153] Theenhanced expression of FR was found in lung macrophagesduring acute inflammation [154] The majority of the nuclearimaging agents based on folic acid or pteroic acid [155] weredeveloped for diagnosis of cancers overexpressing FR recep-tors such as breast cervical ovarian colorectal nasopharyn-geal renal and endometrial cancers Various 68Ga-labelledagents demonstrated accumulation in cell cultures and micebearing folate-receptor positive human nasopharyngeal car-cinoma cell line (KB) xenografts [6 156ndash162] [68Ga]Ga-DOTA-PEG-FA comprising folic acid was investigated forthe detection and quantification of inflammatory response tomedical implants using mice with subcutaneously implantedpolylactic acid and poly(N-isopropylacrylamide) particles asa model [60] The agent was accumulated in the area of theimplant most probably reflecting interaction of [68Ga]Ga-DOTA-PEG-FA with folate receptor expressed on activatedmacrophages Another folic acid based agent [68Ga]Ga-DOTA-folate was successfully tested in an inflammatory pawrat model (Figure 2) [61] Distinct accumulation in inflamedhand and foot joints of rheumatoid arthritis of a 99mTc-labelled folate analogue was observed in a patient while no
8 Contrast Media amp Molecular Imaging
NH ONHONH
OOO
HOHN O
HN
NN
N N
HO
O
N
N
O
O
N
N
O
O
O
Ga+
minus
（3
(a)
2
15
1
05
0
(b)
Figure 2 Accumulation of [68Ga]Ga-DOTA-folate (a) in the site of inflammation of rat inflammatory pawmodel induced by subcutaneouslyinjected Complete Freundrsquos Adjuvant (b) Adapted from [61]
4
2
0
Figure 3 Intense atherosclerotic inflammation (white arrows) was detected by [68Ga]Ga-DOTA-TATE in a patient with acute coronarysyndrome Adapted from [65]
uptake was detected in a nonarthritis patientrsquos hands and feet[163]
57 Targeting Somatostatin Receptors Somatostatin receptor(SSTR) ligand analogues have found an extensive appli-cation in diagnosis and radiotherapy of neuroendocrinetumours The elevated expression of SSTRs is known also insmall cell lung cancer breast cancer renal cell carcinomaprostate cancer and malignant lymphoma A number ofsomatostatin ligand analogues labelled with gamma- andpositron-emitting radionuclides were used clinically foroncological cases [85 164ndash174] 68Ga-labelled somatostatinanalogues demonstrated superior performance in terms ofhigher specificity and sensitivity detection rate shorterexamination time and quantification possibility and havebecome a golden standard for the detection of neuroen-docrine tumours (NETs) taking over that title from [111In]-pentetreotide (OctreoScan) and demonstrating specificityand sensitivity of over 90 [27 175ndash180] 68Ga-labelledagents for the imaging of NETs demonstrated advantages
also over other radionuclides and tracers such as [18F]FDG[174] 123I-metaiodobenzylguanidine ([123I]MIBG) [181 182][18F]DOPA [183] [99mTc]-dicarboxy propane diphosphonate[184] and [18F]NaF
SSTR are also overexpressed on activated macrophagesand T-lymphocytes 68Ga-labelled analogues were used ininflammation related diseases such as idiopathic pulmonaryfibrosis [62] Gravesrsquo and Hashimotorsquos diseases [63] coro-nary artery plaque imaging and characterization [64] andatherosclerotic inflammation with excellent macrophagespecificity (Figure 3) [65] Promising diagnostic potential ofa 99mTc-labelled analogue was demonstrated in patients withrheumatoid arthritis and secondary Sjogrenrsquos syndrome andthe method was suggested for the assistance in anti-TNFalpha antibody treatment planning [185] [68Ga]Ga-DOTA-TOCPET-CT was found superior to 67Ga-CitrateSPECT indetection of sarcoidosis lesions [186] A clinical study demon-strated correlation between uptake of [68Ga]Ga-DOTA-TOCand SST2 mRNA expression and recorded the information ina database [187] providing tools for accurate quantification
Contrast Media amp Molecular Imaging 9
and evaluation of disease progression and treatment responsein cancerous and inflammatory diseases involving SSTRsPreclinical study using atherosclerotic mice demonstratedsuperior targeting properties of [68Ga]Ga-DOTA-NOC ascompared to [18F]FDR-NOC [188] overall confirming thepotential of SSTR targeting for atherosclerotic plaque imag-ing
58 Imaging Neuroinflammation Despite difficulty ofdesigning 68Ga-labelled molecules capable of blood-brainbarrier penetration several agents were suggested for theimaging of neuroinflammation in particular A120573 plaquesdeposited on blood vessels [67ndash69] Bivalent styrylpyridineslabelled with 68Ga demonstrated high specificity and affinityfor A120573 plaques using postmortem Alzheimerrsquos disease (AD)brain sections [67] Benzofuran derivative comprising 68Gashowed promising results in terms of binding specificityand affinity investigated in vitro in sections of Tg2576mice [68] Although the synthesis of a 68Ga-labelledPittsburgh compound analogue was successful the in vitrobinding to amyloid deposits was limited [69] The commondisadvantage of these agents is poor blood-brain barrierpenetration nevertheless the exploration of more successfulanalogues continues Curcumin functions as an antioxidantantimicrobial anti-inflammatory and anticancer agentDiacetyl-curcumin and bis(dehydroxy)curcumin labelledwith 68Ga demonstrated in vitro binding to 120573-amyloid fibrilsand lung cancer cells [189] Potential application of the agentscould include diagnostic imaging of Alzheimerrsquos disease andvarious cancers
6 Imaging Infection
Infection imaging can be indirect utilizing targets involvedin the immune response namely inflammation as presentedin the inflammation targets section above or direct utilizingpathogen related targets The direct imaging is especiallycrucial in cases where inflammatory response is absent Thedifference in biochemistry and structure between bacterialand human cells might exclude physiological uptake byhuman tissuemaking it easier tomeet the favorable character-istics of an imaging agent However discrimination betweenthe various infectious microorganisms pathogenic bacteriaand microbiota targeting specific bacteria type as well asdifficulty of accessing bacteria aggregated in a biofilm makesthe task very challenging [190 191] The specific targetingof infection would require accumulation of the radioactivesignal in the pathogen The radiolabelled targeting agentsfor infection can be roughly divided into several groupsantibiotics based antimicrobial protein and peptide basedsiderophore and other metabolisable compound based andantigen-specific antibodies and antibody fragments (Table 3)
61 Radiolabelled Antibiotics Antimicrobials act on the pro-cesses that are specific to microbes for example bacteria andfungi and thus corresponding imaging agents might distin-guish infection from inflammation [191] They might requireinternalization or may bind to the cell surface dependent on
their biological action mechanism [191ndash193] The possibilityof antibiotic resistance development exists also in the case ofimaging agents even though the amount of such agents wouldbe subnanomolar [194 195] Another complication is possiblenonspecific uptake of antibiotics based agents by leucocytes[196] Considerable number of various antibiotic analogueshave been labelled with 99mTc 111In 131I 11C and 18F[102] and evaluated preclinically and clinically with 99mTc-ciprofloxacin becoming a commercial product (Infecton) [21197 198] However the further improvement of specificityis desirable [191] Antibiotics are accessible and cheap andthey demonstrate high sensitivity [102 191] making thedevelopment of 68Ga-labelled analogues very attractive giventhe earlier mentioned advantages that 68Ga as a radionu-clide in combination with PET provides Two 68Ga-labelledanalogues based on ciprofloxacin demonstrated potential fordiscrimination between bacterial infection and inflammationin rats infected with Staphylococcus aureus [70]
62 Radiolabelled Antimicrobial Proteins and Peptides Anti-microbial proteins and peptides for example serprocidinscathelicidins and defensins produced by the cells of immunesystem target microbial membrane lipids and impose micro-bicidal effect [35 43] They present a large group of poten-tial candidates for microbial imaging including bacteriafungi parasites and viruses Antimicrobial peptides havedemonstrated higher specificity for infection than antibioticanalogues They accumulate at infection but not sterileinflammation sites The most thoroughly studied antimicro-bial peptide ubiquicidin UBI [29ndash41] labelled with 99mTc[199] demonstrated promising results in human clinical trials[200 201] It has the potential for quantification of viableinfecting microorganisms and consequently for monitoringthe efficacy of antimicrobial therapy in patients
Fragments of an antimicrobial peptide ubiquicidin con-jugated to NOTA and labelled with 68Ga [68Ga]Ga-NOTA-UBI29-41 and [68Ga]Ga-NOTA-UBI30-41 demonstratedpossibility for the distinction between infection and inflam-mation in a rabbit model [71 72] Antimicrobial peptidefragments GF-17 and RAWVAWR-NH2 of respectivelyhuman cathelicidin LL-37 andhuman lysozyme active againstE coli and S aureus were labelled with 68Ga and theirbiodistribution in normal rats demonstrated fast clearancefrom liver [75] Antimicrobial depsipeptide based agent[68Ga]Ga-DOTA-TBIA101 targeting bacterial lipopolysac-charides detected muscular E coli-infection in mice (Fig-ure 4) [73] The agent was also studied in healthy rabbitsand various disease model rabbits such as sterile inflam-mation Staphylococcus aureus infection andMycobacteriumtuberculosis [74] The clearance of [68Ga]Ga-DOTA-TBIA101from blood and normal tissue was fast and enhanced uptakein sterile inflammation and Mycobacterium tuberculosis siteswas observed The improvement of the bacterial selectivitywill require modification of the agent structure
63 Radiolabelled Siderophores Bacteria and fungi producevarious siderophores for harvesting iron which is essentialfor their survival and growth [34 98 191] Siderophores
10 Contrast Media amp Molecular Imaging
(a)
(b)
(c) (d)
(e)
Figure 4 Left panel presents maximum intensity projection images of [68Ga]Ga-DOTA-TBIA101 distribution in a healthy mouse (a) and amouse with muscular infection site (MIS) in the right hind muscle tissue (white arrows) Right panel presents coronal (c) sagittal (d) andaxial (e) images with uptake in theMIS (white arrow) and absence of the uptake in the contralateralmuscle tissue Ki and Bl stand respectivelyfor kidney and bladder Reproduced from [73]
can also play a critical role in the development of biofilmsby microbes They are low molecular weight compoundsspecifically chelating Fe(III) and Ga(III) can form stablecomplexes with them mimicking Fe(III) [202 203]
Desferri-triacetylfusarinine C (TAFC) and desferri-ferricrocin (FC) labelled with 68Ga were used for theimaging of invasive pulmonary aspergillosis (IPA) caused byAspergillus fumigatus [15] [68Ga]Ga-TAFC demonstratedsuperior characteristics in terms of specific target bindingmetabolic stability and fast blood clearance in a rat modelof A fumigatus infection Seven analogues were developedin another study with TAFC and ferrioxamine E (FOXE)showing favorable binding clearance elimination andstability characteristics [16] as well as lung uptake inrat of invasive aspergillosis model wherein the uptakeextent was correlated with disease severity [17] [68Ga]Ga-triacetylfusarinine C and [68Ga]Ga-ferrioxamine E wereinvestigated in rat model of A fumigatus and demonstratedrapid uptake in the lungs (Figure 5) [76]
64 Radiolabelled Metabolisable Agents Mammalian micro-biota consumes (poly)saccharides in particular maltose andmaltodextrins [204] The transport mechanism is specific
to bacteria and is absent in mammalian cells making itpossible to utilize these (poly)saccharides for imaging agentdevelopment Maltodextrin functionalized with a fluorescentdye was internalized through the bacteria-specific maltodex-trin transport pathway and discriminated between activebacteria and inflammation in vivo [192] Maltose labelledwith 18F localized specifically bacterial infection in mice[205] Potential to label polysaccharides directly with 68Gamight be utilized extensively
As mentioned above the chemical properties of Ga(III)provide the potential for direct labelling of polysaccharidesDextran was labelled directly and resulting complex demon-strated sufficient stability in human serum however thefeasibility of the bacterial imaging was not demonstrated[206]
Trapping of nucleosides that are substrates of thymidinekinase occurring within bacteria was explored using 18Fand 125I labelled analogues of uracil [207] Promising resultswere obtained in seven bacterial species in mice Anotherstudy in the context of therapeutic bacteria developmentdemonstrated possibility of detecting Salmonella vectorswithin tumours using 18F-labelled uracil [208] However
Contrast Media amp Molecular Imaging 11
N
O
N
ON
HN
O
O
O
OO O
NH
O
O
O
O
NH
O
OGa
（3
（3
（3
（3
（3
（3
（2
(a) (b) (c)
Figure 5 Molecular structure of [68Ga]Ga-triacetylfusarinine C (a) used for the in vivo imaging of a rat with Aspergillus fumigatus infection(b) and negative control of noninfected rat (c) White arrows point at the infected (b) and normal (c) lungs Adapted from [76]
the development of 68Ga-labelled nucleosides that wouldmaintain their biological activity is challenging and fewexamples known from the literature confirm that [4 6]
7 68Ga-Citrate
As mentioned above 68GaPET provides a number of advan-tages over 67GaSPECT and following publications demon-strate it in clinical and preclinical studies [68Ga]Ga-citratedemonstrated high diagnostic accuracy of 90of osteomyeli-tis and diskitis in clinical studies (Figure 6) [18 19] Thisstudy demonstrates that [68Ga]Ga-citrate can be employedfor monitoring the response to treatment [68Ga]Ga-citratewas used clinically to follow-up surgical intervention inpatients with acute osteomyelitis and intra-abdominal infec-tion [77] The agent was also used to successfully visualizelungmalignancy and tuberculosis in patients however in caseof high prevalence of granulomatous diseases the distinctionbetween malignant and benign lung lesions was unclear [7879] Another clinical study conducted head-to-head compar-ison of [68Ga]Ga-citrate (Figure 7) and [18F]FDG in patientswith Staphylococcus aureus bacteremia [80] The detectionrate of osteomyelitis was similar and further investigationof [68Ga]Ga-citrate applicability in cases of osteomyelitisinduced by other pathogens as well as for monitoring healingprocess is warranted
Comparative study of [68Ga]Ga-citrate and [67Ga]Ga-citrate was performed in healthy and infection model rats[77] The performance of [68Ga]Ga-citrate was found supe-rior in terms of image contrast in the lower abdomen and
extremities Potential of [68Ga]Ga-citrate for the differentia-tion of acute interstitial nephritis from acute tubular necrosiswas studied in rat model of the disease and it was demon-strated that the kidney uptake correlated with the extentof mononuclear cell infiltration accompanying inflammation[209] 68Ga-labelled Apo-transferrin demonstrated bacterialinfection detection capacity in rat model with Staphylococcusaureus wherein the infection site was visualized 1 h afteradministration of the agent [14]
71 Radiolabelled Antibodies and Antibody FragmentsHuman immunoglobulin (HIG) binds to bacteria but alsoaccumulates at the sites of fungal and viral infection aswell as sterile inflammation due to binding to leukocytesThe improved specificity for bacteria was achieved for thefragments of HIG It is feasible to develop specific antibodiesto various antigens present on the bacterial cell surface [102]Monoclonal antibodies labelled with 99mTc were used forinfection imaging via granulocytes targeting NCA-95 [210]Various cytokines of interleukin family (IL-1 IL-8) labelledwith 123I or 99mTc demonstrated accumulation in the sitesof infection in various animal models [111 112 211ndash214]Registered antigranulocyte radiopharmaceuticals suchas LeuTech Scintimun and Leukoscan are based on99mTc-labelled antibodies This experience can be translatedto 68Ga however either the size of the antibodies mustbe reduced or pretargeting techniques must be appliedin order to overcome the discrepancy between the shortphysical half-life of 68Ga and slow pharmacokinetics ofantibodies
12 Contrast Media amp Molecular Imaging
(a) (b) (c) (d)
Figure 6 [68Ga]Ga-citrate PETCT examination of a patient affected by acute osteomyelitis before (left panel) and after (right panel) surgicalcurettage showing uptake in the transaxial (a c) and 3D reconstruction images (b d red area) Absence of the uptake after the therapyconfirms complete response to the treatment Adapted from [19]
Figure 7 Vertebral osteomyelitis (spondylodiscitis red arrow-heads) and abscesses in the iliopsoas and paravertebral area (redarrows) were detected by [68Ga]Ga-citrate in a patient admittedto the hospital with back pain and general symptoms The PETacquisition was performed 88min after administration of 245MBqof [68Ga]Ga-citrate Adapted from [80]
72 Radiolabelled Biotin Biotin is a growth factor utilizedin many bacteria An 111In-labelled analogue of biotin wassuccessfully utilized for diagnosis of vertebral infections ina clinical study [215] It would be rational to explore therelevance of 68Ga-labelled analogues given the advantagesof 68Ga over 111In and promising [68Ga]Ga-DOTA-Biotinanalogues [216 217] developed for monitoring survival oftransplanted avidin-coated islets
8 Miscellaneous
Stable Ga(III) complex with thiosemicarbazones demon-strated antimicrobial effect against P aeruginosa and Calbicans due to most probably both displacement of essentialFe(III) with Ga(III) and thiosemicarbazones [101] Substitu-tion of the stable Ga(III) by radioactive 68Ga might result ina specific infection imaging agent
Selective imaging of Enterobacteriaceae using 2-[18F]-fluorodeoxysorbitol (18F-FDS)was demonstrated in amurine
myositis model [218] The uptake of 18F-FDS was correlatedwith bacterial burden moreover the agent differentiatedinfection from sterile inflammation Given the potential of68Ga for the labelling of small biologically active molecules[4] it might be plausible to develop a respective analoguewith added value of the advantages that 68Ga offers includingsimpler production chemistry lowered radiation dose repet-itive examination and accessibility at clinical centers withoutcyclotrons and remote from [18F]-FDG distribution sites Asmentioned above the poor access to bacteria aggregated ina biofilm might make the imaging task challenging Severalpeptide candidates with affinity for S aureus biofilm weredesigned and labelled with 68Ga [219] The resulting agentsdemonstrated binding in vitro however it was not possible toblock the binding with excess of the cold peptide
Ionic 68Ga was found superior to [18F]-FDG in infectiondetection in the rat model with diffuse osteomyelitis [220] Inanother study the uptake of ionic 68Ga was observed in theaortic plaques of atherosclerotic mice specifically at the sitesrich inmacrophages [221] However the slow blood clearanceof ionic 68Ga presents a limitation
Chronic inflammation is the major reason of fibro-sis [222] 68Ga-labelled SST analogue ([68Ga]Ga-DOTA-NOC) demonstrated uptake in pathogenic areas in patientsaffected by idiopathic pulmonary fibrosis with potentialfor monitoring response to treatment and drug develop-ment [62] Another clinical study using [68Ga]Ga-pentixaforalso showed potential of the agent for monitoring dis-ease activity and response to treatment in idiopathic pul-monary fibrosis [223] Peptide based agents CNO2A-PEG2-c[CPGRVMHGLHLGDDEGPC] and [68Ga]Ga-NODAGA-PEG2-c[CPGRVMHGLHLGDDEGPC] for the imaging andquantification of fibrosis by PET were developed and char-acterized preclinically showing fast clearance from normal
Contrast Media amp Molecular Imaging 13
tissue and blood and binding specificity [89] Dosimetrycalculations demonstrated possibility of six examinations peryear in humans assuring disease monitoring in longitudinalstudies and routine clinical setup [224]
Several hyaluronan conjugates of oligonucleotides target-ing CD44 positive cells were developed and tested in healthyrats sham-operated rats and rats with myocardial infarction[225]The uptake of the agents was higher for the latter groupand varied dependent on the difference in the oligonucleotidestructure
TLR2 and TLR4 expression levels in neutrophils werefound higher in individuals with bacterial and viral infectionsthan those in control samples There is a possibility that IL-4IL-8 IL-10 IL-12 and TNF-a might serve as biomarkers forinfections and that IL-2 IL-8 or IL-10 is potentially able todistinguish between bacterial and viral infections [22]
Mannosylated human serum albumin labelled with 68Gavia NOTA chelator moiety ([68Ga]Ga-NOTA-MSA) wastested in a rat model of myocarditis targetingmannose recep-tors expressed onmacrophages infiltratingmyocardium [66]The uptake in the diseased myocardium was considerablyhigher than that of the normal one and it was precludedby administration of excess of nonlabelled MSA indicatingbinding specificity The tracer build-up was also observed inthe organs of macrophage accumulation
[68Ga]Ga-DOTA was investigated for the quantificationof increased blood flow which is one of the key events ininflammation [226] The uptake kinetics of [68Ga]Ga-DOTAin the site of inflammation in rats with induced inflamma-tion correlated well with that of 15O-water suggesting highrelevance [68Ga]Ga-DOTA
9 Pretargeted Imaging
The half-life of 68Ga is shorter than that of 64Cu 67Ga 99mTc89Zr 111In and 123124125I and thus in contrast to the latterit is not compatible with slow pharmacokinetics of largemolecules such as antibodies and glycoproteins The rangeof antigen-specific antibodies relevant to inflammation andinfection is broad and a number of 99mTc-labelled antibodieswere used clinically [20 21 227] The respective range of68Ga-based agents could be similarThe solution to overcomethe incompatibility of half-life time frames could be eitherthe reduction of the antibody size or the application of thepretargeting concept
The history of the pretargeting concept spans threedecades predominantly in the field of oncology [228ndash230]It was developed to improve image contrast and dosimetryin immunoimaging and radioimmunotherapy when usingradiolabelled antibody ligands with slow pharmacokinetics[231] The arsenal of antibodies is vast and diverse encourag-ing extensive investment into development of techniques thatwould allow their exploration to the fullest Pretargeting con-siders at least two major steps wherein a functionalized anti-body is first administered for target localization and clearancefrom blood and normal tissue and thereafter a radiolabelledsmall molecule capable of binding to the functionalized
antibody due to high affinity or covalent interaction is admin-istered The key properties of the radiolabelled molecules arefast pharmacokinetic and clearance Several techniques havebeen developed for the realization of pretargeting conceptincluding avidinstreptavidin-biotin systems [216 217 232233] bispecific antibodies (bsmAb) with haptens [232 234ndash254] antibody-oligonucleotide conjugates with complemen-tary oligonucleotides [255] biorthogonal systems allowingcovalent chemical reactions in vivo (Figure 8)
The high affinity of biotin to avidin and streptavidinproteins was utilized clinically and preclinically in pretar-geting approach for the imaging and therapy of pancreaticadenocarcinoma [232] glioblastoma [256] and lymphoma[257] However this pretargeting technique may requirethree steps in order to eliminate the excess of antibody-(strept)avidin conjugate circulating in the blood and notbound to the target by adding clearing agent Anotherapplication of the technique was monitoring transplantationof islets of Langerhans in the treatment for type 1 diabetesmellitus wherein the cells or cellmimetics were conjugated to(strept)avidin prior to the transplantation [216 217] Severalanalogues of biotin comprising DOTA chelate moiety forlabelling with 68Ga and ethylene glycol linker of variouslength demonstrated the influence of the latter on the affinitytowards avidin
Particular example of hapten molecules is the ones com-prising histamine-succinyl-glycine (HSG) motif and chelatemoiety [251ndash253 258] for the complexationwith 68Ga Severalanalogues were developed for the imaging of carcinoem-bryonic antigen (CEA) pretargeted with anti-CEA bsmAb[254 259 260] and two clinical studies of medullary thyroidcarcinoma and breast carcinoma positive for CEA using68Ga-labelled hapten molecules and bsmAb were initiated[261]
Bioorthogonal reactions are fast regioselective requiringsmall reagent concentration and occurring under mild con-ditions often in aqueous solution and temperature below 37∘C[262 263] Amongst various biorthogonal reaction types thecycloaddition of tetrazines and various dienophiles referredto as inverse-electron-demandDiels-Alder (IEDDA) reactionis themost successful in the context of pretargeting Antibod-ies functionalized with trans-cyclooctene (TCO) and a radi-olabelled tetrazine that can interact in vivo based on IEDDAreaction were studied [264ndash267] In particular 68Ga-labelledtetrazine dextran demonstrated favorable pharmacokineticsin a healthy mouse [264] However the proof of concept is tobe performed in a xenografted animal Accumulation of anti-TAG72 [265] and anti-A33 [266] antibodies functionalizedwith TCO in mouse xenografts was visualized respectivelyby an 111In and 64Cu-labelled tetrazine analogues Anti-CA199 antibody-TCO in combination with 177Lu-labelledtetrazine demonstrated radiotherapeutic effect in pancreaticcancer murine model [267]
Thepretargeted imaging techniquesmay contribute to theexpansion of immuno-PET with 68Ga providing the intrinsicadvantages of 68Ga and PET As mentioned above mostof the developed radiolabelled counterparts of pretargetingtechniques have demonstrated promising results There are
14 Contrast Media amp Molecular Imaging
H
ON
NN
O
OO
OO
NH
NS
NH
ONH
O
HO
ONH
O
Ga
HN
NH
NH
O
OO
HNN
HN
NH
NH
O
OO
HNN
（2
(a)
NH
O
O
NH
N
NNGa
O O
O O
O
O
O
N N
NN
OO
（2
(b)
N
N
O
O
N
N
O
O
O
NH
O
O
ONH
NHS
O
H
HO
NH
+
minus
(c)
Figure 8 Schematic presentation of pretargeting techniques (a) bispecific antibodies engineered to specifically bind with radiolabelledhapten molecules (b) bioorthogonal click chemistry for fast and specific covalent binding between for example a trans-cyclooctenefunctionalized antibody and a radiolabelled tetrazine (c) interaction between antibody-(strept)avidin conjugate and radiolabelled biotinutilizing extremely high affinity of (strept)avidin and biotin
Contrast Media amp Molecular Imaging 15
a considerable number of potential antibody biomarkersthat could be considered for the imaging of infection andinflammation
10 Theranostics Potential
Theranostics [268] embraces realization of personalizedmedicine by conducting diagnosis on individual basis andproviding possibility of predicting the efficacy of a specifictreatment and following up the response to the treatmentenabling adjustment of the latter very early in the processIn the context of nuclear medicine wherein the radiophar-maceuticals targeted at biomarkers specific to a disease cancarry either diagnostic radionuclides or therapeutic ones theconcept can be denoted as radiotheranostics [28] The tar-geted molecular imaging such as PET can offer noninvasivediagnosis specific to the disease for example tumour-typespecific and provide accurate localization of the lesions Thestrongest advantage of PET is the potential for quantificationof the target for example receptor expression investigationof the uptake kinetics and estimation of the dosimetryThesecharacteristics of PET allow for individualized treatmentselection and planning monitoring of treatment responseand detection of recurrent diseaseThe individualized patientmanagement provides such advantages as optimization ofthe treatment regimen for the improved response and exclu-sion of futile treatments minimization of risks and toxicitywith overall outcome of reduced cost and patient distressThe importance of individualized patient management wasdemonstrated by clinical studies wherein the influence ofdose of the administered radiopharmaceutical targeted atreceptors overexpressed in cancer lesions on the diagnosticoutcome was investigated in the same patient [85 269270] 68Ga-labelled SST analogues [26ndash28 271] and Affibodymolecules [5 272ndash274] used respectively in NENs andbreast cancer patients are the most prominent examplesof (radio)theranostics involving 68GaPET wherein 68Ga-labelled analogues were used not only for localization of thelesions but also for staging patient stratification prognosistherapy selection and monitoring of the response to thetreatment of NETs and other cancer types [2ndash4 6 85 176275ndash277]
The methodology can be translated to inflammationand infection allowing for accurate and specific selection oftreatment regimen and for follow-up and evaluation of theresponse to therapy resulting in improved treatment efficacyand decreased cost and side effects The accommodation ofboth imaging function and antibiotic function in the samemolecule is a novel example of a theranostic agent [278]A series of siderophores conjugated with DOTA moiety forthe radiolabelling and with antibiotics for the treatmentof bacterial infection were investigated preclinically Theaccumulation of the intravenously administered ampicillinconjugate in the site of subcutaneously injected P aeruginosain mice was clearly and focally visualized within 06 h withretention for at least 24 h These results obtained usinganalogues carrying dye for optical imaging can be translatedto 68Ga-labelled counterparts for PET
11 Conclusions
The medical need for specific agents for noninvasive quan-titative and whole-body imaging of inflammation and infec-tion has not been met yet despite decades of research How-ever the prerequisites in terms of identification of potentialtargets design and synthesis of the respective ligands andimaging technologies are evolving very fast The potentialof accurate and quantitative lesion localization as well asmonitoring of the treatment response promises personalizedpatient management
The use of 68Ga in oncology is established proving thestrong potential of 68Ga for the promotion of PET technol-ogy for effective and efficient diagnostics and personalizedmedicineThe experience of oncological 68Ga-based agents isgetting translated to inflammation and infection Pretargetedimaging technology opens wide possibilities based on anti-body biomarkers
Conflicts of Interest
The author declares that there are no conflicts of interestregarding the publication of this article
References
[1] I Velikyan ldquoContinued rapid growth inGa applications update2013 to June 2014rdquo Journal of Labelled CompoundsampRadiophar-maceuticals pp 99ndash121 2015
[2] I Velikyan ldquo 68Ga-based radiopharmaceuticals Production andapplication relationshiprdquo Molecules vol 20 no 7 pp 12913ndash12943 2015
[3] M Fani P Peitl and I Velikyan ldquoCurrent status of radiophar-maceuticals for the theranostics of neuroendocrine neoplasmsrdquoPharmaceuticals vol 10 no 1 article no 30 2017
[4] I Velikyan ldquoPositron emitting [68Ga]Ga-based imaging agentsChemistry and diversityrdquoMedicinal Chemistry vol 7 no 5 pp345ndash379 2011
[5] J Sorensen I Velikyan D Sandberg et al ldquoMeasuringHER2-receptor expression in metastatic breast cancer using[68Ga]ABY-025 Affibody PETCTrdquo Theranostics vol 6 no 2pp 262ndash271 2016
[6] I Velikyan ldquoProspective of 68Ga-Radiopharmaceutical devel-opmentrdquoTheranostics vol 4 no 1 pp 47ndash80 2014
[7] P Lankinen T J Makinen T A Poyhonen et al ldquo68Ga-DOTAVAP-P1 PET imaging capable of demonstrating the phaseof inflammation in healing bones and the progress of infectionin osteomyelitic bonesrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 35 no 2 pp 352ndash364 2008
[8] T UjulaMHuttunen P Luoto et al ldquoMatrixmetalloproteinase9 targeting peptides Syntheses 68Ga-labeling and preliminaryevaluation in a rat melanoma xenograft modelrdquo BioconjugateChemistry vol 21 no 9 pp 1612ndash1621 2010
[9] A Autio T Ujula P Luoto S Salomaki S Jalkanen and ARoivainen ldquoPET imaging of inflammation and adenocarcinomaxenografts using vascular adhesion protein 1 targeting peptide68Ga-DOTAVAP-P1 Comparison with 18F-FDGrdquo EuropeanJournal of Nuclear Medicine and Molecular Imaging vol 37 no10 pp 1918ndash1925 2010
16 Contrast Media amp Molecular Imaging
[10] J Silvola A Autio P Luoto S Jalkanen andA Roivainen ldquoPre-liminary evaluation of novel 68Ga-DOTAVAP-PEG-P2 peptidetargeting vascular adhesion protein-1rdquo Clinical Physiology andFunctional Imaging vol 30 no 1 pp 75ndash78 2010
[11] T Ujula S Salomaki P Virsu et al ldquoSynthesis 68Ga labelingand preliminary evaluation of DOTA peptide binding vascularadhesion protein-1 a potential PET imaging agent for diagnos-ing osteomyelitisrdquo Nuclear Medicine and Biology vol 36 no 6pp 631ndash641 2009
[12] A Autio T Henttinen H J Sipila S Jalkanen and ARoivainen ldquoMini-PEG spacering of VAP-1-targeting 68Ga-DOTAVAP-P1 peptide improves PET imaging of inflamma-tionrdquo EJNMMI Research vol 1 no 1 pp 1ndash7 2011
[13] K Aalto A Autio E A Kiss et al ldquoSiglec-9 is a novel leukocyteligand for vascular adhesion protein-1 and can be used in PETimaging of inflammation and cancerrdquo Blood vol 118 no 13 pp3725ndash3733 2011
[14] V Kumar D K Boddeti S G Evans F Roesch and RHowman-Giles ldquoPotential use of 68Ga-apo-transferrin as a PETimaging agent for detecting Staphylococcus aureus infectionrdquoNuclear Medicine and Biology vol 38 no 3 pp 393ndash398 2011
[15] M Petrik H Haas G Dobrozemsky et al ldquo68Ga-siderophoresfor PET imaging of invasive pulmonary aspergillosis Proof ofprinciplerdquo Journal of Nuclear Medicine vol 51 no 4 pp 639ndash645 2010
[16] M Petrik H Haas M Schrettl A Helbok M Blatzer and CDecristoforo ldquoIn vitro and in vivo evaluation of selected 68Ga-siderophores for infection imagingrdquo Nuclear Medicine andBiology vol 39 no 3 pp 361ndash369 2012
[17] M Petrik GM Franssen H Haas et al ldquoPreclinical evaluationof two 68Ga-siderophores as potential radiopharmaceuticals forAspergillus fumigatus infection imagingrdquo European Journal ofNuclearMedicine andMolecular Imaging vol 39 no 7 pp 1175ndash1183 2012
[18] A Rizzello D Di Pierro F Lodi et al ldquoSynthesis and qualitycontrol of 68Ga citrate for routine clinical PETrdquo NuclearMedicine Communications vol 30 no 7 pp 542ndash545 2009
[19] C Nanni C Errani and L Boriani ldquo 68Ga-citrate PETCT forevaluating patients with infections of the bone preliminaryresultsrdquo Journal of Nuclear Medicine vol 51 no 12 pp 1932ndash1936 2010
[20] S S Das A V Hall D W Wareham and K E Britton ldquoInfec-tion imaging with radiopharmaceuticals in the 21st centuryrdquoBrazilian Archives of Biology and Technology vol 45 no spepp 25ndash37 2002
[21] A Signore and A W J M Glaudemans ldquoThe molecularimaging approach to image infections and inflammation bynuclear medicine techniquesrdquo Annals of Nuclear Medicine vol25 no 10 pp 681ndash700 2011
[22] T Yusa K Tateda A Ohara and S Miyazaki ldquoNew possiblebiomarkers for diagnosis of infections and diagnostic distinc-tion between bacterial and viral infections in childrenrdquo Journalof Infection and Chemotherapy vol 23 no 2 pp 96ndash100 2017
[23] A Signore A W J M Glaudemans O Gheysens C Lauriand O A Catalano ldquoNuclear Medicine Imaging in PediatricInfection or Chronic Inflammatory Diseasesrdquo Seminars inNuclear Medicine vol 47 no 3 pp 286ndash303 2017
[24] I Velikyan ldquoMolecular imaging and radiotherapyTheranosticsfor personalized patient managementrdquo Theranostics vol 2 no5 pp 424ndash426 2012
[25] F Rosch and R P Baum ldquoGenerator-based PET radiophar-maceuticals for molecular imaging of tumours On the way
to THERANOSTICSrdquo Dalton Transactions vol 40 no 23 pp6104ndash6111 2011
[26] R P Baum H R Kulkarni and C Carreras ldquoPeptides andreceptors in image-guided therapy Theranostics for neuroen-docrine neoplasmsrdquo Seminars in Nuclear Medicine vol 42 no3 pp 190ndash207 2012
[27] R P Baum and H R Kulkarni ldquoTheranostics From molecularimaging using Ga-68 labeled tracers and PETCT to per-sonalized radionuclide therapy - the bad berka experiencerdquoTheranostics vol 2 no 5 pp 437ndash447 2012
[28] I Velikyan ldquoRadionuclides for Imaging andTherapy in Oncol-ogyrdquo Cancer Theranostics pp 285ndash325 2014
[29] J Czernin andWAWeber ldquoIssues and controversies in nuclearmedicine Introductionrdquo Journal of Nuclear Medicine vol 52no Supplement 2 pp 1Sndash2S 2011
[30] S J Goldsmith and S Vallabhajosula ldquoClinically proven radio-pharmaceuticals for infection imaging mechanisms and appli-cationsrdquo Seminars in Nuclear Medicine vol 39 no 1 pp 2ndash102009
[31] M F Tsan ldquoMechanism of gallium-67 accumulation in inflam-matory lesionsrdquo Journal of Nuclear Medicine vol 26 no 1 pp88ndash92 1985
[32] S L Kipper ldquoRadiolabelled leukocyte imaging of the abdomenrdquoin Nuclear Medicine Annual J Freeman Ed pp 81ndash126 RavenPress New York NY USA 1995
[33] F Jamar J Buscombe A Chiti et al ldquoEANMSNMMI guidelinefor 18F-FDG use in inflammation and infectionrdquo Journal ofNuclear Medicine vol 54 no 4 pp 647ndash658 2013
[34] C J Palestro ldquoThe current role of gallium imaging in infectionrdquoSeminars in Nuclear Medicine vol 24 no 2 pp 128ndash141 1994
[35] M S Akhtar M B Imran M A Nadeem and A ShahidldquoAntimicrobial peptides as infection imaging agents better thanradiolabeled antibioticsrdquo International Journal of Peptides vol2012 Article ID 965238 19 pages 2012
[36] D Delbeke and G M Segall ldquoStatus of and trends in nuclearmedicine in the United Statesrdquo Journal of Nuclear Medicine vol52 no 2 2011
[37] S S Gambhir J Czernin J Schwimmer D H Silverman R EColeman and M E Phelps ldquoA tabulated summary of the FDGPET literaturerdquo Journal of Nuclear Medicine vol 42 pp 1Sndash93S2001
[38] M J Lindsay B A Siegel S R Tunis et al ldquoThe NationalOncologic PET Registry ExpandedMedicare coverage for PETunder coverage with evidence developmentrdquo American Journalof Roentgenology vol 188 no 4 pp 1109ndash1113 2007
[39] F Gemmel H Van Den Wyngaert C Love M M Welling PGemmel and C J Palestro ldquoProsthetic joint infectionsradionuclide state-of-the-art imagingrdquo European Journal ofNuclearMedicine andMolecular Imaging vol 39 no 5 pp 892ndash909 2012
[40] J Sorensen ldquoHow does the patient benefit from clinical PETrdquoTheranostics vol 2 no 5 pp 427ndash436 2012
[41] S L Rice C A Roney P Daumar and J S Lewis ldquoThe nextgeneration of positron emission tomography radiopharmaceu-ticals in oncologyrdquo Seminars in Nuclear Medicine vol 41 no 4pp 265ndash282 2011
[42] R LWahl JMHerman and E Ford ldquoThePromise and Pitfallsof Positron Emission Tomography and Single-Photon EmissionComputed Tomography Molecular Imaging-Guided RadiationTherapyrdquo Seminars in Radiation Oncology vol 21 no 2 pp 88ndash100 2011
Contrast Media amp Molecular Imaging 17
[43] A W J M Glaudemans R H J A Slart J M Van Dijl MVan Oosten and G M Van Dam ldquoMolecular imaging of infec-tious and inflammatory diseases A terra incognitardquo Journal ofNuclear Medicine vol 56 no 5 pp 659ndash661 2015
[44] X Li W Bauer I Israel et al ldquoTargeting p-selectin by gallium-68-labeled fucoidan positron emission tomography for nonin-vasive characterization of vulnerable plaques Correlation within vivo 176t mrirdquo Arteriosclerosis Thrombosis and VascularBiology vol 34 no 8 pp 1661ndash1667 2014
[45] S Eichendorff P Svendsen D Bender et al ldquoBiodistributionand PET Imaging of a Novel [68Ga]-Anti-CD163-AntibodyConjugate in Rats with Collagen-Induced Arthritis and inControlsrdquoMolecular Imaging and Biology vol 17 no 1 pp 87ndash93 2014
[46] Z Zhu Y Yin K Zheng et al ldquoEvaluation of synovial angiogen-esis in patients with rheumatoid arthritis using 68Ga-PRGD2PETCT A prospective proof-of-concept cohort studyrdquo Annalsof the Rheumatic Diseases vol 73 no 6 pp 1269ndash1272 2014
[47] J S Eo J C Paeng S Lee et al ldquoAngiogenesis imaging inmyocardial infarction using 68Ga-NOTA- RGD PET Charac-terization and application to therapeutic efficacy monitoring inratsrdquo Coronary Artery Disease vol 24 no 4 pp 303ndash311 2013
[48] J H Kim Y-H Kim Y J Kim et al ldquoQuantitative positronemission tomography imaging of angiogenesis in rats with fore-limb ischemia using 68Ga-NOTA-c(RGDyK)rdquo Angiogenesisvol 16 no 4 pp 837ndash846 2013
[49] I Laitinen J Notni K Pohle et al ldquoComparison of cyclicRGD peptides for 120572v1205733 integrin detection in a rat model ofmyocardial infarctionrdquo EJNMMI Research vol 3 no 1 pp 1ndash9 2013
[50] M Kiugel I Dijkgraaf V Kyto et al ldquoDimeric [68Ga]DOTA-RGD Peptide Targeting 120572 ltinfgtvltinfgt 120573 ltinfgt3ltinfgt Inte-grin Reveals Extracellular Matrix Alterations after MyocardialInfarctionrdquo Molecular Imaging and Biology vol 16 no 6 pp793ndash801 2014
[51] M Gronman M Tarkia T Kiviniemi et al ldquoImaging of 120572v1205733integrin expression in experimental myocardial ischemia with[68Ga]NODAGA-RGD positron emission tomographyrdquo Jour-nal of Translational Medicine vol 15 no 1 p 144 2017
[52] J Haukkala I Laitinen P Luoto et al ldquo68Ga-DOTA-RGDpep-tide Biodistribution and binding into atherosclerotic plaquesin micerdquo European Journal of Nuclear Medicine and MolecularImaging vol 36 no 12 pp 2058ndash2067 2009
[53] H Virtanen A Autio R Siitonen et al ldquo68Ga-DOTA-Siglec-9- a new imaging tool to detect synovitisrdquo Arthritis Research ampTherapy vol 17 no 1 article no 308 2015
[54] J Retamal J Sorensen M Lubberink et al ldquoFeasibility of(68) Ga-labeled Siglec-9 peptide for the imaging of acutelung inflammation a pilot study in a porcine model of acuterespiratory distress syndromerdquoAm JNuclMedMol Imaging vol6 no 1 pp 18ndash31 2016
[55] J M U Silvola H Virtanen R Siitonen et al ldquoLeukocytetrafficking-associated vascular adhesion protein 1 is expressedand functionally active in atherosclerotic plaquesrdquo ScientificReports vol 6 Article ID 35089 2016
[56] H Ahtinen J Kulkova L Lindholm et al ldquo68Ga-DOTA-Siglec-9 PETCT imaging of peri-implant tissue responses andstaphylococcal infectionsrdquo EJNMMI Research vol 4 no 1article no 45 pp 1ndash11 2014
[57] A Autio S Jalkanen and A Roivainen ldquoNuclear imaging ofinflammation Homing-associated molecules as targetsrdquo EJN-MMI Research vol 3 no 1 pp 1ndash7 2013
[58] J TThackeray T Derlin AHaghikia et al ldquoMolecular Imagingof the Chemokine Receptor CXCR4 after Acute MyocardialInfarctionrdquo JACC Cardiovascular Imaging vol 8 no 12 pp1417ndash1426 2015
[59] J S Schmid A Schirbel A K Buck S Kropf H-J Westerand C Lapa ldquoPentixafor-Positron Emission TomographyComputed Tomography Detects Chemokine Receptor CXCR4Expression after Ischemic Strokerdquo Circulation CardiovascularImaging vol 9 no 9 Article ID e005217 2016
[60] J Zhou G Hao H Weng et al ldquoIn vivo evaluation ofmedical device-associated inflammation using a macrophage-specific positron emission tomography (PET) imaging proberdquoBioorganic amp Medicinal Chemistry Letters vol 23 no 7 pp2044ndash2047 2013
[61] S A Kularatne M-J Belanger X Meng et al ldquoComparativeanalysis of folate derived PET imaging agents with [ 18F]-2-fluoro-2-deoxy-d-glucose using a rodent inflammatory pawmodelrdquo Molecular Pharmaceutics vol 10 no 8 pp 3103ndash31112013
[62] V Ambrosini M Zompatori F De Luca et al ldquo68Ga-DOTANOCPETCTAllows Somatostatin Receptor Imaging inIdiopathic Pulmonary Fibrosis Preliminary Resultsrdquo Journal ofNuclear Medicine vol 51 no 12 pp 1950ndash1955 2010
[63] T Lincke J Singer R Kluge O Sabri and R Paschke ldquoRela-tive quantification of indium-111 pentetreotide and gallium-68DOTATOC uptake in the thyroid gland and association withthyroid pathologiesrdquoThyroid vol 19 no 4 pp 381ndash389 2009
[64] A Rominger T Saam E Vogl et al ldquoIn vivo imaging ofmacrophage activity in the coronary arteries using 68Ga-DOTATATE PETCT correlation with coronary calcium bur-den and risk factorsrdquo Journal of Nuclear Medicine vol 51 no 2pp 193ndash197 2010
[65] J M Tarkin F R Joshi N R Evans et al ldquoDetection ofAtherosclerotic Inflammation by 68Ga-DOTATATE PET Com-pared to [18F]FDG PET Imagingrdquo Journal of the AmericanCollege of Cardiology vol 69 no 14 pp 1774ndash1791 2017
[66] S-P Lee H-J Im S Kang et al ldquoNoninvasive imaging ofmyocardial inflammation in myocarditis using 68Ga-taggedmannosylated human serum albumin positron emissiontomographyrdquoTheranostics vol 7 no 2 pp 413ndash424 2017
[67] Z Zha J Song S R Choi et al ldquo68Ga-Bivalent PolypegylatedStyrylpyridine Conjugates for Imaging A120573 Plaques in CerebralAmyloid Angiopathyrdquo Bioconjugate Chemistry vol 27 no 5 pp1314ndash1323 2016
[68] H Watanabe M Ono S Iikuni et al ldquoA 68Ga complex basedon benzofuran scaffold for the detection of 120573-amyloid plaquesrdquoBioorganic amp Medicinal Chemistry Letters vol 24 no 20 pp4834ndash4837 2014
[69] D Cressier M Dhilly T T Cao Pham et al ldquoGallium-68 Com-plexes Conjugated to Pittsburgh Compound B Radiolabelingand Biological EvaluationrdquoMolecular Imaging and Biology vol18 no 3 pp 334ndash343 2016
[70] D Satpati CArjun R KrishnamohanG Samuel and S Baner-jee ldquo68Ga-labeledCiprofloxacinConjugates as Radiotracers forTargeting Bacterial InfectionrdquoChemical Biology ampDrug Designvol 87 no 5 pp 680ndash686 2016
[71] T Ebenhan N Chadwick and M M Sathekge ldquoPeptidesynthesis characterization and 68Ga-radiolabeling of NOTA-conjugated ubiquicidin fragments for prospective infectionimaging with PETCTrdquo Nuclear Medicine and Biology vol 41no 5 pp 390ndash400 2014
18 Contrast Media amp Molecular Imaging
[72] T Ebenhan J R Zeevaart and J D Venter ldquoPreclinicalevaluation of 68Ga-labeled 1 4 7-triazacyclononane-1 4 7-triacetic acid-ubiquicidin as a radioligand for PET infectionimagingrdquo Journal of Nuclear Medicine vol 55 no 2 pp 308ndash314 2014
[73] B B Mokaleng T Ebenhan S Ramesh et al ldquoSynthesis 68Ga-radiolabeling and preliminary in vivo assessment of adepsipeptide-derived compound as a potential PETCTinfection imaging agentrdquo BioMed Research International vol2015 Article ID 284354 2015
[74] T Ebenhan B Mokaleng J Venter H Kruger J Zeevaart andM Sathekge ldquoPreclinical Assessment of a 68Ga-DOTA-Functionalized Depsipeptide as a Radiodiagnostic InfectionImaging AgentrdquoMolecules vol 22 no 9 p 1403 2017
[75] S Chopra B Singh A Koul A Mishra and H Wester ldquoSyn-thesis of DOTA conjugated GF-17 and RAWVAWR-NH2 andradiolabeling with 68Ga as a potential PET tracer for infectionimagingrdquo J Nucl Med vol 57 Supplement 2 p 1115 2016
[76] M Petrik HHaas P Laverman et al ldquo 68Ga-triacetylfusarinineC and 68Ga-ferrioxamine e for aspergillus infection imaginguptake specificity in various microorganismsrdquoMolecular Imag-ing and Biology vol 16 no 1 pp 102ndash108 2014
[77] V Kumar and D K Boddeti ldquo 68Ga-radiopharmaceuticals forPET imaging of infection and inflammationrdquo Recent Results inCancer Research vol 194 pp 189ndash219 2013
[78] M Vorster A Maes A Jacobs et al ldquoEvaluating the possiblerole of 68Ga-citrate PETCT in the characterization of indeter-minate lung lesionsrdquo Annals of Nuclear Medicine vol 28 no 6pp 523ndash530 2014
[79] M Vorster B Mokaleng M M Sathekge and T Ebenhan ldquoAmodified technique for efficient radiolabeling of 68Ga-citratefrom a SnO2-based 68Ge68Ga generator for better infectionimagingrdquoHellenic Journal of Nuclear Medicine vol 16 no 3 pp193ndash198 2013
[80] S Salomaeki J Kemppainen U Hohenthal et al ldquoHead-to-head comparison of 68Ga-Citrate and 18F-FDG PETCT fordetection of infectious foci in patients with staphylococcusaureus bacteraemiardquo Contrast Media amp Molecular Imaging vol2017 p 8 2017
[81] L Fass ldquoImaging and cancer a reviewrdquoMolecular Oncology vol2 no 2 pp 115ndash152 2008
[82] A Chopra L Shan W C Eckelman et al ldquoMolecular imagingand contrast agent database (MICAD) Evolution and progressrdquoMolecular Imaging and Biology vol 14 no 1 pp 4ndash13 2012
[83] A Sanchez-Crespo P Andreo and S A Larsson ldquoPositronflight in human tissues and its influence on PET image spatialresolutionrdquo European Journal of Nuclear Medicine and Molecu-lar Imaging vol 31 no 1 pp 44ndash51 2004
[84] H W A M De Jong L Perk G W M Visser R Boellaard GAM S Van Dongen and A A Lammertsma ldquoHigh resolutionPET imaging characteristics of68Ga 124i and89Zr comparedto18Frdquo in Proceedings of the Nuclear Science Symposium Con-ference Record 2005 IEEE pp 1624ndash1627 Puerto Rico October2005
[85] I Velikyan A Sundin B Eriksson et al ldquoIn vivo bindingof [68Ga]-DOTATOC to somatostatin receptors in neuroen-docrine tumours - impact of peptide massrdquo Nuclear Medicineand Biology vol 37 no 3 pp 265ndash275 2010
[86] U Eberlein and M Lassmann ldquoDosimetry of [68Ga]-labeledcompoundsrdquo Applied Radiation and Isotopes vol 76 pp 70ndash742013
[87] C PettinatoA SarnelliMDiDonna et al ldquo68Ga-DOTANOCBiodistribution and dosimetry in patients affected by neuroen-docrine tumorsrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 35 no 1 pp 72ndash79 2008
[88] B P Burke G S Clemente and S J Archibald ldquoRecentadvances in chelator design and labelling methodology for68Ga radiopharmaceuticalsrdquo Journal of Labelled Compoundsand Radiopharmaceuticals vol 57 no 4 pp 239ndash243 2014
[89] I Velikyan U Rosenstrom S Estrada et al ldquoSynthesis andpreclinical evaluation of 68Ga-labeled collagelin analogs forimaging and quantification of fibrosisrdquo Nuclear Medicine andBiology vol 41 no 9 pp 728ndash736 2014
[90] M F Ferreira G Pereira J P Andre and etal C ldquoGa[NO2A-N-(120572-amino)propionate] chelates Synthesis and evaluation aspotential tracers for 68Ga PETrdquoDalton Transactions vol 43 no21 pp 8037ndash8047 2014
[91] J Notni J Simecek and H-J Wester ldquoPhosphinic acid func-tionalized polyazacycloalkane chelators for radiodiagnosticsand radiotherapeutics Unique characteristics and applicationsrdquoChemMedChem vol 9 no 6 pp 1107ndash1115 2014
[92] J Simecek O Zemek P Hermann J Notni and H J WesterldquoTailored gallium( III) chelator NOPO synthesis characteriza-tion bioconjugation and application in preclinical Ga-68-PETimagingrdquoMolecular Pharmaceutics 2013
[93] D Parker B P Waldron and D S Yufit ldquoCrystallographicand solution NMR structural analyses of four hexacoordinatedgallium(iii) complexes based on ligands derived from 6-amino-perhydro-14-diazepinerdquo Dalton Transactions vol 42 no 22pp 8001ndash8008 2013
[94] B P Waldron D Parker C Burchardt D S Yufit M ZimnyandF Roesch ldquoStructure and stability of hexadentate complexesof ligands based on AAZTA for efficient PET labelling withgallium-68rdquo Chemical Communications vol 49 no 6 pp 579ndash581 2013
[95] D Parker and B PWaldron ldquoConformational analysis and syn-thetic approaches to polydentate perhydro-diazepine ligandsfor the complexation of gallium(iii)rdquo Organic amp BiomolecularChemistry vol 11 no 17 pp 2827ndash2838 2013
[96] I Velikyan H Maecke and B Langstrom ldquoConvenient prepa-ration of 68Ga-based PET-radiopharmaceuticals at room tem-peraturerdquo Bioconjugate Chemistry vol 19 no 2 pp 569ndash5732008
[97] J Erchegyi R Cescato B Waser J E Rivier and J C ReubildquoN-Imidazolebenzyl-histidine substitution in somatostatin andin its octapeptide analogue modulates receptor selectivity andfunctionrdquo Journal of Medicinal Chemistry vol 54 no 17 pp5981ndash5987 2011
[98] R Saha N Saha R S Donofrio and L L Bestervelt ldquoMicrobialsiderophores Amini reviewrdquo Journal of Basic Microbiology vol53 no 4 pp 303ndash317 2013
[99] V Nikolova S Angelova N Markova and T Dudev ldquoGalliumas a Therapeutic Agent A Thermodynamic Evaluation of theCompetition between Ga3+ and Fe3+ Ions in MetalloproteinsrdquoThe Journal of Physical Chemistry B vol 120 no 9 pp 2241ndash2248 2016
[100] C R Chitambar ldquoGallium and its competing roles with ironin biological systemsrdquo Biochimica et Biophysica Acta (BBA) -Molecular Cell Research vol 1863 no 8 pp 2044ndash2053 2016
[101] J A Lessa M A Soares and R G dos Santos ldquoGallium(III)complexes with 2-acetylpyridine-derived thiosemicarbazonesantimicrobial and cytotoxic effects and investigation on theinteractions with tubulinrdquo BioMetals vol 26 pp 151ndash165 2013
Contrast Media amp Molecular Imaging 19
[102] M van Oosten M Hahn L M A Crane et al ldquoTargetedimaging of bacterial infections Advances hurdles and hopesrdquoFEMS Microbiology Reviews vol 39 no 6 pp 892ndash916 2015
[103] M Vorster AMaes C V DWiele andM Sathekge ldquoGallium-68 PET A Powerful Generator-based Alternative to Infectionand Inflammation Imagingrdquo Seminars in Nuclear Medicine vol46 no 5 pp 436ndash447 2016
[104] M Kircher and C Lapa ldquoNovel Noninvasive Nuclear MedicineImaging Techniques for Cardiac Inflammationrdquo Current Car-diovascular Imaging Reports vol 10 no 2 article no 6 2017
[105] D AHammoud ldquoMolecular imaging of inflammation Currentstatusrdquo Journal of Nuclear Medicine vol 57 no 8 pp 1161ndash11652016
[106] D R Brenner D Scherer K Muir et al ldquoA review of the appli-cation of inflammatory biomarkers in epidemiologic cancerresearchrdquo Cancer Epidemiology Biomarkers amp Prevention vol23 no 9 pp 1729ndash1751 2014
[107] M D Turner B Nedjai T Hurst and D J PenningtonldquoCytokines and chemokines at the crossroads of cell signallingand inflammatory diseaserdquo Biochimica et Biophysica Acta (BBA)- Molecular Cell Research vol 1843 no 11 pp 2563ndash2582 2014
[108] L Werner H Guzner-Gur and I Dotan ldquoInvolvement ofCXCR4CXCR7CXCL12 interactions in inflammatory boweldiseaserdquoTheranostics vol 3 no 1 pp 40ndash46 2013
[109] S Jalkanen and M Salmi ldquoVAP-1 and CD73 endothelial cellsurface enzymes in leukocyte extravasationrdquo ArteriosclerosisThrombosis and Vascular Biology vol 28 no 1 pp 18ndash26 2008
[110] G Malviya F Galli I Sonni and A Signore ldquoImaging T-lymphocytes in inflammatory diseases A nuclear medicineapproachrdquo The Quarterly Journal of Nuclear Medicine andMolecular Imaging vol 58 no 3 pp 237ndash257 2014
[111] S Gratz H J RennenO C BoermanW J Oyen and P Burmaldquo(99m)Tc-interleukin-8 for imaging acute osteomyelitisrdquo Jour-nal of Nuclear Medicine vol 42 no 8 pp 1257ndash1264 2001
[112] S Gratz H J Rennen O C Boerman W J Oyen andF H Corstens ldquoRapid imaging of experimental colitis with(99m)Tc-interleukin-8 in rabbitsrdquo Journal of Nuclear Medicnevol 42 no 6 pp 917ndash923 2001
[113] C Alkim H Alkim A R Koksal S Boga and I SenldquoAngiogenesis in inflammatory bowel diseaserdquo InternationalJournal of Inflammation vol 2015 Article ID 970890 2015
[114] I S Alam T H Witney G Tomasi et al ldquoRadiolabeled RGDtracer kinetics annotates differential 120572v1205733 integrin expressionlinked to cell intrinsic and vessel expressionrdquoMolecular Imagingand Biology vol 16 no 4 pp 558ndash566 2014
[115] J Notni K Pohle and H-J Wester ldquoBe spoilt for choice withradiolabelled RGD peptides Preclinical evaluation of 68Ga-TRAP(RGD)3rdquoNuclear Medicine and Biology vol 40 no 1 pp33ndash41 2013
[116] J Oxboel M Brandt-Larsen C Schjoeth-Eskesen et al ldquoCom-parison of two new angiogenesis PET tracers 68Ga-NODAGA-E[c(RGDyK)]2 and 64Cu-NODAGA-E[c(RGDyK)]2 in vivoimaging studies in human xenograft tumorsrdquo Nuclear Medicineand Biology vol 41 no 3 pp 259ndash267 2014
[117] J Simecek J Notni T G Kapp H Kessler and H-J WesterldquoBenefits of NOPO as chelator in gallium-68 peptides exempli-fied by preclinical characterization of 68Ga-NOPO-c(RGDfK)rdquoMolecular Pharmaceutics vol 11 no 5 pp 1687ndash1695 2014
[118] M Trajkovic-Arsic P Mohajerani A Sarantopoulos et alldquoMultimodal molecular imaging of integrin avb3 for in vivodetection of pancreatic cancerrdquo Journal of NuclearMedicine vol55 no 3 pp 446ndash451 2014
[119] H Cai and P S Conti ldquoRGD-based PET tracers for imagingreceptor integrin 120572 v1205733 expressionrdquo Journal of Labelled Com-pounds and Radiopharmaceuticals vol 56 no 5 pp 264ndash2792013
[120] I Dijkgraaf S Y A Terry W J Mcbride et al ldquoImagingintegrin alpha-v-beta-3 expression in tumors with an 18F-labeled dimeric RGD peptiderdquo Contrast Media amp MolecularImaging vol 8 no 3 pp 238ndash245 2013
[121] P A Knetsch M Petrik C Rangger et al ldquo[68Ga]NS3-RGD and [68Ga] Oxo-DO3A-RGD for imaging 120572v1205733 integrinexpression Synthesis evaluation and comparisonrdquo NuclearMedicine and Biology vol 40 no 1 pp 65ndash72 2013
[122] Z Liu and F Wang ldquoDevelopment of RGD-based radiotracersfor tumor imaging and therapy Translating from bench tobedsiderdquo Current Molecular Medicine vol 13 no 10 pp 1487ndash1505 2013
[123] H Choi J H Phi J C Paeng et al ldquoImaging of integrin 120572v1205733expression using 68Ga-RGD positron emission tomography inpediatric cerebral infarctrdquoMolecular Imaging vol 12 no 4 pp213ndash217 2013
[124] H-J Yoon K W Kang I K Chun et al ldquoCorrelation of breastcancer subtypes based on estrogen receptor progesteronereceptor and HER2 with functional imaging parameters from68Ga-RGD PETCT and 18F-FDG PETCTrdquo European Journalof Nuclear Medicine and Molecular Imaging vol 41 no 8 pp1534ndash1543 2014
[125] R P Baum H R Kulkarni D Muller et al ldquoFirst-in-human study demonstrating tumor-angiogenesis by PETCTimaging with 68Ga-NODAGA-THERANOST a high-affinitypeptidomimetic for 120572v1205733 integrin receptor targetingrdquo CancerBiotherapy andRadiopharmaceuticals vol 30 no 4 pp 152ndash1592015
[126] R Haubner A Finkenstedt A Stegmayr et alldquo[68Ga]NODAGA-RGD ndash Metabolic stability biodistributionand dosimetry data from patients with hepatocellularcarcinoma and liver cirrhosisrdquo European Journal of NuclearMedicine and Molecular Imaging vol 43 no 11 pp 2005ndash20132016
[127] V Lopez-Rodrıguez C Galindo-Sarco F O Garcıa-Perez GFerro-Flores O Arrieta and M A Avila-Rodrıguez ldquoPET-based human dosimetry of the dimeric 120572v1205733 integrin ligand68Ga-DOTA-E-[c(RGDfK)]2 a potential tracer for imagingtumor angiogenesisrdquo Journal of Nuclear Medicine vol 57 no 3pp 404ndash409 2016
[128] M V Backer Z Levashova V Patel et al ldquoMolecular imagingof VEGF receptors in angiogenic vasculature with single-chainVEGF-based probesrdquo Nature Medicine vol 13 no 4 pp 504ndash509 2007
[129] MV Backer Z Levashova R Levenson F G Blankenberg andJ M Backer ldquoCysteine-containing fusion tag for site-specificconjugation of therapeutic and imaging agents to targetingproteinsrdquoMethods in Molecular Biology (Clifton NJ) vol 494pp 275ndash294 2008
[130] M Eder A V Krivoshein M Backer J M Backer UHaberkorn and M Eisenhut ldquoScVEGF-PEG-HBED-CC andscVEGF-PEG-NOTA conjugates comparison of easy-to-labelrecombinant proteins for [68Ga]PET imaging of VEGF recep-tors in angiogenic vasculaturerdquo Nuclear Medicine and Biologyvol 37 no 4 pp 405ndash412 2010
[131] E Blom I Velikyan A Monazzam P Razifar et al ldquoSynthe-sis and characterization of scVEGF-PEG-[ 68Ga]NOTA andscVEGF-PEG-[ 68Ga]DOTA PET tracersrdquo Journal of Labelled
20 Contrast Media amp Molecular Imaging
Compounds and Radiopharmaceuticals vol 54 no 11 pp 685ndash692 2011
[132] S Gratz M Behe and O C Boerman ldquo 99119898Tc-E-selectinbinding peptide for imaging acute osteomyelitis in a novel ratmodelrdquo Nuclear Medicine Communications vol 22 no 9 pp1003ndash1013 2001
[133] S B Jensen M Kakela L Joslashdal et al ldquoExploring the radiosyn-thesis and in vitro characteristics of [68Ga]Ga-DOTA-Siglec-9rdquoJournal of Labelled Compounds and Radiopharmaceuticals vol60 no 9 pp 439ndash449 2017
[134] B A Teicher and S P Fricker ldquoCXCL12 (SDF-1)CXCR4pathway in cancerrdquo Clinical Cancer Research vol 16 no 11 pp2927ndash2931 2010
[135] O Jacobson I D Weiss D O Kiesewetter J M Farber andX Chen ldquoPET of tumor CXCR4 expression with 4-18F-T140rdquoJournal of Nuclear Medicine vol 51 no 11 pp 1796ndash1804 2010
[136] A Aghanejad A R Jalilian Y Fazaeli et al ldquoSynthesis andevaluation of [67Ga]-AMD3100 A novel imaging agent fortargeting the chemokine receptorCXCR4rdquo Scientia Pharmaceu-tica vol 82 no 1 pp 29ndash42 2014
[137] O Jacobson I D Weiss L P Szajek et al ldquoPET imaging ofCXCR4 using copper-64 labeled peptide antagonistrdquoTheranos-tics vol 1 pp 251ndash262 2011
[138] O Jacobson I D Weiss L P Szajek et al ldquoImprovement ofCXCR4 tracer specificity for PET imagingrdquo Journal of Con-trolled Release vol 157 no 2 pp 216ndash223 2012
[139] H J Wester U Keller M Schottelius et al ldquoDisclosing theCXCR4 expression in lymphoproliferative diseases by targetedmolecular imagingrdquo Theranostics vol 5 no 6 pp 618ndash6302015
[140] E Gourni O Demmer M Schottelius et al ldquoPET of CXCR4expression by a 68Ga-labeled highly specific targeted contrastagentrdquo Journal of NuclearMedicine vol 52 no 11 pp 1803ndash18102011
[141] O Demmer I Dijkgraaf U Schumacher et al ldquoDesignsynthesis and functionalization of dimeric peptides targetingchemokine receptor CXCR4rdquo Journal of Medicinal Chemistryvol 54 no 21 pp 7648ndash7662 2011
[142] O Demmer E Gourni U Schumacher H Kessler and H-JWester ldquoPET Imaging of CXCR4 Receptors in Cancer by a NewOptimized Ligandrdquo ChemMedChem vol 6 no 10 pp 1789ndash1791 2011
[143] U Hennrich L Seyler M Schafer et al ldquoSynthesis and invitro evaluation of 68Ga-DOTA-4-FBn-TN14003 a novel tracerfor the imaging of CXCR4 expressionrdquo Bioorganic amp MedicinalChemistry vol 20 no 4 pp 1502ndash1510 2012
[144] G P C George E Stevens O Aberg et al ldquoPreclinical evalua-tion of a CXCR4-specific 68Ga-labelled TN14003 derivative forcancer PET imagingrdquo Bioorganic amp Medicinal Chemistry vol22 no 2 pp 796ndash803 2014
[145] S Poty E Gourni P Desogere et al ldquoAMD3100 A VersatilePlatform for CXCR4 Targeting 68Ga-Based Radiopharmaceu-ticalsrdquo Bioconjugate Chemistry vol 27 no 3 pp 752ndash761 2016
[146] K Philipp-Abbrederis K Herrmann S Knop et al ldquoIn vivomolecular imaging of chemokine receptor CXCR4 expressionin patients with advancedmultiple myelomardquo EMBOMolecularMedicine vol 7 no 4 pp 477ndash487 2015
[147] Z Wang M Zhang L Wang et al ldquoProspective study of 68Ga-NOTA-NFB Radiation dosimetry in healthy volunteers andfirst application in glioma patientsrdquo Theranostics vol 5 no 8pp 882ndash889 2015
[148] I M Jackson P J Scott and S Thompson ldquoClinical Applica-tions of Radiolabeled Peptides for PETrdquo Seminars in NuclearMedicine vol 47 no 5 pp 493ndash523 2017
[149] C Lapa T Reiter R A Werner et al ldquo[68Ga]Pentixafor-PETCT for Imaging of Chemokine Receptor 4 Expression afterMyocardial Infarctionrdquo JACC Cardiovascular Imaging vol 8no 12 pp 1466ndash1468 2015
[150] C Rischpler S G Nekolla H Kossmann et al ldquoUpregu-lated myocardial CXCR4-expression after myocardial infarc-tion assessed by simultaneous GA-68 pentixafor PETMRIrdquoJournal of Nuclear Cardiology vol 23 no 1 pp 131ndash133 2016
[151] F Hyafil J Pelisek I Laitinen et al ldquoImaging the CytokineReceptorCXCR4 in atherosclerotic plaqueswith the radiotracer68Ga-Pentixafor for PETrdquo Journal of Nuclear Medicine vol 58no 3 pp 499ndash506 2017
[152] Y Yi ldquoFolate receptor-targeted diagnostics and therapeutics forinflammatory diseasesrdquo ImmuneNetwork vol 16 no 6 pp 337ndash343 2016
[153] C M Paulos M J Turk G J Breur and P S Low ldquoFolatereceptor-mediated targeting of therapeutic and imaging agentsto activated macrophages in rheumatoid arthritisrdquo AdvancedDrug Delivery Reviews vol 56 no 8 pp 1205ndash1217 2004
[154] W Han R Zaynagetdinov F E Yull et al ldquoMolecular imagingof folate receptor 120573-positive macrophages during acute lunginflammationrdquo American Journal of Respiratory Cell and Molec-ular Biology vol 53 no 1 pp 50ndash59 2015
[155] B Kuhle C Muller and T L Ross ldquoA Novel 68Ga-Labeledpteroic acid-based PET tracer for tumor imaging via the folatereceptorrdquo Recent Results in Cancer Research vol 194 pp 257ndash267 2013
[156] C Brand V A Longo M Groaning W A Weber and TReiner ldquoDevelopment of a New Folate-Derived Ga-68-BasedPET Imaging AgentrdquoMolecular Imaging and Biology vol 19 no5 pp 754ndash761 2017
[157] M Fani XWang G Nicolas et al ldquoDevelopment of new folate-based PET radiotracers Preclinical evaluation of 68Ga-DOTA-folate conjugatesrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 38 no 1 pp 108ndash119 2011
[158] C J Mathias M R Lewis D E Reichert et al ldquoPreparationof 66Ga- and 68Ga-labeled Ga(III)-deferoxamine-folate aspotential folate-receptor-targeted PET radiopharmaceuticalsrdquoNuclear Medicine and Biology vol 30 no 7 pp 725ndash731 2003
[159] S-M Kim N Choi S Hwang et al ldquoFolate receptor-specific positron emission tomography imaging with folic acid-conjugated tissue inhibitor of metalloproteinase-2rdquo Bulletin ofthe Korean Chemical Society vol 34 no 11 pp 3243ndash3248 2013
[160] M Fani M-L Tamma G P Nicolas et al ldquoIn vivo imagingof folate receptor positive tumor xenografts using novel 68Ga-NODAGA-folate conjugatesrdquo Molecular Pharmaceutics vol 9no 5 pp 1136ndash1145 2012
[161] C Muller and R Schibli ldquoProspects in folate receptor-targetedradionuclide therapyrdquo Frontiers in Oncology vol 3 Article IDArticle 249 2013
[162] A Jain A Mathur U Pandey et al ldquoSynthesis and evaluationof a 68Ga labeled folic acid derivative for targeting folatereceptorsrdquo Applied Radiation and Isotopes vol 116 pp 77ndash842016
[163] W Xia A R Hilgenbrink E L Matteson M B Lockwood J-X Cheng and P S Low ldquoA functional folate receptor is inducedduring macrophage activation and can be used to target drugsto activated macrophagesrdquo Blood vol 113 no 2 pp 438ndash4462009
Contrast Media amp Molecular Imaging 21
[164] E P Krenning W A P Breeman P P M Kooij et alldquoLocalisation of endocrine-related tumours with radioiodi-nated analogue of somatostatinrdquoThe Lancet vol 1 no 8632 pp242ndash244 1989
[165] E P Krenning D J KwekkeboomWH Bakker et al ldquoSomato-statin receptor scintigraphy with [111In-DTPA-d-Phe1]- and[123I-Tyr3]-octreotide the Rotterdam experience with morethan 1000 patientsrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 20 no 8 pp 716ndash731 1993
[166] A Stahl G Meisetschlager M Schottelius et al ldquo[123I]Mtr-TOCA a radioiodinated and carbohydrated analogue ofoctreotide Scintigraphic comparison with [111In]octreotiderdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 33 no 1 pp 45ndash52 2006
[167] R Lebtahi J le Cloirec C Houzard et al ldquoDetection of neu-roendocrine tumors 99mTc-P829 scintigraphy compared with111In-pentetreotide scintigraphyrdquo Journal of Nuclear Medicinevol 43 no 7 pp 889ndash895 2002
[168] C Decristoforo T Maina B Nock M Gabriel P Cordopatisand R Moncayo ldquo99mTc-demotate 1 First data in tumourpatients - Results of a pilotphase I studyrdquo European Journal ofNuclearMedicine andMolecular Imaging vol 30 no 9 pp 1211ndash1219 2003
[169] C Decristoforo S J Mather W Cholewinski E DonnemillerG Riccabona and R Moncayo ldquo(99m)Tc-EDDAHYNIC-TOC A new (99m)Tc-labelled radiopharmaceutical forimaging somatostatin receptor-positive tumours First clinicalresults and intra-patient comparison with 111In-labelledoctreotide derivativesrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 27 no 9 pp 1318ndash1325 2000
[170] A Hubalewska-Dydejczyk K Fross-Baron R Mikołajczak etal ldquo99mTc-EDDAHYNIC-octreotate scintigraphy an efficientmethod for the detection and staging of carcinoid tumoursResults of 3 yearsrsquo experiencerdquo European Journal of NuclearMedicine and Molecular Imaging vol 33 no 10 pp 1123ndash11332006
[171] M Bangard M Behe S Guhlke et al ldquoDetection of somato-statin receptor-positive tumours using the new 99mC-tricine-HYNIC-D-Phe1-Tyr3-octreotide First results in patients andcomparison with 111In-DTPA-D-Phe1-octreotiderdquo EuropeanJournal of Nuclear Medicine and Molecular Imaging vol 27 no6 pp 628ndash637 2000
[172] A Helisch G J Forster H Reber et al ldquoPre-therapeuticdosimetry and biodistribution of 86Y-DOTA- Phe1-Tyr3-octreotide versus 111In-pentetreotide in patients with advancedneuroendocrine tumoursrdquo European Journal of NuclearMedicine and Molecular Imaging vol 31 no 10 pp 1386ndash13922004
[173] M Henze J Schuhmacher P Hipp et al ldquoPET imaging ofsomatostatin receptors using [68GA]DOTA-D-Phe1-Tyr3-Octreotide First results in patients with meningiomasrdquo Journalof Nuclear Medicine vol 42 no 7 pp 1053ndash1056 2001
[174] I Kayani J B Bomanji A Groves et al ldquoFunctional imaging ofneuroendocrine tumors with combined PETCT using 68Ga-DOTATATE (Dota-DPhe1 Tyr3-octreotate) and 18F-FDGrdquoCancer vol 112 no 11 pp 2447ndash2455 2008
[175] A Al-Nahhas ldquoNuclear medicine imaging of neuroendocrinetumoursrdquo Clinical Medicine vol 12 no 4 pp 377ndash380 2012
[176] V Ambrosini S Nicolini P Caroli et al ldquoPETCT imaging indifferent types of lung cancer an overviewrdquo European Journal ofRadiology vol 81 no 5 pp 988ndash1001 2012
[177] V Ambrosini D Campana P Tomassetti and S Fanti ldquo68Ga-labelled peptides for diagnosis of gastroenteropancreatic NETrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 39 no 1 pp S52ndashS60 2012
[178] K E Oberg J-C Reubi D J Kwekkeboom and E P KrenningldquoRole of somatostatins in gastroenteropancreatic neuroen-docrine tumor development and therapyrdquoGastroenterology vol139 no 3 pp 753-753 2010
[179] K Oberg ldquoGallium-68 somatostatin receptor PETCT Is ittime to replace 111Indium DTPA octreotide for patients withneuroendocrine tumorsrdquo Endocrine Journal vol 42 no 1 pp3-4 2012
[180] R Srirajaskanthan I Kayani A M Quigley J Soh M ECaplin and J Bomanji ldquoThe role of 68Ga-DOTATATE PET inpatients with neuroendocrine tumors and negative or equivocalfindings on 111In-DTPA-octreotide scintigraphyrdquo Journal ofNuclear Medicine vol 51 no 6 pp 875ndash882 2010
[181] A Kroiss D Putzer and C Uprimny ldquoFunctional imag-ing in phaeochromocytoma and neuroblastoma with 68Ga-DOTA-Tyr3-octreotide positron emission tomography and123I-metaiodobenzylguanidinerdquo European Journal of NuclearMedicine and Molecular Imaging vol 38 no 5 pp 865ndash8732011
[182] M Naji C Zhao S J Welsh et al ldquo68Ga-DOTA-TATE PETvs 123I-MIBG in identifying malignant neural crest tumoursrdquoMolecular Imaging and Biology vol 13 no 4 pp 769ndash775 2011
[183] V Ambrosini P Tomassetti P Castellucci et al ldquoComparisonbetween 68Ga-DOTA-NOC and 18F-DOPA PET for the detec-tion of gastro-entero-pancreatic and lung neuro-endocrinetumoursrdquo European Journal of Nuclear Medicine and MolecularImaging vol 35 no 8 pp 1431ndash1438 2008
[184] D Putzer M Gabriel B Henninger et al ldquoBone metastasesin patients with neuroendocrine tumor 68Ga- DOTA-Tyr3-octreotide PET in comparison to CT and bone scintigraphyrdquoJournal of Nuclear Medicine vol 50 no 8 pp 1214ndash1221 2009
[185] L K Anzola-Fuentes M Chianelli F Galli et al ldquoSomatostatinreceptor scintigraphy in patients with rheumatoid arthritis andsecondary Sjogrenrsquos syndrome treated with Infliximab a pilotstudyrdquo EJNMMI Research vol 6 no 1 article no 49 2016
[186] T Nobashi Y Nakamoto T Kubo et al ldquoThe utility of PETCTwith 68Ga-DOTATOC in sarcoidosis comparison with 67Ga-scintigraphyrdquoAnnals ofNuclearMedicine vol 30 no 8 pp 544ndash552 2016
[187] C Boy T A Heusner T D Poeppel et al ldquo68Ga-DOTATOCPETCT and somatostatin receptor (sst1-sst5) expression innormal human tissue Correlation of sst2mRNAand SUVmaxrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 38 no 7 pp 1224ndash1236 2011
[188] P Rinne S Hellberg M Kiugel et al ldquoComparison of Somato-statin Receptor 2-Targeting PET Tracers in the Detection ofMouse Atherosclerotic Plaquesrdquo Molecular Imaging and Biol-ogy vol 18 no 1 pp 99ndash108 2016
[189] M Asti E Ferrari S Croci et al ldquoSynthesis and characteri-zation of 68Ga-labeled curcumin and curcuminoid complexesas potential radiotracers for imaging of cancer and alzheimersdiseaserdquo Inorganic Chemistry vol 53 no 10 pp 4922ndash49332014
[190] A Signore I Santino and A W J M Glaudemans ldquoIn vivoimaging of microorganismsrdquo Clinical and Translational Imag-ing vol 4 no 3 pp 161-162 2016
[191] S Auletta F Galli C Lauri D Martinelli I Santino andA Signore ldquoImaging bacteria with radiolabelled quinolones
22 Contrast Media amp Molecular Imaging
cephalosporins and siderophores for imaging infection a sys-tematic reviewrdquo Clinical and Translational Imaging vol 4 no 4pp 229ndash252 2016
[192] X Ning S Lee Z Wang et al ldquoMaltodextrin-based imagingprobes detect bacteria in vivo with high sensitivity and speci-ficityrdquo Nature Materials vol 10 no 8 pp 602ndash607 2011
[193] J Ady andY Fong ldquoImaging for infection Fromvisualization ofinflammation to visualization of microbesrdquo Surgical Infectionsvol 15 no 6 pp 700ndash707 2014
[194] J M Sierra D Rodriguez-Puig A Soriano J Mensa C Pieraand J Vila ldquoAccumulation of 99mTc-ciprofloxacin in Staphy-lococcus aureus and Pseudomonas aeruginosardquo AntimicrobialAgents and Chemotherapy vol 52 no 7 pp 2691-2692 2008
[195] D I Andersson and D Hughes ldquoMicrobiological effects ofsublethal levels of antibioticsrdquoNature ReviewsMicrobiology vol12 no 7 pp 465ndash478 2014
[196] N Dumarey D Blocklet T Appelboom L Tant and ASchoutens ldquoInfecton is not specific for bacterial osteo-articularinfective pathologyrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 29 no 4 pp 530ndash535 2002
[197] K E Britton D W Wareham S S Das et al ldquoImaging bacte-rial infection with 99mTc-ciprofloxacin (Infecton)rdquo Journal ofClinical Pathology vol 55 no 11 pp 817ndash823 2002
[198] G Ferro-Flores M A Avila-Rodrıguez and F O Garcıa-PerezldquoImaging of bacteria with radiolabeled ubiquicidin by SPECTand PET techniquesrdquo Clinical and Translational Imaging vol 4no 3 pp 175ndash182 2016
[199] P S Hiemstra M T van den Barselaar M Roest P H Nibber-ing and R van Furth ldquoUbiquicidin a novel murine microbi-cidal protein present in the cytosolic fraction of macrophagesrdquoJournal of Leukocyte Biology vol 66 no 3 pp 423ndash428 1999
[200] M S Akhtar A Qaisar J Irfanullah et al ldquoAntimicrobialpeptide 99mTc-ubiquicidin 29ndash41 as human infection-imagingagent clinical trialrdquo Journal of Nuclear Medicne vol 46 no 4pp 567ndash573 2005
[201] M Assadi K Vahdat I Nabipour et al ldquoDiagnostic value of99mTc-ubiquicidin scintigraphy for osteomyelitis and compar-isons with 99mTc-methylene diphosphonate scintigraphy andmagnetic resonance imagingrdquo Nuclear Medicine Communica-tions vol 32 no 8 pp 716ndash723 2011
[202] T Emery ldquoExchange of Iron by Gallium in SiderophoresrdquoBiochemistry vol 25 no 16 pp 4629ndash4633 1986
[203] M Petrik C Zhai H Haas and C Decristoforo ldquoSiderophoresfor molecular imaging applicationsrdquo Clinical and TranslationalImaging vol 5 no 1 pp 15ndash27 2017
[204] H J Flint E A BayerM T Rincon R Lamed and B AWhiteldquoPolysaccharide utilization by gut bacteria potential for newinsights from genomic analysisrdquo Nature Reviews Microbiologyvol 6 no 2 pp 121ndash131 2008
[205] GGowrishankarMNamavari E B Jouannot et al ldquoInvestiga-tion of 6-[18F]-fluoromaltose as a novel PET tracer for imagingbacterial infectionrdquo PLoS ONE vol 9 no 9 Article ID e1079512014
[206] N Gholipour M Akhlaghi A M Kheirabadi et al ldquoChelator-free radiolabeling of dextran with 68Ga for PET studiesrdquoJournal of Radioanalytical and Nuclear Chemistry vol 311 no3 pp 1811ndash1817 2017
[207] C Bettegowda C A Foss I Cheong et al ldquoImaging bac-terial infections with radiolabeled 1-(21015840-deoxy-21015840- fluoro-120573-D-arabinofuranosyl)-5-iodouracilrdquo Proceedings of the NationalAcadamy of Sciences of the United States of America vol 102 no4 pp 1145ndash1150 2005
[208] S A Soghomonyan M Doubrovin J Pike et al ldquoPositronemission tomography (PET) imaging of tumor-localizedSalmonella expressing HSV1-TKrdquo Cancer GeneTherapy vol 12no 1 pp 101ndash108 2005
[209] C Palestro K Nichols S Sheikh-Fayyaz S Dewey P Singhaland K Bhargava ldquoCan Gallium-68 PET differentiate acuteinterstitial nephritis from acute tubular necrosisrdquo Journal ofNuclear Medicne vol 57 Supplement 2 p 551 2016
[210] A J Morguet D L Munz V Ivancevic et al ldquoImmunoscintig-raphy using technetium-99m-labeled anti-NCA-95 antigranu-locyte antibodies as an adjunct to echocardiography in subacuteinfective endocarditisrdquo Journal of the American College ofCardiology vol 23 no 5 pp 1171ndash1178 1994
[211] C van der Laken O Boerman W Oyen et al ldquoIn Vivo Expres-sion of Interleukin-1 Receptors during Various ExperimentallyInduced Inflammatory Conditionsrdquo The Journal of InfectiousDiseases vol 177 no 5 pp 1398ndash1401 1998
[212] C J Van Der Laken O C Boerman W J G Oyen M T PVan De Ven J W M Van Der Meer and F H M CorstensldquoScintigraphic detection of infection and inflammation Newdevelopments with special emphasis on receptor interactionrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 25 no 5 pp 535ndash546 1998
[213] C J van der LakenOC BoermanW J GOyenM T P van deVen J W M van der Meer and F H M Corstens ldquoImaging ofinfection in rabbits with radioiodinated interleukin-1 (120572 and 120573)its receptor antagonist and a chemotactic peptide a comparativestudyrdquo European Journal of Nuclear Medicine and MolecularImaging vol 25 no 4 pp 347ndash352 1998
[214] C J Van Der Laken O C BoermanW J G Oyen M T P VanDe Ven F H M Corstens and J W M Ven Der Meer ldquoThekinetics of radiolabelled interleukin-8 in infection and sterileinflammationrdquo Nuclear Medicine Communications vol 19 no3 pp 271ndash282 1998
[215] E Lazzeri P Erba M Perri et al ldquoScintigraphic imaging ofvertebral osteomyelitis with 111in-biotinrdquoThe Spine Journal vol33 no 7 pp E198ndashE204 2008
[216] E Blom B Langstrom and I Velikyan ldquo68Ga-labeling of biotinanalogues and their characterizationrdquo Bioconjugate Chemistryvol 20 no 6 pp 1146ndash1151 2009
[217] O Eriksson F Carlsson E Blom et al ldquoPreclinical evaluationof a 68Ga-labeled biotin analogue for applications in islettransplantationrdquo Nuclear Medicine and Biology vol 39 no 3pp 415ndash421 2012
[218] E A Weinstein A A Ordonez V P DeMarco et alldquoImaging Enterobacteriaceae infection in vivo with 18F-fluoro-deoxysorbitol positron emission tomographyrdquo Science Transla-tional Medicine vol 6 no 259 p 259ra146 2014
[219] K M Nielsen M H Kyneb A K O Alstrup et alldquo68Ga-labeled phage-display selected peptides as tracers forpositron emission tomography imaging of Staphylococcusaureus biofilm-associated infections Selection radiolabellingand preliminary biological evaluationrdquo Nuclear Medicine andBiology vol 43 no 10 pp 593ndash605 2016
[220] T J Makinen P Lankinen T Poyhonen J Jalava H T Aroand A Roivainen ldquoComparison of 18F-FDG and 68Ga PETimaging in the assessment of experimental osteomyelitis due toStaphylococcus aureusrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 32 no 11 pp 1259ndash1268 2005
[221] JMU Silvola I LaitinenH J Sipila et al ldquoUptake of 68galliumin atherosclerotic plaques in LDLRminusminusApoB100100micerdquo EJN-MMI Research vol 1 no 1 pp 1ndash8 2011
Contrast Media amp Molecular Imaging 23
[222] T A Wynn ldquoCellular and molecular mechanisms of fibrosisrdquoThe Journal of Pathology vol 214 no 2 pp 199ndash210 2008
[223] T Derlin D Jonigk J Bauersachs and FM Bengel ldquoMolecularImaging of Chemokine Receptor CXCR4 in NonndashSmall CellLung Cancer Using 68Ga-Pentixafor PETCT ComparisonWith 18F-FDGrdquo Clinical Nuclear Medicine 2016
[224] I Velikyan U Rosenstrom T N Bulenga O Eriksson andG Antoni ldquoFeasibility of multiple examinations using68ga-labelled collagelin analogues Organ distribution in rat forextrapolation to human organ and whole-body radiationdosimetryrdquo Pharmaceuticals vol 9 no 2 article no 31 2016
[225] S Jadhav M Kakela J Makila et al ldquoSynthesis and in VivoPET Imaging of Hyaluronan Conjugates of OligonucleotidesrdquoBioconjugate Chemistry vol 27 no 2 pp 391ndash403 2016
[226] A Autio A Saraste N Kudomi et al ldquoAssessment of bloodflow with (68) Ga-DOTA PET in experimental inflammation avalidation study using (15) O-waterrdquo American Journal ofNuclear Medicine and Molecular Imaging vol 4 no 6 pp 571ndash579 2014
[227] G Davies A Rolle A Maurer et al ldquoTowards translationalimmunoPETMR imaging of invasive pulmonary aspergillosisthe Humanised Monoclonal Antibody JF5 detects in vivordquoTheranostics vol 7 no 14 pp 3398ndash3414 2017
[228] DGoodwin CMeares GDavid et al ldquoMonoclonal antibodiesas reversible equilibrium carriers of radiopharmaceuticalsrdquoInternational Journal of Radiation Applications and Instrumen-tation Part B Nuclear Medicine and Biology vol 13 no 4 pp383ndash391 1986
[229] D A Goodwin C F Mears M McTigue and G S DavidldquoMonoclonal antibody hapten radiopharmaceutical deliveryrdquoNuclear Medicine Communications vol 7 no 8 pp 569ndash5801986
[230] S E Halpern and R O Dillman ldquoProblems associated withradioimmunodetection and possibilities for future solutionsrdquo JBiol Response Mod vol 6 no 3 pp 235ndash262 1987
[231] H Hong J Sun and W Cai ldquoRadionuclide-based cancerimaging targeting the carcinoembryonic antigenrdquo BiomarkerInsights vol 3 pp 435ndash451 2008
[232] G J Forster E B Santos P M Smith-Jones P Zanzonico andS M Larson ldquoPretargeted radioimmunotherapy with a single-chain antibodystreptavidin construct and radiolabeledDOTA-biotin Strategies for reduction of the renal doserdquo Journal ofNuclear Medicine vol 47 no 1 pp 140ndash149 2006
[233] Z Yao M Zhang H Kobayashi et al ldquoImproved targeting ofradiolabeled streptavidin in tumors pretargeted with biotiny-lated monoclonal antibodies through an avidin chaserdquo Journalof Nuclear Medicine vol 36 no 5 pp 837ndash841 1995
[234] C-H Chang R M Sharkey E A Rossi et al ldquoMolecularAdvances in Pretargeting Radioimunotherapy with BispecificAntibodies 1 Supported in part by USPHS Grant R01-CA-84379from the NIH and Department of Energy Grant DE-FG01-00NE22941 (both to R M S)1rdquo Mol Cancer Ther vol 1 no 7pp 553ndash563 2002
[235] R M Sharkey E A Rossi W J McBride C-H Chang andD M Goldenberg ldquoRecombinant Bispecific Monoclonal Anti-bodies Prepared by theDock-and-Lock Strategy for PretargetedRadioimmunotherapyrdquo Seminars in Nuclear Medicine vol 40no 3 pp 190ndash203 2010
[236] R M Sharkey E A Rossi C-H Chang and D M Golden-berg ldquoImproved cancer therapy and molecular imaging withmultivalent multispecific antibodiesrdquo Cancer Biotherapy andRadiopharmaceuticals vol 25 no 1 pp 1ndash12 2010
[237] D M Goldenberg R M Sharkey G Paganelli J Barbet andJ Chatal ldquoAntibody pretargeting advances cancer radioim-munodetection and radioimmunotherapyrdquo Journal of ClinicalOncology vol 24 no 5 pp 823ndash834 2006
[238] O C Boerman F G van Schaijk W J G Oyen and FH M Corstens ldquoPretargeted radioimmunotherapy of cancerprogress step by steprdquo Journal of Nuclear Medicine vol 44 no3 pp 400ndash411 2003
[239] J Schuhmacher S Kaul G Klivenyi et al ldquoImmunoscintigra-phy with positron emission tomography Gallium-68 chelateimaging of breast cancer pretargeted with bispecific anti-MUC1anti-Ga chelate antibodiesrdquo Cancer Research vol 61 no9 pp 3712ndash3717 2001
[240] J Schuhmacher G Klivenyi S Kaul et al ldquoPretargeting ofhuman mammary carcinoma xenografts with bispecific anti-MUC1anti-Ga chelate antibodies and immunoscintigraphywith PETrdquo Nuclear Medicine and Biology vol 28 no 7 pp 821ndash828 2001
[241] C Somasundaram S Matzku J Schuhmacher and M ZollerldquoDevelopment of a bispecific monoclonal antibody against agallium-67 chelate and the human melanoma-associated anti-gen p97 for potential use in pretargeted immunoscintigraphyrdquoCancer Immunology Immunotherapy vol 36 no 5 pp 337ndash3451993
[242] E A Rossi D L Rossi R Stein D M Goldenberg and C-H Chang ldquoA bispecific antibody-IFN1205722b immunocytokine tar-geting CD20 and HLA-DR is highly toxic to human lymphomaandmultiplemyeloma cellsrdquoCancer Research vol 70 no 19 pp7600ndash7609 2010
[243] R M Sharkey H Karacay S Litwin et al ldquoImproved ther-apeutic results by pretargeted radioimmunotherapy of non-Hodgkinrsquos lymphoma with a new recombinant trivalent anti-CD20 bispecific antibodyrdquo Cancer Research vol 68 no 13 pp5282ndash5290 2008
[244] G L Griffiths C-H Chang W J McBride et al ldquoReagentsandmethods for PETusing bispecific antibody pretargeting and68Ga-radiolabeled bivalent hapten-peptide-chelate conjugatesrdquoJournal of Nuclear Medicine vol 45 no 1 pp 30ndash39 2004
[245] J Watine M Miedouge and B Friedberg ldquoCarcinoembryonicantigen as an independent prognostic factor of recurrence andsurvival in patients resected for colorectal liver metastases Asystematic reviewrdquo Diseases of the Colon amp Rectum vol 44 no12 pp 1791ndash1799 2001
[246] M J Goldstein and E P Mitchell ldquoCarcinoembryonic antigenin the staging and follow-up of patients with colorectal cancerrdquoCancer Investigation vol 23 no 4 pp 338ndash351 2005
[247] D V Gold D M Goldenberg H Karacay et al ldquoA novelbispecific trivalent antibody construct for targeting pancreaticcarcinomardquo Cancer Research vol 68 no 12 pp 4819ndash48262008
[248] J Schuhmacher G Klivenyi R Matys et al ldquoMultistep tumortargeting in nudemice using bispecific antibodies and a galliumchelate suitable for immunoscintigraphy with positron emis-sion tomographyrdquo Cancer Research vol 55 no 1 pp 115ndash1231995
[249] G Klivenyi J Schuhmacher E Patzelt et al ldquoGallium-68chelate imaging of human colon carcinoma xenografts pre-targeted with bispecific anti-CD44(V6)anti-gallium chelateantibodiesrdquo Journal ofNuclearMedicine vol 39 no 10 pp 1769ndash1776 1998
[250] M Zoller J Schuhmacher J Reed W Maier-Borst and SMatzku ldquoEstablishment and characterization of monoclonal
24 Contrast Media amp Molecular Imaging
antibodies against an octahedral gallium chelate suitable forimmunoscintigraphy with PETrdquo Journal of Nuclear Medicinevol 33 no 7 pp 1366ndash1372 1992
[251] R M Sharkey T M Cardillo E A Rossi et al ldquoSignal ampli-fication in molecular imaging by pretargeting a multivalentbispecific antibodyrdquo Nature Medicine vol 11 no 11 pp 1250ndash1255 2005
[252] D M Goldenberg and R M Sharkey ldquoNovel radiolabeledantibody conjugatesrdquo Oncogene vol 26 no 25 pp 3734ndash37442007
[253] D M Goldenberg E A Rossi R M Sharkey W J McBrideand C-H Chang ldquoMultifunctional antibodies by the dock-and-lock method for improved cancer imaging and therapy bypretargetingrdquo Journal of NuclearMedicine vol 49 no 1 pp 158ndash163 2008
[254] R Schoffelen R M Sharkey D M Goldenberg et al ldquoPre-targeted immuno-positron emission tomography imaging ofcarcinoembryonic antigen-expressing tumors with a bispecificantibody and a68Ga- And18F-labeled hapten peptide in micewith human tumor xenograftsrdquoMolecular Cancer Therapeuticsvol 9 no 4 pp 1019ndash1027 2010
[255] E S Bos W H Kuijpers M Meesters-Winters et al ldquoIn vitroevaluation of DNA-DNA hybridization as a two-step approachin radioimmunotherapy of cancerrdquoCancer Research vol 54 no13 pp 3479ndash3486 1994
[256] G Paganelli M Bartolomei M Ferrari et al ldquoPre-TargetedLocoregional Radioimmunotherapy withrdquo Cancer biotherapyand radiopharmaceuticals vol 16 no 3 pp 227ndash235 2001
[257] A Forero P L Weiden J M Vose et al ldquoPhase 1 trial of a novelanti-CD20 fusion protein in pretargeted radioimmunotherapyfor B-cell non-Hodgkin lymphomardquo Blood vol 104 no 1 pp227ndash236 2004
[258] DM Goldenberg C-H Chang E A RossiW J McBride andR M Sharkey ldquoPretargeted molecular imaging and radioim-munotherapyrdquoTheranostics vol 2 no 5 pp 523ndash540 2012
[259] H Karacay R M Sharkey W J McBride E A Rossi C-HChang and D M Goldenberg ldquoOptimization of hapten-peptide labeling for pretargeted immunoPET of bispecificantibody using generator-produced 68Gardquo Journal of NuclearMedicine vol 52 no 4 pp 555ndash559 2011
[260] J R Oh and B C Ahn ldquoFalse-positive uptake on radioiodinewhole-body scintigraphy physiologic and pathologic variantsunrelated to thyroid cancerrdquo American Journal of NuclearMedicine and Molecular Imaging vol 2 no 2 pp 141ndash150 2012
[261] E Frampas C Rousseau C Bodet-Milin J Barbet J-F Chataland F Kraeber-Bodere ldquoImprovement of radioimmunotherapyusing pretargetingrdquo Frontiers in Oncology vol 3 Article ID00159 2013
[262] C S McKay and M G Finn ldquoClick chemistry in complexmixtures Bioorthogonal bioconjugationrdquo Chemistry amp Biologyvol 21 no 9 pp 1075ndash1101 2014
[263] B L Oliveira Z Guo and G J Bernardes ldquoInverse electrondemand DielsndashAlder reactions in chemical biologyrdquo ChemicalSociety Reviews vol 46 no 16 pp 4895ndash4950 2017
[264] B Nichols Z Qin J Yang D R Vera and N K Devaraj ldquo68Gachelating bioorthogonal tetrazine polymers for the multisteplabeling of cancer biomarkersrdquo Chemical Communications vol50 no 40 pp 5215ndash5217 2014
[265] R Rossin P R Verkerk S M van den Bosch et al ldquoInvivo chemistry for pretargeted tumor imaging in live micerdquoAngewandte Chemie International Edition vol 49 no 19 pp3375ndash3378 2010
[266] B M Zeglis K K Sevak T Reiner et al ldquoA pretargetedPET imaging strategy based on bioorthogonal diels-alder clickchemistryrdquo Journal of Nuclear Medicine vol 54 no 8 pp 1389ndash1396 2013
[267] J L Houghton R Membreno D Abdel-Atti et al ldquoEstablish-ment of the invivo efficacy of pretargeted radioimmunotherapyutilizing inverse electron demand diels-alder click chemistryrdquoMolecular Cancer Therapeutics vol 16 no 1 pp 124ndash133 2017
[268] J Funkhouser ldquoReinventing pharma the theranostic revolu-tionrdquo Current Drug Discovery pp 17ndash19 2002
[269] J Sorensen I Velikyan A Wennborg et al ldquoMeasuring HER2-expression in metastatic breast cancer using 68Ga-ABY025PETCTrdquo European Journal of Nuclear Medicine and MolecularImaging vol 41 pp S226ndashS226 2014
[270] I Velikyan A Wennborg J Feldwisch et al ldquoGMP compliantpreparation of a 68Gallium-labeled Affibody analogue forbreast cancer patient examination first-in-manrdquoEur JNuclMedMol Imaging vol 41 pp S228ndashS229 2014
[271] K Oberg ldquoMolecular imaging radiotherapy Theranostics forpersonalized patient management of neuroendocrine tumors(NETs)rdquoTheranostics vol 2 no 5 pp 448ndash458 2012
[272] I Velikyan AWennborg J FeldwischH Lindman J Carlssonand J Sorensen ldquoGood manufacturing practice production of [(68) Ga]Ga-ABY-025 for HER2 specific breast cancer imagingrdquoAmerican Journal of Nuclear Medicine and Molecular Imagingvol 6 no 2 pp 135ndash153 2016
[273] M Sandstrom K Lindskog I Velikyan et al ldquoBiodistributionand radiation dosimetry of the anti-HER2 Affibody molecule68Ga-ABY-025 in breast cancer patientsrdquo Journal of NuclearMedicine vol 57 no 6 pp 867ndash871 2016
[274] D Sandberg V Tolmachev I Velikyan et al ldquoIntra-imagereferencing for simplified assessment of HER2-expression inbreast cancer metastases using the Affibody molecule ABY-025with PET and SPECTrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 44 no 8 pp 1337ndash1346 2017
[275] H ZhangM AMoroz I Serganova et al ldquoImaging expressionof the human somatostatin receptor subtype-2 reporter genewith 68Ga-DOTATOCrdquo Journal ofNuclearMedicine vol 52 no1 pp 123ndash131 2011
[276] M Naji and A Al-Nahhas ldquo68Ga-labelled peptides in themanagement of neuroectodermal tumoursrdquo European Journalof Nuclear Medicine and Molecular Imaging vol 39 no 1 ppS61ndashS67 2012
[277] I Velikyan ldquoThe diversity of 68Ga-Based imaging agentsrdquoRecent Results in Cancer Research vol 194 pp 101ndash131 2013
[278] K Ferreira H-Y Hu V Fetz et al ldquoMultivalent siderophore-dotam conjugates as theranostics for imaging and treatment ofbacterial infectionsrdquo Angewandte Chemie International Editionvol 56 no 28 pp 8272ndash8276 2017
Computational and Mathematical Methods in Medicine
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2 Contrast Media amp Molecular Imaging
related to the pathogens or be sterile It can be classified asacute or chronic and the latter has been investigated as themajor cause of inflammatory autoimmune cardiovascularneurological and cancerous diseases
In order to control infectious diseases and provide effi-cient treatment early diagnosis as well as discriminationbetween bacterial and sterile inflammation is crucial Thedisease specificity of the diagnostic tools is a desirablecharacteristic Currently available diagnostic means presentsome disadvantages Clinical laboratory tests such as whiteblood cell (WBC) counts and C-reactive protein (CRP)cannot unambiguously distinguish between bacterial andviral infection and may result in unnecessary treatmentwith antibiotics [22] Radiological imaging techniques suchas magnetic resonance imaging (MRI) X-ray computedtomography (CT) and ultrasound are morphological andrely on the anatomical changes that occur at later stage ofthe disease Moreover these methods are not specific toneither inflammation nor infection type Detection of viralinfection is even more challenging since it does not produceanatomic changes as bacterial infection does even when theviral infection is severe
In contrast to morphological imaging techniques func-tional methods such as gamma scintigraphy (Single Pho-ton Emission Computed Tomography (SPECT) and planargamma imaging) and Positron Emission Tomography (PET)provide fast whole-body and noninvasive real time evalu-ation of physiology and pathology on molecular level earlyin disease processes before noticeable changes in anatomicalstructure occur The whole-body examination might be ofgreat importance especially in cases of occult infection [23]The respective examinations can be repeated in order tomonitor the treatment outcome resulting in personalizedmedicine approach [24ndash27] The advantages of PET overSPECT are intrinsic to the technology and are presented withhigher examination throughput considerably higher sensi-tivity possibility of detection and quantification of tracerpicomolar amounts as well as tracer uptake kinetics recordingand dynamic image reconstruction [28] In recent years thestand-alone PET scanners have been substituted with hybridPET-CT scanners that offer both high sensitivity of functionalPET and temporalspatial resolution of morphological CT inone examination The hybrid PET-MRI scanners have alsoentered market providing advantages of MRI over CT inhigher soft tissue contrast and absence of radiation dose tothe patient PET has demonstrated efficiency and profitabilityin individualized patient diagnostics especially in oncologyand its impact on patient management has been recognizedby Medicare and Medicaid Services [29]
21 Common Clinical Imaging Agents for Inflammation andInfection There are a few radiopharmaceuticals used inclinical routine and they are nonspecific in their action 67Ga-Citrate 99mTc111In-white blood cells (WBC) and [18F]-fluo-rodeoxyglucose ([18F]FDG) [30] They target components ofinflammatory response to injury and infection and accumu-late in the lesions as a result of an increased blood flow andenhanced vascular permeability 67Ga-Citrate presumably
transfers 67Ga to transferrin and lactoferrin that accumulateat the inflammation site on the cells such as leukocytes and B-lymphocytes expressing respective receptors [31] Moreover67Ga can be accumulated in the macrophages bacteria andfungi via siderophores Radiolabelled WBCs accumulate inthe sites of leukocyte infiltration and do not discriminateinfective from sterile inflammation [32] [18F]FDG accumu-lates in leukocytes macrophages monocytes lymphocytesand giant cells due to upregulation of glucose transporters[33]67Ga-Citrate has been in clinical use for imaging of infec-
tion and inflammation for over 40 years It is applicable forexample for the diagnosis of lung infections acutechronicosteomyelitis tuberculosis sarcoidosis and retroperitonealfibrosis [34] However the specificity of the agent is subopti-mal with accumulation inmalignancies and bone remodelingsites as well as bowel excretion pathway Moreover radiationdoses to the healthy organs and tissues are unfavorableand the examination requires several visits to the hospitalwith an interval of 1ndash3 days between radiopharmaceuticaladministration and examination
Radiolabelled autologous WBCs have been used for awide range of infections such as peripheral osteomyelitispostoperative infection joint prosthesis infection diabeticfoot infection cardiovascular infection fever of unknownorigin (FUO) opportunistic infection central nervous sys-tem infection musculoskeletal infection and inflammatorybowel disease for over three decades Various labelling tech-niques using 111In-oxine 99mTc-sulfur colloids and 99mTc-exametazime (HMPAO) have been developed however theradiopharmaceutical preparation procedure is complicatedand potentially hazardous for both personnel and patient [2130]Moreover the examination process is very demanding onthe patient [35]
Most nuclear medicine applications worldwide (90)stand for diagnostics with leading position for 99mTc-basedradiopharmaceuticals especially in cardiology [36]Themostessential contribution to the improvement of the patientmanagement in oncology has been presented by [18F]-fluorodeoxyglucose ([18F]FDG)PET-CT reflecting the ele-vation of glucose transporter expression in tumour cellsand providing nearly universal application in the evalua-tion of various fast growing cancer types [18F]FDGPET-CT stands for over 90 of all PET-CT examinations [3738] [18F]FDGPET is an established diagnostic means alsoin infection and inflammation and the major indicationsfor it are FUO sarcoidosis peripheral bone osteomyelitissuspected spinal infection metastatic infection bacteremiaand vasculitis [33] However demand for the imaging agentstowards disease specific targets in cancer and inflamma-tioninfection is growing [39 40] since [18F]FDG fails todetect slowly growing tumours and to discriminate malig-nancy from sterile inflammation infection wound healingtuberculosis sarcoidosis and reactive lymph nodes [41 42]Another disadvantage is high accumulation of [18F]FDG inhealthy organs such as brain and gut resulting in suboptimalimage contrast and consequently potential risk for lesiondetection failure
Contrast Media amp Molecular Imaging 3
Table 1 Positron-emitting gamma-emitting and therapeutic radionuclides their physical characteristics and production mode Adaptedfrom [4]
18F 110min 634 120573+ (97) Accelerator64Cu 128 h 656 120573+ (19) Accelerator68Ga 676min 1899 770 120573+ (89) Generator89Zr 784 h 900 120573+ (23) Accelerator124I 417 d 2100 120573+ (23) Accelerator
Gamma emitters67Ga 7826 h 91 93 185 296 388 120574 Accelerator99mTc 60 h 141 120574 Generator111In 679 h 245 172 (05ndash25) 120574 Auger electrons Accelerator123I 133 h 159 120574 Accelerator
Therapeutic radionuclides177Lu 671 d 113 2084 (598) 120574 (120573minus) Reactor
22 Unmet Medical Need Noninvasive and specific diag-nosis of many inflammatory diseases such as sarcoidosisosteomyelitis inflammatory bowel disease and rheumatoidarthritis as well as early and accurate diagnosis of deep-seated infectious diseases such as septic arthritis abscessesendocarditis and infections of prosthetics and implantswould benefit patients [20] Introduction of specific imagingagents disclosing cellular mechanisms of various diseaseson molecular level would allow improvement in patientmanagement and treatment outcome There is a strong needfor specific imaging agents not only for the accurate andquantitative diagnosis but also for the prognosis treatmentselection planning and adjustment as well as response mon-itoring as for example requirement for a certain antibioticand treatment duration Moreover the imaging could guidesurgical procedures and monitor implants of medical devicesor transplanted organs [43] Such imaging guided treatmentwould decrease the cost side effects and overtreatmentavoiding immune suppression effects in inflammation andpossibly reducing the problem of antimicrobial resistance bythe termination of an accomplished successful treatment asearly as possible There are potential challenges in targetingboth components of inflammatory response and microbesspecifically discrimination between infectious and sterileinflammation discrimination between acute and chronicinflammation discrimination between various infectiousmicroorganisms discrimination between pathogenic bac-teria and microbiota targeting specific types of bacteriadifficulty of accessing bacteria aggregated in a biofilm andquantification of reproducing bacteria
Health care requires further improvement of efficiencysafety and quality of treatment with patient personalizedapproach that would allow early diagnosis which is a crucialfactor in the reduction of mortality and patient managementcost [81] The concept of individualized patient managementon molecular level with regard to both diagnostics andtherapy is based on discoveries and success in genomicsproteomics and biotechnology Those achievements alsoaccelerate the development of various imaging agents and
the application of molecular imaging diagnostic techniquesis expanding very fast globally contributing considerably tothe realization of personalized medicine
3 Advantages of 68Ga NuclideProperties and Chemistry
Such radionuclides as 11C 18F 64Cu 68Ga 89Zr 99mTc 111Inand 124I are used in various radiopharmaceuticals for diag-nostic imaging with PET and SPECT (Table 1) With regardto PET 18F stands for 41 11C stands for 31 and 64Cu 68Ga89Zr and 124I stand for 28 of the radiopharmaceuticals [82]With regard to SPECT 99mTc and 111In stand respectivelyfor 42 and 29 of the radiopharmaceuticals As mentionedabove in the field of inflammation and infection gammaemitting 67Ga 99mTc 111In and positron-emitting 18F arecommonly in use The choice of a radionuclide depends onvarious aspects of production and application availabilityproduction mode and cost of the radionuclide nuclearcharacteristics and decay mode of the radionuclide labellingchemistry pathways and duration radiation dose to subjectsrelevance of the physical half-life of the radionuclide to thepharmacokinetic time frame of the imaging agentWithin thegroup of gamma emitters used for SPECT the productionvia generator system is an advantage that contributes to theleading position of 99mTc due to ready accessibility and lowercost Moreover the single and lower gamma energy of 99mTcresults in higher image resolution as compared to 67Ga and111In and shorter half-life of 99mTc reduces radiation dose tothe patient (Table 2)
The advantages of PET such as higher spatial resolutionsensitivity and accurate signal quantification are crucialespecially in the case of small size lesions Furthermoredynamic scanning allows modeling and investigation of themechanism of the interaction between the imaging agentand target Even though 68Ga has a relatively high positronenergy the resolution of the images is comparable to thatof 18F since it is the scanner detector resolution (4ndash6mm)
4 Contrast Media amp Molecular Imaging
Table 2 Effective doses for some PET and SPECT imaging agents Reproduced from [6]
Agent Examination time Effective dose [mSv][111In]In-DTPA-octreotideSPECT 24ndash48 h 108[68Ga]Ga-DOTA-TOCPET 30ndash60min 23[18F]FDGPET 60ndash120min 56[99mTc]-BPAMDSPECT 2ndash6 h 6[99mTc]-MDPSPECT 2ndash6 h 3-4[68Ga]Ga-BPAMDPET 30ndash60min 3-4
which is the limiting factor [4 83 84]The 68-min half-life of68Ga is not compatiblewith ligands of slowpharmacokineticsfor example antibodies Thus other positron emitters suchas 124I 89Zr and 64Cu with longer half-lives allowing 2ndash4days required for the clearance of the agent for the bloodcirculation and washout for the nontarget tissue are morerelevantThe relatively short half-life of 68Ga presents advan-tage in cases when repetitive examinations on the same dayare of interest [85] The high fraction of positron emission isanother advantage of 68Ga (89) as compared to 64Cu (19)and 124I (23) Comparison of some clinically used imagingagents demonstrates the lower effective dose that patient isexposed to when using 68Ga-based agent as compared tothe agents comprising 18F 99mTc and 111In (Table 2) [686 87] Moreover the duration of patient examinations isshorter for 68Ga-agents than that for SPECT agents and tosome extend for [18F]FDG In summary the use of 68Gawould be beneficial in terms of accessibility high sensitivityand resolution quantification dynamic scanning fast scan-ning protocol repetitive examinations and low radiationburden
The chemical form in aqueous solution is Ga(III)cation which provides robust coordination chemistry 68Ga-labelling can be direct or chelator mediated The directlabelling utilizes the chelating ability of macromolecules forexample lactoferrin and transferrin comprising Tyr His andAsp AA residues that can chelate Ga(III) in the presence ofsynergetic bicarbonate ion Lowmolecular weight ligands canform stable complexes of variable lipophilicity and charge fornontargeting imaging The chelator mediated 68Ga-labellingrequires presence of a bifunctional chelator (BFC) for the sub-sequent straightforward and side specific coordination withGa(III) Considerable number of chelators was successfullydeveloped [4 6 88ndash95]Themost commonly used are DOTAand NOTA based chelators The former requires heatingunder over 60∘C for the complexation with 68Ga while thelatter can chelate 68Ga at ambient temperature which mightbe crucial in case of temperature sensitive ligands and italso allows for cold kit type radiopharmaceutical prepara-tion under radiopharmacy practice [96] DOTA presents anadvantage in the context of radiotheranostics since it canform stable complexes with 68Ga for PET diagnostics and177Lu for radiotherapy
The chelator or prosthetic group mediated labellingmost commonly results in agents comprising biologicallyactive vectormolecule chelatorprosthetic groupmoiety and
radionuclide Very often pharmacokinetic modifiers (PKM)are incorporated in order to modulate pharmacokinetics andagent organ distribution and improve in vivo stability as wellas separate the binding site from the bulky chelatorprostheticgroup moiety which may deteriorate the biological activityof the vector molecule Considerable number of publicationsreveal strong influence of even slight modifications in any ofthe agent structural components and the accurate predictionof pharmacokinetics and pharmacodynamics of a new agentis not straightforward [97] Nevertheless vast experience andknowledge have been intensively gathered during last twodecades providing possibility for more efficient and effectivedevelopment The labelling chemistry of 68Ga is well charac-terized and is relevant to small molecules macromoleculesand particles
Ga(III) as a chemical element presents a unique advan-tage over other radionuclides as it has properties closelyresembling those of Fe(III) which is involved in manybiochemical processes including inflammation MoreoverFe(III) is an essential nutrient and limiting factor ofmicrobiallife [98] Stable Ga(III) has been used in treatment of variousdiseases including cancer infection and inflammation [99ndash101] The ability of Ga(III) to bind iron proteins for examplelactoferrin and transferrin as well as siderophores andenzymes can be utilized in the imaging agent development
4 Biomarkers andRadiopharmaceutical Development
The development of imaging agents relies strongly on theadvances experience and knowledge of the research ofbiomarkers for example receptors and antigens transportsystems substances involved in angiogenesis glycolysishypoxia proliferation and apoptosis and enzyme activityTargeting biomarkers that are specific for a given diseaseis one the major aims of an agent development for bothdiagnostic imaging and therapy The knowledge and accessto respective vector molecules have considerably expandeddue to the achievements in proteomics and genomics Infec-tion inflammation and fibrosis are closely interrelated pro-cesses and corresponding biomarkers might present practicalinterest in developing respective imaging agents Favorablecharacteristics of a target in general include expressionupregulation absence of expression in normal tissue andinternalization or stable binding of the respective ligand forthe longitudinal accumulation of the latter [102]
Contrast Media amp Molecular Imaging 5
5 Imaging Inflammation
Inflammatory response is a complex process involvingimmune system cells (T- and B-lymphocytes NK cellsmacrophages monocytes neutrophils eosinophils andmastcells) and products of their (patho)physiological activity forexample cytokines involved in the cell signaling Variousfunctions of the cells and their products as well as theirreceptors provide a broad range of potential imaging targets[103ndash107] Targeting the white blood cells of the immunesystem such as macrophages monocytes lymphocytes andneutrophils for the detection of their upregulation and traf-ficking secretion of cytokines and chemokines and phago-cytosis has been investigated both clinically and preclinicallyReceptors such as SSTRNCA-90 integrins folate bombesinvascular cell adhesion protein-1 and interleukins expressedby activated T-cells CXCR2 expressed on neutrophils andCXCR4 overexpressed by leukocytes have demonstratedpotential for in vivo targeted imaging [108] Respectiveligands and substrates can be considered for radiolabellingCytokines including interferons lymphokines interleukinsand chemokines bind to various receptors for example IL1and IL2 receptor types IFN CD40 CD37 CD30 CD4CCR5 and IL1-17R receptor family Folate CD64 NCA90and CD15 receptors expressed on macrophages leukocytesand granulocytes can serve as targets Not only do moleculesof such super families as chemokine integrin selectin andimmunoglobulin participate in the cell emigration cascadebut also enzymes on the surface of endothelia cells andleukocytes contribute to the leukocyte extravasation [109]Receptors on the endothelial wall for example for bindingof IL1 and TNF120572 are another category of the targets Theseare only few examples of targets for potential imaging agentdevelopment (Table 3) Many targets were utilized in oncol-ogy [28] and their translation to inflammation is feasible
51 Targeting Cell Receptors with Antibodies Radiolabelled(99mTc 111In and 123I) anti-CD2 anti-CD5 anti-CD25 anti-CD45 antibodies and their fragments were used for the imag-ing of T-lymphocyte infiltration in various inflammatorydiseases [110] Typically for antibody slow pharmacokineticsthe time delay between the administration and examina-tion stretches up to 24 hours Interleukin-8 labelled with99mTc was studied in rabbits with induced acute pyogenicosteomyelitis [111] and induced acute colitis [112] The agentwas found suitable for the scintigraphic evaluation of therespective diseases CD163 receptor expressed in monocytesand activated macrophages was targeted with an anti-CD163antibody labelled with 68Ga in rats with acute collagen-induced arthritis [45]The agent demonstrated specific bind-ing and thus potential for studies of inflammatory diseases
52 Targeting Angiogenesis Angiogenesis plays an importantrole in wound healing chronic inflammation and tumourgrowth [113] The family of vascular endothelial growthfactors (VEGF) and integrins play crucial role in the angio-genesis cascade Integrin receptors are overexpressed on thesurface of vascular endothelial cells during angiogenesis inmalignances tissue healing and inflammation The largest
group is radiolabelled peptide ligands comprising arginine-glycine-aspartic acid (RGD) sequence and peptidomimeticstargeting 120572v1205733 integrin receptors Various analogues weredeveloped introducing cyclization andmultimerization vari-ety of chelatecoligand moieties PKM such as carbohy-drate and polyethylene glycol chains [114ndash121] Various RGDanalogues labelled with 18F 68Ga and 99mTc were usedin oncological clinical trials [122] The majority of themcomprised 18F however advantages of 68Ga such as accessi-bility of the radionuclide more straightforward and efficientlabelling chemistry lower radiation dose and better imagecontrast renderedmore extensive development of 68Ga-basedanalogues [123ndash127]
The imaging agents tested in cancer systems can berelevant for the imaging of inflammation related diseasesTheimaging and evaluation of synovial angiogenesis in patientswith rheumatoid arthritis was accomplished using [68Ga]Ga-PRGD2 [46] The elevated agent uptake was detected inthe sites of active inflammation rich neovasculature andphysiological integrin receptor expression while no traceraccumulationwas detected in axillary lymphnodeswith reac-tive hyperplasia and strenuous skeletal muscles [68Ga]Ga-PRGD2PET-CT was found useful for the evaluation of syn-ovial angiogenesis and follow-up of the treatment response
[68Ga]Ga-NOTA-c(RGDyK)was developed for the imag-ing of myocardial infarction (MI) and follow-up of theresponse to the therapeutic intervention and demonstratedpromising results preclinically [47] The uptake in the MIlesions was enhanced and correlated with the vascularendothelial growth factor expression Dynamic [68Ga]Ga-NOTA-c(RGDyK)PET scanning with subsequent kineticmodeling studies in rats with forelimb ischemia showedhigher uptake and distribution volume in the ischemicarea as compared to that of sham operation and controlregions [48] Monitoring myocardial repair and angiogenesisafter ischemic injury was found plausible using [68Ga]Ga-NODAGA-RGD and [68Ga]Ga-TRAP-(RGD)3 in rat model[49] Elevated uptake of [68Ga]Ga-DOTA-E-[c(RGDfK)]2was observed in the infarcted area while no accumulationwas detected in the noninfarcted myocardium of the samerats [50]The uptake of [68Ga]Ga-DOTA-RGD in atheroscle-rotic plaques was studied in vivo in atherosclerotic micewith promising results [52] Elevated uptake of [68Ga]Ga-NODAGA-RGD in injured myocardium as compared toviable ischemic areas in pig model presumably indicatedincreased expression of 120572V1205733 receptors associated with injuryrepair in the presence of coronary stenosis [51]
Although targeting VEGF receptors were studied in thecontext of cancerous diseases chronic inflammation can alsobe considered A ligand consisting of a single chain (scVEGF3ndash112 amino acids of human VEGF121) [128 129] was labelledwith 68Ga and the resulting agent showed distinct uptake inthe tumour xenografts in mice however high kidney uptakeneeded to be addressed [130 131]
53 Targeting Selectins P-selectin is expressed on the activeendothelium surface and platelets and operates the migra-tion of leukocytes in response to inflammatory cytokines
6 Contrast Media amp Molecular Imaging
Table 3 68Ga-based imaging agents for inflammation and infection investigated preclinically and clinically
E-selectin binding peptide labelled with 99mTc accumu-lated in acute osteomyelitic lesions in rats presumably byinteraction with activated vascular endothelium [132] Ananalogue of P-selectin natural ligand fucoidan labelled with68Ga could discriminate active and inactive atheroschleroticplaques in mice [44]
54 Targeting Vascular Adhesion Protein-1 Vascular adhe-sion protein-1 (VAP-1) and CD73 are endothelial surfaceenzymes involved in the recruitment of leukocytes and theirmovement from the blood into the tissue [109] Endothelialactivation that takes place during inflammation can be uti-lized for specific targeting imaging Several peptide analogues
Contrast Media amp Molecular Imaging 7
300
250
200
150
100
50
0
(kBq
ml)
Inflammation
Kidneys
Muscle
Inflammation
Kidneys
Muscle
Figure 1 PET images of the distribution of [68Ga]Ga-DOTAVAP-P1 [68Ga]Ga-DOTAVAP-PEG-P1 and [68Ga]Ga-DOTA-Siglec-9 inturpentine-induced rat model of sterile inflammation All three peptide analogues showed target-to-nontarget ratio above 6 with rapidaccumulation in the inflammation site and renal clearance Adapted from [57]
labelledwith 68Gawere designed for the visualization ofVAP-1 and showed promising results in animals with inducedinfection and sterile inflammation [7ndash13 133] The bindingwas proven specific and it was possible to differentiate inflam-mation from infection [68Ga]Ga-Siglec targeting VAP-1demonstrated preclinical potential for imaging of synovialinflammation in patients with rheumatic diseases [53] Thesame agent was utilized for respiratory distress syndrome(ARDS an inflammatory lung injury) imaging in a porcinemodel [54] Imaging VAP-1 with [68Ga]Ga-Siglec was foundpromising also for the detection of inflamed atheroscle-rotic lesions [55] and inflammatory response induced bycatheter implantation and staphylococcal infection [56]68Ga-Siglec and two more peptide analogues with affinityto VAP-1 ([68Ga]Ga-DOTAVAP-P1 [68Ga]Ga-DOTAVAP-PEG-P1 and [68Ga]Ga-DOTA-Siglec-9) were investigated inrat model of sterile skinmuscle inflammation (Figure 1) [57]They showed distinct uptake in the affected sites
55 Targeting Chemokines Cytokines are produced bymacrophages B-lymphocytes T-lymphocytes and mast cellsand act through receptors modulating for example immuneresponse to infection and inflammation Cytokines includechemokines interleukins interferons and lymphokines thatcan be classified in broad families exhibiting diverse func-tions for example IL-1 and IL-6 superfamilies and TNFTNFreceptor superfamily Therapeutics targeting cytokines are inclinical use for example inhibiting TNF or IL-6 in rheumaticdiseases
Chemokine receptors are physiologically expressed onB-lymphocytes T-lymphocytes macrophages neutrophilseosinophils monocytes and hematopoietic stem cells [134]Imaging agents targeting CXCR4 are based on inhibitors(AMD3100) or small peptides (NFB T140 pentixafor andTN14003) and comprise 18F 67Ga 68Ga or 64Cu [135ndash148] They were developed and studied for the imaging of
various cancerous diseases lung breast prostate cancersacute myeloid leukemia and glioblastoma
The application of CXCR4 targeting agents was extendedbeyond oncology Clinical caseimage reports [149 150]were published on the utilization of [68Ga]Ga-pentixafor fordetection and quantification of CXCR4 receptor density inischemic heart diseases reflecting the role of the receptorin inflammatory and progenitor cell recruitment [58 59]The same agent was successfully used in the assessment ofmacrophage infiltration in atherosclerotic plaques in rabbitdisease model [151]
56 Targeting Folate Receptors Folate receptors (FRs) areoverexpressed on a variety of cancer cells and activatedmacrophages but not on normal cells [152 153] Theenhanced expression of FR was found in lung macrophagesduring acute inflammation [154] The majority of the nuclearimaging agents based on folic acid or pteroic acid [155] weredeveloped for diagnosis of cancers overexpressing FR recep-tors such as breast cervical ovarian colorectal nasopharyn-geal renal and endometrial cancers Various 68Ga-labelledagents demonstrated accumulation in cell cultures and micebearing folate-receptor positive human nasopharyngeal car-cinoma cell line (KB) xenografts [6 156ndash162] [68Ga]Ga-DOTA-PEG-FA comprising folic acid was investigated forthe detection and quantification of inflammatory response tomedical implants using mice with subcutaneously implantedpolylactic acid and poly(N-isopropylacrylamide) particles asa model [60] The agent was accumulated in the area of theimplant most probably reflecting interaction of [68Ga]Ga-DOTA-PEG-FA with folate receptor expressed on activatedmacrophages Another folic acid based agent [68Ga]Ga-DOTA-folate was successfully tested in an inflammatory pawrat model (Figure 2) [61] Distinct accumulation in inflamedhand and foot joints of rheumatoid arthritis of a 99mTc-labelled folate analogue was observed in a patient while no
8 Contrast Media amp Molecular Imaging
NH ONHONH
OOO
HOHN O
HN
NN
N N
HO
O
N
N
O
O
N
N
O
O
O
Ga+
minus
（3
(a)
2
15
1
05
0
(b)
Figure 2 Accumulation of [68Ga]Ga-DOTA-folate (a) in the site of inflammation of rat inflammatory pawmodel induced by subcutaneouslyinjected Complete Freundrsquos Adjuvant (b) Adapted from [61]
4
2
0
Figure 3 Intense atherosclerotic inflammation (white arrows) was detected by [68Ga]Ga-DOTA-TATE in a patient with acute coronarysyndrome Adapted from [65]
uptake was detected in a nonarthritis patientrsquos hands and feet[163]
57 Targeting Somatostatin Receptors Somatostatin receptor(SSTR) ligand analogues have found an extensive appli-cation in diagnosis and radiotherapy of neuroendocrinetumours The elevated expression of SSTRs is known also insmall cell lung cancer breast cancer renal cell carcinomaprostate cancer and malignant lymphoma A number ofsomatostatin ligand analogues labelled with gamma- andpositron-emitting radionuclides were used clinically foroncological cases [85 164ndash174] 68Ga-labelled somatostatinanalogues demonstrated superior performance in terms ofhigher specificity and sensitivity detection rate shorterexamination time and quantification possibility and havebecome a golden standard for the detection of neuroen-docrine tumours (NETs) taking over that title from [111In]-pentetreotide (OctreoScan) and demonstrating specificityand sensitivity of over 90 [27 175ndash180] 68Ga-labelledagents for the imaging of NETs demonstrated advantages
also over other radionuclides and tracers such as [18F]FDG[174] 123I-metaiodobenzylguanidine ([123I]MIBG) [181 182][18F]DOPA [183] [99mTc]-dicarboxy propane diphosphonate[184] and [18F]NaF
SSTR are also overexpressed on activated macrophagesand T-lymphocytes 68Ga-labelled analogues were used ininflammation related diseases such as idiopathic pulmonaryfibrosis [62] Gravesrsquo and Hashimotorsquos diseases [63] coro-nary artery plaque imaging and characterization [64] andatherosclerotic inflammation with excellent macrophagespecificity (Figure 3) [65] Promising diagnostic potential ofa 99mTc-labelled analogue was demonstrated in patients withrheumatoid arthritis and secondary Sjogrenrsquos syndrome andthe method was suggested for the assistance in anti-TNFalpha antibody treatment planning [185] [68Ga]Ga-DOTA-TOCPET-CT was found superior to 67Ga-CitrateSPECT indetection of sarcoidosis lesions [186] A clinical study demon-strated correlation between uptake of [68Ga]Ga-DOTA-TOCand SST2 mRNA expression and recorded the information ina database [187] providing tools for accurate quantification
Contrast Media amp Molecular Imaging 9
and evaluation of disease progression and treatment responsein cancerous and inflammatory diseases involving SSTRsPreclinical study using atherosclerotic mice demonstratedsuperior targeting properties of [68Ga]Ga-DOTA-NOC ascompared to [18F]FDR-NOC [188] overall confirming thepotential of SSTR targeting for atherosclerotic plaque imag-ing
58 Imaging Neuroinflammation Despite difficulty ofdesigning 68Ga-labelled molecules capable of blood-brainbarrier penetration several agents were suggested for theimaging of neuroinflammation in particular A120573 plaquesdeposited on blood vessels [67ndash69] Bivalent styrylpyridineslabelled with 68Ga demonstrated high specificity and affinityfor A120573 plaques using postmortem Alzheimerrsquos disease (AD)brain sections [67] Benzofuran derivative comprising 68Gashowed promising results in terms of binding specificityand affinity investigated in vitro in sections of Tg2576mice [68] Although the synthesis of a 68Ga-labelledPittsburgh compound analogue was successful the in vitrobinding to amyloid deposits was limited [69] The commondisadvantage of these agents is poor blood-brain barrierpenetration nevertheless the exploration of more successfulanalogues continues Curcumin functions as an antioxidantantimicrobial anti-inflammatory and anticancer agentDiacetyl-curcumin and bis(dehydroxy)curcumin labelledwith 68Ga demonstrated in vitro binding to 120573-amyloid fibrilsand lung cancer cells [189] Potential application of the agentscould include diagnostic imaging of Alzheimerrsquos disease andvarious cancers
6 Imaging Infection
Infection imaging can be indirect utilizing targets involvedin the immune response namely inflammation as presentedin the inflammation targets section above or direct utilizingpathogen related targets The direct imaging is especiallycrucial in cases where inflammatory response is absent Thedifference in biochemistry and structure between bacterialand human cells might exclude physiological uptake byhuman tissuemaking it easier tomeet the favorable character-istics of an imaging agent However discrimination betweenthe various infectious microorganisms pathogenic bacteriaand microbiota targeting specific bacteria type as well asdifficulty of accessing bacteria aggregated in a biofilm makesthe task very challenging [190 191] The specific targetingof infection would require accumulation of the radioactivesignal in the pathogen The radiolabelled targeting agentsfor infection can be roughly divided into several groupsantibiotics based antimicrobial protein and peptide basedsiderophore and other metabolisable compound based andantigen-specific antibodies and antibody fragments (Table 3)
61 Radiolabelled Antibiotics Antimicrobials act on the pro-cesses that are specific to microbes for example bacteria andfungi and thus corresponding imaging agents might distin-guish infection from inflammation [191] They might requireinternalization or may bind to the cell surface dependent on
their biological action mechanism [191ndash193] The possibilityof antibiotic resistance development exists also in the case ofimaging agents even though the amount of such agents wouldbe subnanomolar [194 195] Another complication is possiblenonspecific uptake of antibiotics based agents by leucocytes[196] Considerable number of various antibiotic analogueshave been labelled with 99mTc 111In 131I 11C and 18F[102] and evaluated preclinically and clinically with 99mTc-ciprofloxacin becoming a commercial product (Infecton) [21197 198] However the further improvement of specificityis desirable [191] Antibiotics are accessible and cheap andthey demonstrate high sensitivity [102 191] making thedevelopment of 68Ga-labelled analogues very attractive giventhe earlier mentioned advantages that 68Ga as a radionu-clide in combination with PET provides Two 68Ga-labelledanalogues based on ciprofloxacin demonstrated potential fordiscrimination between bacterial infection and inflammationin rats infected with Staphylococcus aureus [70]
62 Radiolabelled Antimicrobial Proteins and Peptides Anti-microbial proteins and peptides for example serprocidinscathelicidins and defensins produced by the cells of immunesystem target microbial membrane lipids and impose micro-bicidal effect [35 43] They present a large group of poten-tial candidates for microbial imaging including bacteriafungi parasites and viruses Antimicrobial peptides havedemonstrated higher specificity for infection than antibioticanalogues They accumulate at infection but not sterileinflammation sites The most thoroughly studied antimicro-bial peptide ubiquicidin UBI [29ndash41] labelled with 99mTc[199] demonstrated promising results in human clinical trials[200 201] It has the potential for quantification of viableinfecting microorganisms and consequently for monitoringthe efficacy of antimicrobial therapy in patients
Fragments of an antimicrobial peptide ubiquicidin con-jugated to NOTA and labelled with 68Ga [68Ga]Ga-NOTA-UBI29-41 and [68Ga]Ga-NOTA-UBI30-41 demonstratedpossibility for the distinction between infection and inflam-mation in a rabbit model [71 72] Antimicrobial peptidefragments GF-17 and RAWVAWR-NH2 of respectivelyhuman cathelicidin LL-37 andhuman lysozyme active againstE coli and S aureus were labelled with 68Ga and theirbiodistribution in normal rats demonstrated fast clearancefrom liver [75] Antimicrobial depsipeptide based agent[68Ga]Ga-DOTA-TBIA101 targeting bacterial lipopolysac-charides detected muscular E coli-infection in mice (Fig-ure 4) [73] The agent was also studied in healthy rabbitsand various disease model rabbits such as sterile inflam-mation Staphylococcus aureus infection andMycobacteriumtuberculosis [74] The clearance of [68Ga]Ga-DOTA-TBIA101from blood and normal tissue was fast and enhanced uptakein sterile inflammation and Mycobacterium tuberculosis siteswas observed The improvement of the bacterial selectivitywill require modification of the agent structure
63 Radiolabelled Siderophores Bacteria and fungi producevarious siderophores for harvesting iron which is essentialfor their survival and growth [34 98 191] Siderophores
10 Contrast Media amp Molecular Imaging
(a)
(b)
(c) (d)
(e)
Figure 4 Left panel presents maximum intensity projection images of [68Ga]Ga-DOTA-TBIA101 distribution in a healthy mouse (a) and amouse with muscular infection site (MIS) in the right hind muscle tissue (white arrows) Right panel presents coronal (c) sagittal (d) andaxial (e) images with uptake in theMIS (white arrow) and absence of the uptake in the contralateralmuscle tissue Ki and Bl stand respectivelyfor kidney and bladder Reproduced from [73]
can also play a critical role in the development of biofilmsby microbes They are low molecular weight compoundsspecifically chelating Fe(III) and Ga(III) can form stablecomplexes with them mimicking Fe(III) [202 203]
Desferri-triacetylfusarinine C (TAFC) and desferri-ferricrocin (FC) labelled with 68Ga were used for theimaging of invasive pulmonary aspergillosis (IPA) caused byAspergillus fumigatus [15] [68Ga]Ga-TAFC demonstratedsuperior characteristics in terms of specific target bindingmetabolic stability and fast blood clearance in a rat modelof A fumigatus infection Seven analogues were developedin another study with TAFC and ferrioxamine E (FOXE)showing favorable binding clearance elimination andstability characteristics [16] as well as lung uptake inrat of invasive aspergillosis model wherein the uptakeextent was correlated with disease severity [17] [68Ga]Ga-triacetylfusarinine C and [68Ga]Ga-ferrioxamine E wereinvestigated in rat model of A fumigatus and demonstratedrapid uptake in the lungs (Figure 5) [76]
64 Radiolabelled Metabolisable Agents Mammalian micro-biota consumes (poly)saccharides in particular maltose andmaltodextrins [204] The transport mechanism is specific
to bacteria and is absent in mammalian cells making itpossible to utilize these (poly)saccharides for imaging agentdevelopment Maltodextrin functionalized with a fluorescentdye was internalized through the bacteria-specific maltodex-trin transport pathway and discriminated between activebacteria and inflammation in vivo [192] Maltose labelledwith 18F localized specifically bacterial infection in mice[205] Potential to label polysaccharides directly with 68Gamight be utilized extensively
As mentioned above the chemical properties of Ga(III)provide the potential for direct labelling of polysaccharidesDextran was labelled directly and resulting complex demon-strated sufficient stability in human serum however thefeasibility of the bacterial imaging was not demonstrated[206]
Trapping of nucleosides that are substrates of thymidinekinase occurring within bacteria was explored using 18Fand 125I labelled analogues of uracil [207] Promising resultswere obtained in seven bacterial species in mice Anotherstudy in the context of therapeutic bacteria developmentdemonstrated possibility of detecting Salmonella vectorswithin tumours using 18F-labelled uracil [208] However
Contrast Media amp Molecular Imaging 11
N
O
N
ON
HN
O
O
O
OO O
NH
O
O
O
O
NH
O
OGa
（3
（3
（3
（3
（3
（3
（2
(a) (b) (c)
Figure 5 Molecular structure of [68Ga]Ga-triacetylfusarinine C (a) used for the in vivo imaging of a rat with Aspergillus fumigatus infection(b) and negative control of noninfected rat (c) White arrows point at the infected (b) and normal (c) lungs Adapted from [76]
the development of 68Ga-labelled nucleosides that wouldmaintain their biological activity is challenging and fewexamples known from the literature confirm that [4 6]
7 68Ga-Citrate
As mentioned above 68GaPET provides a number of advan-tages over 67GaSPECT and following publications demon-strate it in clinical and preclinical studies [68Ga]Ga-citratedemonstrated high diagnostic accuracy of 90of osteomyeli-tis and diskitis in clinical studies (Figure 6) [18 19] Thisstudy demonstrates that [68Ga]Ga-citrate can be employedfor monitoring the response to treatment [68Ga]Ga-citratewas used clinically to follow-up surgical intervention inpatients with acute osteomyelitis and intra-abdominal infec-tion [77] The agent was also used to successfully visualizelungmalignancy and tuberculosis in patients however in caseof high prevalence of granulomatous diseases the distinctionbetween malignant and benign lung lesions was unclear [7879] Another clinical study conducted head-to-head compar-ison of [68Ga]Ga-citrate (Figure 7) and [18F]FDG in patientswith Staphylococcus aureus bacteremia [80] The detectionrate of osteomyelitis was similar and further investigationof [68Ga]Ga-citrate applicability in cases of osteomyelitisinduced by other pathogens as well as for monitoring healingprocess is warranted
Comparative study of [68Ga]Ga-citrate and [67Ga]Ga-citrate was performed in healthy and infection model rats[77] The performance of [68Ga]Ga-citrate was found supe-rior in terms of image contrast in the lower abdomen and
extremities Potential of [68Ga]Ga-citrate for the differentia-tion of acute interstitial nephritis from acute tubular necrosiswas studied in rat model of the disease and it was demon-strated that the kidney uptake correlated with the extentof mononuclear cell infiltration accompanying inflammation[209] 68Ga-labelled Apo-transferrin demonstrated bacterialinfection detection capacity in rat model with Staphylococcusaureus wherein the infection site was visualized 1 h afteradministration of the agent [14]
71 Radiolabelled Antibodies and Antibody FragmentsHuman immunoglobulin (HIG) binds to bacteria but alsoaccumulates at the sites of fungal and viral infection aswell as sterile inflammation due to binding to leukocytesThe improved specificity for bacteria was achieved for thefragments of HIG It is feasible to develop specific antibodiesto various antigens present on the bacterial cell surface [102]Monoclonal antibodies labelled with 99mTc were used forinfection imaging via granulocytes targeting NCA-95 [210]Various cytokines of interleukin family (IL-1 IL-8) labelledwith 123I or 99mTc demonstrated accumulation in the sitesof infection in various animal models [111 112 211ndash214]Registered antigranulocyte radiopharmaceuticals suchas LeuTech Scintimun and Leukoscan are based on99mTc-labelled antibodies This experience can be translatedto 68Ga however either the size of the antibodies mustbe reduced or pretargeting techniques must be appliedin order to overcome the discrepancy between the shortphysical half-life of 68Ga and slow pharmacokinetics ofantibodies
12 Contrast Media amp Molecular Imaging
(a) (b) (c) (d)
Figure 6 [68Ga]Ga-citrate PETCT examination of a patient affected by acute osteomyelitis before (left panel) and after (right panel) surgicalcurettage showing uptake in the transaxial (a c) and 3D reconstruction images (b d red area) Absence of the uptake after the therapyconfirms complete response to the treatment Adapted from [19]
Figure 7 Vertebral osteomyelitis (spondylodiscitis red arrow-heads) and abscesses in the iliopsoas and paravertebral area (redarrows) were detected by [68Ga]Ga-citrate in a patient admittedto the hospital with back pain and general symptoms The PETacquisition was performed 88min after administration of 245MBqof [68Ga]Ga-citrate Adapted from [80]
72 Radiolabelled Biotin Biotin is a growth factor utilizedin many bacteria An 111In-labelled analogue of biotin wassuccessfully utilized for diagnosis of vertebral infections ina clinical study [215] It would be rational to explore therelevance of 68Ga-labelled analogues given the advantagesof 68Ga over 111In and promising [68Ga]Ga-DOTA-Biotinanalogues [216 217] developed for monitoring survival oftransplanted avidin-coated islets
8 Miscellaneous
Stable Ga(III) complex with thiosemicarbazones demon-strated antimicrobial effect against P aeruginosa and Calbicans due to most probably both displacement of essentialFe(III) with Ga(III) and thiosemicarbazones [101] Substitu-tion of the stable Ga(III) by radioactive 68Ga might result ina specific infection imaging agent
Selective imaging of Enterobacteriaceae using 2-[18F]-fluorodeoxysorbitol (18F-FDS)was demonstrated in amurine
myositis model [218] The uptake of 18F-FDS was correlatedwith bacterial burden moreover the agent differentiatedinfection from sterile inflammation Given the potential of68Ga for the labelling of small biologically active molecules[4] it might be plausible to develop a respective analoguewith added value of the advantages that 68Ga offers includingsimpler production chemistry lowered radiation dose repet-itive examination and accessibility at clinical centers withoutcyclotrons and remote from [18F]-FDG distribution sites Asmentioned above the poor access to bacteria aggregated ina biofilm might make the imaging task challenging Severalpeptide candidates with affinity for S aureus biofilm weredesigned and labelled with 68Ga [219] The resulting agentsdemonstrated binding in vitro however it was not possible toblock the binding with excess of the cold peptide
Ionic 68Ga was found superior to [18F]-FDG in infectiondetection in the rat model with diffuse osteomyelitis [220] Inanother study the uptake of ionic 68Ga was observed in theaortic plaques of atherosclerotic mice specifically at the sitesrich inmacrophages [221] However the slow blood clearanceof ionic 68Ga presents a limitation
Chronic inflammation is the major reason of fibro-sis [222] 68Ga-labelled SST analogue ([68Ga]Ga-DOTA-NOC) demonstrated uptake in pathogenic areas in patientsaffected by idiopathic pulmonary fibrosis with potentialfor monitoring response to treatment and drug develop-ment [62] Another clinical study using [68Ga]Ga-pentixaforalso showed potential of the agent for monitoring dis-ease activity and response to treatment in idiopathic pul-monary fibrosis [223] Peptide based agents CNO2A-PEG2-c[CPGRVMHGLHLGDDEGPC] and [68Ga]Ga-NODAGA-PEG2-c[CPGRVMHGLHLGDDEGPC] for the imaging andquantification of fibrosis by PET were developed and char-acterized preclinically showing fast clearance from normal
Contrast Media amp Molecular Imaging 13
tissue and blood and binding specificity [89] Dosimetrycalculations demonstrated possibility of six examinations peryear in humans assuring disease monitoring in longitudinalstudies and routine clinical setup [224]
Several hyaluronan conjugates of oligonucleotides target-ing CD44 positive cells were developed and tested in healthyrats sham-operated rats and rats with myocardial infarction[225]The uptake of the agents was higher for the latter groupand varied dependent on the difference in the oligonucleotidestructure
TLR2 and TLR4 expression levels in neutrophils werefound higher in individuals with bacterial and viral infectionsthan those in control samples There is a possibility that IL-4IL-8 IL-10 IL-12 and TNF-a might serve as biomarkers forinfections and that IL-2 IL-8 or IL-10 is potentially able todistinguish between bacterial and viral infections [22]
Mannosylated human serum albumin labelled with 68Gavia NOTA chelator moiety ([68Ga]Ga-NOTA-MSA) wastested in a rat model of myocarditis targetingmannose recep-tors expressed onmacrophages infiltratingmyocardium [66]The uptake in the diseased myocardium was considerablyhigher than that of the normal one and it was precludedby administration of excess of nonlabelled MSA indicatingbinding specificity The tracer build-up was also observed inthe organs of macrophage accumulation
[68Ga]Ga-DOTA was investigated for the quantificationof increased blood flow which is one of the key events ininflammation [226] The uptake kinetics of [68Ga]Ga-DOTAin the site of inflammation in rats with induced inflamma-tion correlated well with that of 15O-water suggesting highrelevance [68Ga]Ga-DOTA
9 Pretargeted Imaging
The half-life of 68Ga is shorter than that of 64Cu 67Ga 99mTc89Zr 111In and 123124125I and thus in contrast to the latterit is not compatible with slow pharmacokinetics of largemolecules such as antibodies and glycoproteins The rangeof antigen-specific antibodies relevant to inflammation andinfection is broad and a number of 99mTc-labelled antibodieswere used clinically [20 21 227] The respective range of68Ga-based agents could be similarThe solution to overcomethe incompatibility of half-life time frames could be eitherthe reduction of the antibody size or the application of thepretargeting concept
The history of the pretargeting concept spans threedecades predominantly in the field of oncology [228ndash230]It was developed to improve image contrast and dosimetryin immunoimaging and radioimmunotherapy when usingradiolabelled antibody ligands with slow pharmacokinetics[231] The arsenal of antibodies is vast and diverse encourag-ing extensive investment into development of techniques thatwould allow their exploration to the fullest Pretargeting con-siders at least two major steps wherein a functionalized anti-body is first administered for target localization and clearancefrom blood and normal tissue and thereafter a radiolabelledsmall molecule capable of binding to the functionalized
antibody due to high affinity or covalent interaction is admin-istered The key properties of the radiolabelled molecules arefast pharmacokinetic and clearance Several techniques havebeen developed for the realization of pretargeting conceptincluding avidinstreptavidin-biotin systems [216 217 232233] bispecific antibodies (bsmAb) with haptens [232 234ndash254] antibody-oligonucleotide conjugates with complemen-tary oligonucleotides [255] biorthogonal systems allowingcovalent chemical reactions in vivo (Figure 8)
The high affinity of biotin to avidin and streptavidinproteins was utilized clinically and preclinically in pretar-geting approach for the imaging and therapy of pancreaticadenocarcinoma [232] glioblastoma [256] and lymphoma[257] However this pretargeting technique may requirethree steps in order to eliminate the excess of antibody-(strept)avidin conjugate circulating in the blood and notbound to the target by adding clearing agent Anotherapplication of the technique was monitoring transplantationof islets of Langerhans in the treatment for type 1 diabetesmellitus wherein the cells or cellmimetics were conjugated to(strept)avidin prior to the transplantation [216 217] Severalanalogues of biotin comprising DOTA chelate moiety forlabelling with 68Ga and ethylene glycol linker of variouslength demonstrated the influence of the latter on the affinitytowards avidin
Particular example of hapten molecules is the ones com-prising histamine-succinyl-glycine (HSG) motif and chelatemoiety [251ndash253 258] for the complexationwith 68Ga Severalanalogues were developed for the imaging of carcinoem-bryonic antigen (CEA) pretargeted with anti-CEA bsmAb[254 259 260] and two clinical studies of medullary thyroidcarcinoma and breast carcinoma positive for CEA using68Ga-labelled hapten molecules and bsmAb were initiated[261]
Bioorthogonal reactions are fast regioselective requiringsmall reagent concentration and occurring under mild con-ditions often in aqueous solution and temperature below 37∘C[262 263] Amongst various biorthogonal reaction types thecycloaddition of tetrazines and various dienophiles referredto as inverse-electron-demandDiels-Alder (IEDDA) reactionis themost successful in the context of pretargeting Antibod-ies functionalized with trans-cyclooctene (TCO) and a radi-olabelled tetrazine that can interact in vivo based on IEDDAreaction were studied [264ndash267] In particular 68Ga-labelledtetrazine dextran demonstrated favorable pharmacokineticsin a healthy mouse [264] However the proof of concept is tobe performed in a xenografted animal Accumulation of anti-TAG72 [265] and anti-A33 [266] antibodies functionalizedwith TCO in mouse xenografts was visualized respectivelyby an 111In and 64Cu-labelled tetrazine analogues Anti-CA199 antibody-TCO in combination with 177Lu-labelledtetrazine demonstrated radiotherapeutic effect in pancreaticcancer murine model [267]
Thepretargeted imaging techniquesmay contribute to theexpansion of immuno-PET with 68Ga providing the intrinsicadvantages of 68Ga and PET As mentioned above mostof the developed radiolabelled counterparts of pretargetingtechniques have demonstrated promising results There are
14 Contrast Media amp Molecular Imaging
H
ON
NN
O
OO
OO
NH
NS
NH
ONH
O
HO
ONH
O
Ga
HN
NH
NH
O
OO
HNN
HN
NH
NH
O
OO
HNN
（2
(a)
NH
O
O
NH
N
NNGa
O O
O O
O
O
O
N N
NN
OO
（2
(b)
N
N
O
O
N
N
O
O
O
NH
O
O
ONH
NHS
O
H
HO
NH
+
minus
(c)
Figure 8 Schematic presentation of pretargeting techniques (a) bispecific antibodies engineered to specifically bind with radiolabelledhapten molecules (b) bioorthogonal click chemistry for fast and specific covalent binding between for example a trans-cyclooctenefunctionalized antibody and a radiolabelled tetrazine (c) interaction between antibody-(strept)avidin conjugate and radiolabelled biotinutilizing extremely high affinity of (strept)avidin and biotin
Contrast Media amp Molecular Imaging 15
a considerable number of potential antibody biomarkersthat could be considered for the imaging of infection andinflammation
10 Theranostics Potential
Theranostics [268] embraces realization of personalizedmedicine by conducting diagnosis on individual basis andproviding possibility of predicting the efficacy of a specifictreatment and following up the response to the treatmentenabling adjustment of the latter very early in the processIn the context of nuclear medicine wherein the radiophar-maceuticals targeted at biomarkers specific to a disease cancarry either diagnostic radionuclides or therapeutic ones theconcept can be denoted as radiotheranostics [28] The tar-geted molecular imaging such as PET can offer noninvasivediagnosis specific to the disease for example tumour-typespecific and provide accurate localization of the lesions Thestrongest advantage of PET is the potential for quantificationof the target for example receptor expression investigationof the uptake kinetics and estimation of the dosimetryThesecharacteristics of PET allow for individualized treatmentselection and planning monitoring of treatment responseand detection of recurrent diseaseThe individualized patientmanagement provides such advantages as optimization ofthe treatment regimen for the improved response and exclu-sion of futile treatments minimization of risks and toxicitywith overall outcome of reduced cost and patient distressThe importance of individualized patient management wasdemonstrated by clinical studies wherein the influence ofdose of the administered radiopharmaceutical targeted atreceptors overexpressed in cancer lesions on the diagnosticoutcome was investigated in the same patient [85 269270] 68Ga-labelled SST analogues [26ndash28 271] and Affibodymolecules [5 272ndash274] used respectively in NENs andbreast cancer patients are the most prominent examplesof (radio)theranostics involving 68GaPET wherein 68Ga-labelled analogues were used not only for localization of thelesions but also for staging patient stratification prognosistherapy selection and monitoring of the response to thetreatment of NETs and other cancer types [2ndash4 6 85 176275ndash277]
The methodology can be translated to inflammationand infection allowing for accurate and specific selection oftreatment regimen and for follow-up and evaluation of theresponse to therapy resulting in improved treatment efficacyand decreased cost and side effects The accommodation ofboth imaging function and antibiotic function in the samemolecule is a novel example of a theranostic agent [278]A series of siderophores conjugated with DOTA moiety forthe radiolabelling and with antibiotics for the treatmentof bacterial infection were investigated preclinically Theaccumulation of the intravenously administered ampicillinconjugate in the site of subcutaneously injected P aeruginosain mice was clearly and focally visualized within 06 h withretention for at least 24 h These results obtained usinganalogues carrying dye for optical imaging can be translatedto 68Ga-labelled counterparts for PET
11 Conclusions
The medical need for specific agents for noninvasive quan-titative and whole-body imaging of inflammation and infec-tion has not been met yet despite decades of research How-ever the prerequisites in terms of identification of potentialtargets design and synthesis of the respective ligands andimaging technologies are evolving very fast The potentialof accurate and quantitative lesion localization as well asmonitoring of the treatment response promises personalizedpatient management
The use of 68Ga in oncology is established proving thestrong potential of 68Ga for the promotion of PET technol-ogy for effective and efficient diagnostics and personalizedmedicineThe experience of oncological 68Ga-based agents isgetting translated to inflammation and infection Pretargetedimaging technology opens wide possibilities based on anti-body biomarkers
Conflicts of Interest
The author declares that there are no conflicts of interestregarding the publication of this article
References
[1] I Velikyan ldquoContinued rapid growth inGa applications update2013 to June 2014rdquo Journal of Labelled CompoundsampRadiophar-maceuticals pp 99ndash121 2015
[2] I Velikyan ldquo 68Ga-based radiopharmaceuticals Production andapplication relationshiprdquo Molecules vol 20 no 7 pp 12913ndash12943 2015
[3] M Fani P Peitl and I Velikyan ldquoCurrent status of radiophar-maceuticals for the theranostics of neuroendocrine neoplasmsrdquoPharmaceuticals vol 10 no 1 article no 30 2017
[4] I Velikyan ldquoPositron emitting [68Ga]Ga-based imaging agentsChemistry and diversityrdquoMedicinal Chemistry vol 7 no 5 pp345ndash379 2011
[5] J Sorensen I Velikyan D Sandberg et al ldquoMeasuringHER2-receptor expression in metastatic breast cancer using[68Ga]ABY-025 Affibody PETCTrdquo Theranostics vol 6 no 2pp 262ndash271 2016
[6] I Velikyan ldquoProspective of 68Ga-Radiopharmaceutical devel-opmentrdquoTheranostics vol 4 no 1 pp 47ndash80 2014
[7] P Lankinen T J Makinen T A Poyhonen et al ldquo68Ga-DOTAVAP-P1 PET imaging capable of demonstrating the phaseof inflammation in healing bones and the progress of infectionin osteomyelitic bonesrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 35 no 2 pp 352ndash364 2008
[8] T UjulaMHuttunen P Luoto et al ldquoMatrixmetalloproteinase9 targeting peptides Syntheses 68Ga-labeling and preliminaryevaluation in a rat melanoma xenograft modelrdquo BioconjugateChemistry vol 21 no 9 pp 1612ndash1621 2010
[9] A Autio T Ujula P Luoto S Salomaki S Jalkanen and ARoivainen ldquoPET imaging of inflammation and adenocarcinomaxenografts using vascular adhesion protein 1 targeting peptide68Ga-DOTAVAP-P1 Comparison with 18F-FDGrdquo EuropeanJournal of Nuclear Medicine and Molecular Imaging vol 37 no10 pp 1918ndash1925 2010
16 Contrast Media amp Molecular Imaging
[10] J Silvola A Autio P Luoto S Jalkanen andA Roivainen ldquoPre-liminary evaluation of novel 68Ga-DOTAVAP-PEG-P2 peptidetargeting vascular adhesion protein-1rdquo Clinical Physiology andFunctional Imaging vol 30 no 1 pp 75ndash78 2010
[11] T Ujula S Salomaki P Virsu et al ldquoSynthesis 68Ga labelingand preliminary evaluation of DOTA peptide binding vascularadhesion protein-1 a potential PET imaging agent for diagnos-ing osteomyelitisrdquo Nuclear Medicine and Biology vol 36 no 6pp 631ndash641 2009
[12] A Autio T Henttinen H J Sipila S Jalkanen and ARoivainen ldquoMini-PEG spacering of VAP-1-targeting 68Ga-DOTAVAP-P1 peptide improves PET imaging of inflamma-tionrdquo EJNMMI Research vol 1 no 1 pp 1ndash7 2011
[13] K Aalto A Autio E A Kiss et al ldquoSiglec-9 is a novel leukocyteligand for vascular adhesion protein-1 and can be used in PETimaging of inflammation and cancerrdquo Blood vol 118 no 13 pp3725ndash3733 2011
[14] V Kumar D K Boddeti S G Evans F Roesch and RHowman-Giles ldquoPotential use of 68Ga-apo-transferrin as a PETimaging agent for detecting Staphylococcus aureus infectionrdquoNuclear Medicine and Biology vol 38 no 3 pp 393ndash398 2011
[15] M Petrik H Haas G Dobrozemsky et al ldquo68Ga-siderophoresfor PET imaging of invasive pulmonary aspergillosis Proof ofprinciplerdquo Journal of Nuclear Medicine vol 51 no 4 pp 639ndash645 2010
[16] M Petrik H Haas M Schrettl A Helbok M Blatzer and CDecristoforo ldquoIn vitro and in vivo evaluation of selected 68Ga-siderophores for infection imagingrdquo Nuclear Medicine andBiology vol 39 no 3 pp 361ndash369 2012
[17] M Petrik GM Franssen H Haas et al ldquoPreclinical evaluationof two 68Ga-siderophores as potential radiopharmaceuticals forAspergillus fumigatus infection imagingrdquo European Journal ofNuclearMedicine andMolecular Imaging vol 39 no 7 pp 1175ndash1183 2012
[18] A Rizzello D Di Pierro F Lodi et al ldquoSynthesis and qualitycontrol of 68Ga citrate for routine clinical PETrdquo NuclearMedicine Communications vol 30 no 7 pp 542ndash545 2009
[19] C Nanni C Errani and L Boriani ldquo 68Ga-citrate PETCT forevaluating patients with infections of the bone preliminaryresultsrdquo Journal of Nuclear Medicine vol 51 no 12 pp 1932ndash1936 2010
[20] S S Das A V Hall D W Wareham and K E Britton ldquoInfec-tion imaging with radiopharmaceuticals in the 21st centuryrdquoBrazilian Archives of Biology and Technology vol 45 no spepp 25ndash37 2002
[21] A Signore and A W J M Glaudemans ldquoThe molecularimaging approach to image infections and inflammation bynuclear medicine techniquesrdquo Annals of Nuclear Medicine vol25 no 10 pp 681ndash700 2011
[22] T Yusa K Tateda A Ohara and S Miyazaki ldquoNew possiblebiomarkers for diagnosis of infections and diagnostic distinc-tion between bacterial and viral infections in childrenrdquo Journalof Infection and Chemotherapy vol 23 no 2 pp 96ndash100 2017
[23] A Signore A W J M Glaudemans O Gheysens C Lauriand O A Catalano ldquoNuclear Medicine Imaging in PediatricInfection or Chronic Inflammatory Diseasesrdquo Seminars inNuclear Medicine vol 47 no 3 pp 286ndash303 2017
[24] I Velikyan ldquoMolecular imaging and radiotherapyTheranosticsfor personalized patient managementrdquo Theranostics vol 2 no5 pp 424ndash426 2012
[25] F Rosch and R P Baum ldquoGenerator-based PET radiophar-maceuticals for molecular imaging of tumours On the way
to THERANOSTICSrdquo Dalton Transactions vol 40 no 23 pp6104ndash6111 2011
[26] R P Baum H R Kulkarni and C Carreras ldquoPeptides andreceptors in image-guided therapy Theranostics for neuroen-docrine neoplasmsrdquo Seminars in Nuclear Medicine vol 42 no3 pp 190ndash207 2012
[27] R P Baum and H R Kulkarni ldquoTheranostics From molecularimaging using Ga-68 labeled tracers and PETCT to per-sonalized radionuclide therapy - the bad berka experiencerdquoTheranostics vol 2 no 5 pp 437ndash447 2012
[28] I Velikyan ldquoRadionuclides for Imaging andTherapy in Oncol-ogyrdquo Cancer Theranostics pp 285ndash325 2014
[29] J Czernin andWAWeber ldquoIssues and controversies in nuclearmedicine Introductionrdquo Journal of Nuclear Medicine vol 52no Supplement 2 pp 1Sndash2S 2011
[30] S J Goldsmith and S Vallabhajosula ldquoClinically proven radio-pharmaceuticals for infection imaging mechanisms and appli-cationsrdquo Seminars in Nuclear Medicine vol 39 no 1 pp 2ndash102009
[31] M F Tsan ldquoMechanism of gallium-67 accumulation in inflam-matory lesionsrdquo Journal of Nuclear Medicine vol 26 no 1 pp88ndash92 1985
[32] S L Kipper ldquoRadiolabelled leukocyte imaging of the abdomenrdquoin Nuclear Medicine Annual J Freeman Ed pp 81ndash126 RavenPress New York NY USA 1995
[33] F Jamar J Buscombe A Chiti et al ldquoEANMSNMMI guidelinefor 18F-FDG use in inflammation and infectionrdquo Journal ofNuclear Medicine vol 54 no 4 pp 647ndash658 2013
[34] C J Palestro ldquoThe current role of gallium imaging in infectionrdquoSeminars in Nuclear Medicine vol 24 no 2 pp 128ndash141 1994
[35] M S Akhtar M B Imran M A Nadeem and A ShahidldquoAntimicrobial peptides as infection imaging agents better thanradiolabeled antibioticsrdquo International Journal of Peptides vol2012 Article ID 965238 19 pages 2012
[36] D Delbeke and G M Segall ldquoStatus of and trends in nuclearmedicine in the United Statesrdquo Journal of Nuclear Medicine vol52 no 2 2011
[37] S S Gambhir J Czernin J Schwimmer D H Silverman R EColeman and M E Phelps ldquoA tabulated summary of the FDGPET literaturerdquo Journal of Nuclear Medicine vol 42 pp 1Sndash93S2001
[38] M J Lindsay B A Siegel S R Tunis et al ldquoThe NationalOncologic PET Registry ExpandedMedicare coverage for PETunder coverage with evidence developmentrdquo American Journalof Roentgenology vol 188 no 4 pp 1109ndash1113 2007
[39] F Gemmel H Van Den Wyngaert C Love M M Welling PGemmel and C J Palestro ldquoProsthetic joint infectionsradionuclide state-of-the-art imagingrdquo European Journal ofNuclearMedicine andMolecular Imaging vol 39 no 5 pp 892ndash909 2012
[40] J Sorensen ldquoHow does the patient benefit from clinical PETrdquoTheranostics vol 2 no 5 pp 427ndash436 2012
[41] S L Rice C A Roney P Daumar and J S Lewis ldquoThe nextgeneration of positron emission tomography radiopharmaceu-ticals in oncologyrdquo Seminars in Nuclear Medicine vol 41 no 4pp 265ndash282 2011
[42] R LWahl JMHerman and E Ford ldquoThePromise and Pitfallsof Positron Emission Tomography and Single-Photon EmissionComputed Tomography Molecular Imaging-Guided RadiationTherapyrdquo Seminars in Radiation Oncology vol 21 no 2 pp 88ndash100 2011
Contrast Media amp Molecular Imaging 17
[43] A W J M Glaudemans R H J A Slart J M Van Dijl MVan Oosten and G M Van Dam ldquoMolecular imaging of infec-tious and inflammatory diseases A terra incognitardquo Journal ofNuclear Medicine vol 56 no 5 pp 659ndash661 2015
[44] X Li W Bauer I Israel et al ldquoTargeting p-selectin by gallium-68-labeled fucoidan positron emission tomography for nonin-vasive characterization of vulnerable plaques Correlation within vivo 176t mrirdquo Arteriosclerosis Thrombosis and VascularBiology vol 34 no 8 pp 1661ndash1667 2014
[45] S Eichendorff P Svendsen D Bender et al ldquoBiodistributionand PET Imaging of a Novel [68Ga]-Anti-CD163-AntibodyConjugate in Rats with Collagen-Induced Arthritis and inControlsrdquoMolecular Imaging and Biology vol 17 no 1 pp 87ndash93 2014
[46] Z Zhu Y Yin K Zheng et al ldquoEvaluation of synovial angiogen-esis in patients with rheumatoid arthritis using 68Ga-PRGD2PETCT A prospective proof-of-concept cohort studyrdquo Annalsof the Rheumatic Diseases vol 73 no 6 pp 1269ndash1272 2014
[47] J S Eo J C Paeng S Lee et al ldquoAngiogenesis imaging inmyocardial infarction using 68Ga-NOTA- RGD PET Charac-terization and application to therapeutic efficacy monitoring inratsrdquo Coronary Artery Disease vol 24 no 4 pp 303ndash311 2013
[48] J H Kim Y-H Kim Y J Kim et al ldquoQuantitative positronemission tomography imaging of angiogenesis in rats with fore-limb ischemia using 68Ga-NOTA-c(RGDyK)rdquo Angiogenesisvol 16 no 4 pp 837ndash846 2013
[49] I Laitinen J Notni K Pohle et al ldquoComparison of cyclicRGD peptides for 120572v1205733 integrin detection in a rat model ofmyocardial infarctionrdquo EJNMMI Research vol 3 no 1 pp 1ndash9 2013
[50] M Kiugel I Dijkgraaf V Kyto et al ldquoDimeric [68Ga]DOTA-RGD Peptide Targeting 120572 ltinfgtvltinfgt 120573 ltinfgt3ltinfgt Inte-grin Reveals Extracellular Matrix Alterations after MyocardialInfarctionrdquo Molecular Imaging and Biology vol 16 no 6 pp793ndash801 2014
[51] M Gronman M Tarkia T Kiviniemi et al ldquoImaging of 120572v1205733integrin expression in experimental myocardial ischemia with[68Ga]NODAGA-RGD positron emission tomographyrdquo Jour-nal of Translational Medicine vol 15 no 1 p 144 2017
[52] J Haukkala I Laitinen P Luoto et al ldquo68Ga-DOTA-RGDpep-tide Biodistribution and binding into atherosclerotic plaquesin micerdquo European Journal of Nuclear Medicine and MolecularImaging vol 36 no 12 pp 2058ndash2067 2009
[53] H Virtanen A Autio R Siitonen et al ldquo68Ga-DOTA-Siglec-9- a new imaging tool to detect synovitisrdquo Arthritis Research ampTherapy vol 17 no 1 article no 308 2015
[54] J Retamal J Sorensen M Lubberink et al ldquoFeasibility of(68) Ga-labeled Siglec-9 peptide for the imaging of acutelung inflammation a pilot study in a porcine model of acuterespiratory distress syndromerdquoAm JNuclMedMol Imaging vol6 no 1 pp 18ndash31 2016
[55] J M U Silvola H Virtanen R Siitonen et al ldquoLeukocytetrafficking-associated vascular adhesion protein 1 is expressedand functionally active in atherosclerotic plaquesrdquo ScientificReports vol 6 Article ID 35089 2016
[56] H Ahtinen J Kulkova L Lindholm et al ldquo68Ga-DOTA-Siglec-9 PETCT imaging of peri-implant tissue responses andstaphylococcal infectionsrdquo EJNMMI Research vol 4 no 1article no 45 pp 1ndash11 2014
[57] A Autio S Jalkanen and A Roivainen ldquoNuclear imaging ofinflammation Homing-associated molecules as targetsrdquo EJN-MMI Research vol 3 no 1 pp 1ndash7 2013
[58] J TThackeray T Derlin AHaghikia et al ldquoMolecular Imagingof the Chemokine Receptor CXCR4 after Acute MyocardialInfarctionrdquo JACC Cardiovascular Imaging vol 8 no 12 pp1417ndash1426 2015
[59] J S Schmid A Schirbel A K Buck S Kropf H-J Westerand C Lapa ldquoPentixafor-Positron Emission TomographyComputed Tomography Detects Chemokine Receptor CXCR4Expression after Ischemic Strokerdquo Circulation CardiovascularImaging vol 9 no 9 Article ID e005217 2016
[60] J Zhou G Hao H Weng et al ldquoIn vivo evaluation ofmedical device-associated inflammation using a macrophage-specific positron emission tomography (PET) imaging proberdquoBioorganic amp Medicinal Chemistry Letters vol 23 no 7 pp2044ndash2047 2013
[61] S A Kularatne M-J Belanger X Meng et al ldquoComparativeanalysis of folate derived PET imaging agents with [ 18F]-2-fluoro-2-deoxy-d-glucose using a rodent inflammatory pawmodelrdquo Molecular Pharmaceutics vol 10 no 8 pp 3103ndash31112013
[62] V Ambrosini M Zompatori F De Luca et al ldquo68Ga-DOTANOCPETCTAllows Somatostatin Receptor Imaging inIdiopathic Pulmonary Fibrosis Preliminary Resultsrdquo Journal ofNuclear Medicine vol 51 no 12 pp 1950ndash1955 2010
[63] T Lincke J Singer R Kluge O Sabri and R Paschke ldquoRela-tive quantification of indium-111 pentetreotide and gallium-68DOTATOC uptake in the thyroid gland and association withthyroid pathologiesrdquoThyroid vol 19 no 4 pp 381ndash389 2009
[64] A Rominger T Saam E Vogl et al ldquoIn vivo imaging ofmacrophage activity in the coronary arteries using 68Ga-DOTATATE PETCT correlation with coronary calcium bur-den and risk factorsrdquo Journal of Nuclear Medicine vol 51 no 2pp 193ndash197 2010
[65] J M Tarkin F R Joshi N R Evans et al ldquoDetection ofAtherosclerotic Inflammation by 68Ga-DOTATATE PET Com-pared to [18F]FDG PET Imagingrdquo Journal of the AmericanCollege of Cardiology vol 69 no 14 pp 1774ndash1791 2017
[66] S-P Lee H-J Im S Kang et al ldquoNoninvasive imaging ofmyocardial inflammation in myocarditis using 68Ga-taggedmannosylated human serum albumin positron emissiontomographyrdquoTheranostics vol 7 no 2 pp 413ndash424 2017
[67] Z Zha J Song S R Choi et al ldquo68Ga-Bivalent PolypegylatedStyrylpyridine Conjugates for Imaging A120573 Plaques in CerebralAmyloid Angiopathyrdquo Bioconjugate Chemistry vol 27 no 5 pp1314ndash1323 2016
[68] H Watanabe M Ono S Iikuni et al ldquoA 68Ga complex basedon benzofuran scaffold for the detection of 120573-amyloid plaquesrdquoBioorganic amp Medicinal Chemistry Letters vol 24 no 20 pp4834ndash4837 2014
[69] D Cressier M Dhilly T T Cao Pham et al ldquoGallium-68 Com-plexes Conjugated to Pittsburgh Compound B Radiolabelingand Biological EvaluationrdquoMolecular Imaging and Biology vol18 no 3 pp 334ndash343 2016
[70] D Satpati CArjun R KrishnamohanG Samuel and S Baner-jee ldquo68Ga-labeledCiprofloxacinConjugates as Radiotracers forTargeting Bacterial InfectionrdquoChemical Biology ampDrug Designvol 87 no 5 pp 680ndash686 2016
[71] T Ebenhan N Chadwick and M M Sathekge ldquoPeptidesynthesis characterization and 68Ga-radiolabeling of NOTA-conjugated ubiquicidin fragments for prospective infectionimaging with PETCTrdquo Nuclear Medicine and Biology vol 41no 5 pp 390ndash400 2014
18 Contrast Media amp Molecular Imaging
[72] T Ebenhan J R Zeevaart and J D Venter ldquoPreclinicalevaluation of 68Ga-labeled 1 4 7-triazacyclononane-1 4 7-triacetic acid-ubiquicidin as a radioligand for PET infectionimagingrdquo Journal of Nuclear Medicine vol 55 no 2 pp 308ndash314 2014
[73] B B Mokaleng T Ebenhan S Ramesh et al ldquoSynthesis 68Ga-radiolabeling and preliminary in vivo assessment of adepsipeptide-derived compound as a potential PETCTinfection imaging agentrdquo BioMed Research International vol2015 Article ID 284354 2015
[74] T Ebenhan B Mokaleng J Venter H Kruger J Zeevaart andM Sathekge ldquoPreclinical Assessment of a 68Ga-DOTA-Functionalized Depsipeptide as a Radiodiagnostic InfectionImaging AgentrdquoMolecules vol 22 no 9 p 1403 2017
[75] S Chopra B Singh A Koul A Mishra and H Wester ldquoSyn-thesis of DOTA conjugated GF-17 and RAWVAWR-NH2 andradiolabeling with 68Ga as a potential PET tracer for infectionimagingrdquo J Nucl Med vol 57 Supplement 2 p 1115 2016
[76] M Petrik HHaas P Laverman et al ldquo 68Ga-triacetylfusarinineC and 68Ga-ferrioxamine e for aspergillus infection imaginguptake specificity in various microorganismsrdquoMolecular Imag-ing and Biology vol 16 no 1 pp 102ndash108 2014
[77] V Kumar and D K Boddeti ldquo 68Ga-radiopharmaceuticals forPET imaging of infection and inflammationrdquo Recent Results inCancer Research vol 194 pp 189ndash219 2013
[78] M Vorster A Maes A Jacobs et al ldquoEvaluating the possiblerole of 68Ga-citrate PETCT in the characterization of indeter-minate lung lesionsrdquo Annals of Nuclear Medicine vol 28 no 6pp 523ndash530 2014
[79] M Vorster B Mokaleng M M Sathekge and T Ebenhan ldquoAmodified technique for efficient radiolabeling of 68Ga-citratefrom a SnO2-based 68Ge68Ga generator for better infectionimagingrdquoHellenic Journal of Nuclear Medicine vol 16 no 3 pp193ndash198 2013
[80] S Salomaeki J Kemppainen U Hohenthal et al ldquoHead-to-head comparison of 68Ga-Citrate and 18F-FDG PETCT fordetection of infectious foci in patients with staphylococcusaureus bacteraemiardquo Contrast Media amp Molecular Imaging vol2017 p 8 2017
[81] L Fass ldquoImaging and cancer a reviewrdquoMolecular Oncology vol2 no 2 pp 115ndash152 2008
[82] A Chopra L Shan W C Eckelman et al ldquoMolecular imagingand contrast agent database (MICAD) Evolution and progressrdquoMolecular Imaging and Biology vol 14 no 1 pp 4ndash13 2012
[83] A Sanchez-Crespo P Andreo and S A Larsson ldquoPositronflight in human tissues and its influence on PET image spatialresolutionrdquo European Journal of Nuclear Medicine and Molecu-lar Imaging vol 31 no 1 pp 44ndash51 2004
[84] H W A M De Jong L Perk G W M Visser R Boellaard GAM S Van Dongen and A A Lammertsma ldquoHigh resolutionPET imaging characteristics of68Ga 124i and89Zr comparedto18Frdquo in Proceedings of the Nuclear Science Symposium Con-ference Record 2005 IEEE pp 1624ndash1627 Puerto Rico October2005
[85] I Velikyan A Sundin B Eriksson et al ldquoIn vivo bindingof [68Ga]-DOTATOC to somatostatin receptors in neuroen-docrine tumours - impact of peptide massrdquo Nuclear Medicineand Biology vol 37 no 3 pp 265ndash275 2010
[86] U Eberlein and M Lassmann ldquoDosimetry of [68Ga]-labeledcompoundsrdquo Applied Radiation and Isotopes vol 76 pp 70ndash742013
[87] C PettinatoA SarnelliMDiDonna et al ldquo68Ga-DOTANOCBiodistribution and dosimetry in patients affected by neuroen-docrine tumorsrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 35 no 1 pp 72ndash79 2008
[88] B P Burke G S Clemente and S J Archibald ldquoRecentadvances in chelator design and labelling methodology for68Ga radiopharmaceuticalsrdquo Journal of Labelled Compoundsand Radiopharmaceuticals vol 57 no 4 pp 239ndash243 2014
[89] I Velikyan U Rosenstrom S Estrada et al ldquoSynthesis andpreclinical evaluation of 68Ga-labeled collagelin analogs forimaging and quantification of fibrosisrdquo Nuclear Medicine andBiology vol 41 no 9 pp 728ndash736 2014
[90] M F Ferreira G Pereira J P Andre and etal C ldquoGa[NO2A-N-(120572-amino)propionate] chelates Synthesis and evaluation aspotential tracers for 68Ga PETrdquoDalton Transactions vol 43 no21 pp 8037ndash8047 2014
[91] J Notni J Simecek and H-J Wester ldquoPhosphinic acid func-tionalized polyazacycloalkane chelators for radiodiagnosticsand radiotherapeutics Unique characteristics and applicationsrdquoChemMedChem vol 9 no 6 pp 1107ndash1115 2014
[92] J Simecek O Zemek P Hermann J Notni and H J WesterldquoTailored gallium( III) chelator NOPO synthesis characteriza-tion bioconjugation and application in preclinical Ga-68-PETimagingrdquoMolecular Pharmaceutics 2013
[93] D Parker B P Waldron and D S Yufit ldquoCrystallographicand solution NMR structural analyses of four hexacoordinatedgallium(iii) complexes based on ligands derived from 6-amino-perhydro-14-diazepinerdquo Dalton Transactions vol 42 no 22pp 8001ndash8008 2013
[94] B P Waldron D Parker C Burchardt D S Yufit M ZimnyandF Roesch ldquoStructure and stability of hexadentate complexesof ligands based on AAZTA for efficient PET labelling withgallium-68rdquo Chemical Communications vol 49 no 6 pp 579ndash581 2013
[95] D Parker and B PWaldron ldquoConformational analysis and syn-thetic approaches to polydentate perhydro-diazepine ligandsfor the complexation of gallium(iii)rdquo Organic amp BiomolecularChemistry vol 11 no 17 pp 2827ndash2838 2013
[96] I Velikyan H Maecke and B Langstrom ldquoConvenient prepa-ration of 68Ga-based PET-radiopharmaceuticals at room tem-peraturerdquo Bioconjugate Chemistry vol 19 no 2 pp 569ndash5732008
[97] J Erchegyi R Cescato B Waser J E Rivier and J C ReubildquoN-Imidazolebenzyl-histidine substitution in somatostatin andin its octapeptide analogue modulates receptor selectivity andfunctionrdquo Journal of Medicinal Chemistry vol 54 no 17 pp5981ndash5987 2011
[98] R Saha N Saha R S Donofrio and L L Bestervelt ldquoMicrobialsiderophores Amini reviewrdquo Journal of Basic Microbiology vol53 no 4 pp 303ndash317 2013
[99] V Nikolova S Angelova N Markova and T Dudev ldquoGalliumas a Therapeutic Agent A Thermodynamic Evaluation of theCompetition between Ga3+ and Fe3+ Ions in MetalloproteinsrdquoThe Journal of Physical Chemistry B vol 120 no 9 pp 2241ndash2248 2016
[100] C R Chitambar ldquoGallium and its competing roles with ironin biological systemsrdquo Biochimica et Biophysica Acta (BBA) -Molecular Cell Research vol 1863 no 8 pp 2044ndash2053 2016
[101] J A Lessa M A Soares and R G dos Santos ldquoGallium(III)complexes with 2-acetylpyridine-derived thiosemicarbazonesantimicrobial and cytotoxic effects and investigation on theinteractions with tubulinrdquo BioMetals vol 26 pp 151ndash165 2013
Contrast Media amp Molecular Imaging 19
[102] M van Oosten M Hahn L M A Crane et al ldquoTargetedimaging of bacterial infections Advances hurdles and hopesrdquoFEMS Microbiology Reviews vol 39 no 6 pp 892ndash916 2015
[103] M Vorster AMaes C V DWiele andM Sathekge ldquoGallium-68 PET A Powerful Generator-based Alternative to Infectionand Inflammation Imagingrdquo Seminars in Nuclear Medicine vol46 no 5 pp 436ndash447 2016
[104] M Kircher and C Lapa ldquoNovel Noninvasive Nuclear MedicineImaging Techniques for Cardiac Inflammationrdquo Current Car-diovascular Imaging Reports vol 10 no 2 article no 6 2017
[105] D AHammoud ldquoMolecular imaging of inflammation Currentstatusrdquo Journal of Nuclear Medicine vol 57 no 8 pp 1161ndash11652016
[106] D R Brenner D Scherer K Muir et al ldquoA review of the appli-cation of inflammatory biomarkers in epidemiologic cancerresearchrdquo Cancer Epidemiology Biomarkers amp Prevention vol23 no 9 pp 1729ndash1751 2014
[107] M D Turner B Nedjai T Hurst and D J PenningtonldquoCytokines and chemokines at the crossroads of cell signallingand inflammatory diseaserdquo Biochimica et Biophysica Acta (BBA)- Molecular Cell Research vol 1843 no 11 pp 2563ndash2582 2014
[108] L Werner H Guzner-Gur and I Dotan ldquoInvolvement ofCXCR4CXCR7CXCL12 interactions in inflammatory boweldiseaserdquoTheranostics vol 3 no 1 pp 40ndash46 2013
[109] S Jalkanen and M Salmi ldquoVAP-1 and CD73 endothelial cellsurface enzymes in leukocyte extravasationrdquo ArteriosclerosisThrombosis and Vascular Biology vol 28 no 1 pp 18ndash26 2008
[110] G Malviya F Galli I Sonni and A Signore ldquoImaging T-lymphocytes in inflammatory diseases A nuclear medicineapproachrdquo The Quarterly Journal of Nuclear Medicine andMolecular Imaging vol 58 no 3 pp 237ndash257 2014
[111] S Gratz H J RennenO C BoermanW J Oyen and P Burmaldquo(99m)Tc-interleukin-8 for imaging acute osteomyelitisrdquo Jour-nal of Nuclear Medicine vol 42 no 8 pp 1257ndash1264 2001
[112] S Gratz H J Rennen O C Boerman W J Oyen andF H Corstens ldquoRapid imaging of experimental colitis with(99m)Tc-interleukin-8 in rabbitsrdquo Journal of Nuclear Medicnevol 42 no 6 pp 917ndash923 2001
[113] C Alkim H Alkim A R Koksal S Boga and I SenldquoAngiogenesis in inflammatory bowel diseaserdquo InternationalJournal of Inflammation vol 2015 Article ID 970890 2015
[114] I S Alam T H Witney G Tomasi et al ldquoRadiolabeled RGDtracer kinetics annotates differential 120572v1205733 integrin expressionlinked to cell intrinsic and vessel expressionrdquoMolecular Imagingand Biology vol 16 no 4 pp 558ndash566 2014
[115] J Notni K Pohle and H-J Wester ldquoBe spoilt for choice withradiolabelled RGD peptides Preclinical evaluation of 68Ga-TRAP(RGD)3rdquoNuclear Medicine and Biology vol 40 no 1 pp33ndash41 2013
[116] J Oxboel M Brandt-Larsen C Schjoeth-Eskesen et al ldquoCom-parison of two new angiogenesis PET tracers 68Ga-NODAGA-E[c(RGDyK)]2 and 64Cu-NODAGA-E[c(RGDyK)]2 in vivoimaging studies in human xenograft tumorsrdquo Nuclear Medicineand Biology vol 41 no 3 pp 259ndash267 2014
[117] J Simecek J Notni T G Kapp H Kessler and H-J WesterldquoBenefits of NOPO as chelator in gallium-68 peptides exempli-fied by preclinical characterization of 68Ga-NOPO-c(RGDfK)rdquoMolecular Pharmaceutics vol 11 no 5 pp 1687ndash1695 2014
[118] M Trajkovic-Arsic P Mohajerani A Sarantopoulos et alldquoMultimodal molecular imaging of integrin avb3 for in vivodetection of pancreatic cancerrdquo Journal of NuclearMedicine vol55 no 3 pp 446ndash451 2014
[119] H Cai and P S Conti ldquoRGD-based PET tracers for imagingreceptor integrin 120572 v1205733 expressionrdquo Journal of Labelled Com-pounds and Radiopharmaceuticals vol 56 no 5 pp 264ndash2792013
[120] I Dijkgraaf S Y A Terry W J Mcbride et al ldquoImagingintegrin alpha-v-beta-3 expression in tumors with an 18F-labeled dimeric RGD peptiderdquo Contrast Media amp MolecularImaging vol 8 no 3 pp 238ndash245 2013
[121] P A Knetsch M Petrik C Rangger et al ldquo[68Ga]NS3-RGD and [68Ga] Oxo-DO3A-RGD for imaging 120572v1205733 integrinexpression Synthesis evaluation and comparisonrdquo NuclearMedicine and Biology vol 40 no 1 pp 65ndash72 2013
[122] Z Liu and F Wang ldquoDevelopment of RGD-based radiotracersfor tumor imaging and therapy Translating from bench tobedsiderdquo Current Molecular Medicine vol 13 no 10 pp 1487ndash1505 2013
[123] H Choi J H Phi J C Paeng et al ldquoImaging of integrin 120572v1205733expression using 68Ga-RGD positron emission tomography inpediatric cerebral infarctrdquoMolecular Imaging vol 12 no 4 pp213ndash217 2013
[124] H-J Yoon K W Kang I K Chun et al ldquoCorrelation of breastcancer subtypes based on estrogen receptor progesteronereceptor and HER2 with functional imaging parameters from68Ga-RGD PETCT and 18F-FDG PETCTrdquo European Journalof Nuclear Medicine and Molecular Imaging vol 41 no 8 pp1534ndash1543 2014
[125] R P Baum H R Kulkarni D Muller et al ldquoFirst-in-human study demonstrating tumor-angiogenesis by PETCTimaging with 68Ga-NODAGA-THERANOST a high-affinitypeptidomimetic for 120572v1205733 integrin receptor targetingrdquo CancerBiotherapy andRadiopharmaceuticals vol 30 no 4 pp 152ndash1592015
[126] R Haubner A Finkenstedt A Stegmayr et alldquo[68Ga]NODAGA-RGD ndash Metabolic stability biodistributionand dosimetry data from patients with hepatocellularcarcinoma and liver cirrhosisrdquo European Journal of NuclearMedicine and Molecular Imaging vol 43 no 11 pp 2005ndash20132016
[127] V Lopez-Rodrıguez C Galindo-Sarco F O Garcıa-Perez GFerro-Flores O Arrieta and M A Avila-Rodrıguez ldquoPET-based human dosimetry of the dimeric 120572v1205733 integrin ligand68Ga-DOTA-E-[c(RGDfK)]2 a potential tracer for imagingtumor angiogenesisrdquo Journal of Nuclear Medicine vol 57 no 3pp 404ndash409 2016
[128] M V Backer Z Levashova V Patel et al ldquoMolecular imagingof VEGF receptors in angiogenic vasculature with single-chainVEGF-based probesrdquo Nature Medicine vol 13 no 4 pp 504ndash509 2007
[129] MV Backer Z Levashova R Levenson F G Blankenberg andJ M Backer ldquoCysteine-containing fusion tag for site-specificconjugation of therapeutic and imaging agents to targetingproteinsrdquoMethods in Molecular Biology (Clifton NJ) vol 494pp 275ndash294 2008
[130] M Eder A V Krivoshein M Backer J M Backer UHaberkorn and M Eisenhut ldquoScVEGF-PEG-HBED-CC andscVEGF-PEG-NOTA conjugates comparison of easy-to-labelrecombinant proteins for [68Ga]PET imaging of VEGF recep-tors in angiogenic vasculaturerdquo Nuclear Medicine and Biologyvol 37 no 4 pp 405ndash412 2010
[131] E Blom I Velikyan A Monazzam P Razifar et al ldquoSynthe-sis and characterization of scVEGF-PEG-[ 68Ga]NOTA andscVEGF-PEG-[ 68Ga]DOTA PET tracersrdquo Journal of Labelled
20 Contrast Media amp Molecular Imaging
Compounds and Radiopharmaceuticals vol 54 no 11 pp 685ndash692 2011
[132] S Gratz M Behe and O C Boerman ldquo 99119898Tc-E-selectinbinding peptide for imaging acute osteomyelitis in a novel ratmodelrdquo Nuclear Medicine Communications vol 22 no 9 pp1003ndash1013 2001
[133] S B Jensen M Kakela L Joslashdal et al ldquoExploring the radiosyn-thesis and in vitro characteristics of [68Ga]Ga-DOTA-Siglec-9rdquoJournal of Labelled Compounds and Radiopharmaceuticals vol60 no 9 pp 439ndash449 2017
[134] B A Teicher and S P Fricker ldquoCXCL12 (SDF-1)CXCR4pathway in cancerrdquo Clinical Cancer Research vol 16 no 11 pp2927ndash2931 2010
[135] O Jacobson I D Weiss D O Kiesewetter J M Farber andX Chen ldquoPET of tumor CXCR4 expression with 4-18F-T140rdquoJournal of Nuclear Medicine vol 51 no 11 pp 1796ndash1804 2010
[136] A Aghanejad A R Jalilian Y Fazaeli et al ldquoSynthesis andevaluation of [67Ga]-AMD3100 A novel imaging agent fortargeting the chemokine receptorCXCR4rdquo Scientia Pharmaceu-tica vol 82 no 1 pp 29ndash42 2014
[137] O Jacobson I D Weiss L P Szajek et al ldquoPET imaging ofCXCR4 using copper-64 labeled peptide antagonistrdquoTheranos-tics vol 1 pp 251ndash262 2011
[138] O Jacobson I D Weiss L P Szajek et al ldquoImprovement ofCXCR4 tracer specificity for PET imagingrdquo Journal of Con-trolled Release vol 157 no 2 pp 216ndash223 2012
[139] H J Wester U Keller M Schottelius et al ldquoDisclosing theCXCR4 expression in lymphoproliferative diseases by targetedmolecular imagingrdquo Theranostics vol 5 no 6 pp 618ndash6302015
[140] E Gourni O Demmer M Schottelius et al ldquoPET of CXCR4expression by a 68Ga-labeled highly specific targeted contrastagentrdquo Journal of NuclearMedicine vol 52 no 11 pp 1803ndash18102011
[141] O Demmer I Dijkgraaf U Schumacher et al ldquoDesignsynthesis and functionalization of dimeric peptides targetingchemokine receptor CXCR4rdquo Journal of Medicinal Chemistryvol 54 no 21 pp 7648ndash7662 2011
[142] O Demmer E Gourni U Schumacher H Kessler and H-JWester ldquoPET Imaging of CXCR4 Receptors in Cancer by a NewOptimized Ligandrdquo ChemMedChem vol 6 no 10 pp 1789ndash1791 2011
[143] U Hennrich L Seyler M Schafer et al ldquoSynthesis and invitro evaluation of 68Ga-DOTA-4-FBn-TN14003 a novel tracerfor the imaging of CXCR4 expressionrdquo Bioorganic amp MedicinalChemistry vol 20 no 4 pp 1502ndash1510 2012
[144] G P C George E Stevens O Aberg et al ldquoPreclinical evalua-tion of a CXCR4-specific 68Ga-labelled TN14003 derivative forcancer PET imagingrdquo Bioorganic amp Medicinal Chemistry vol22 no 2 pp 796ndash803 2014
[145] S Poty E Gourni P Desogere et al ldquoAMD3100 A VersatilePlatform for CXCR4 Targeting 68Ga-Based Radiopharmaceu-ticalsrdquo Bioconjugate Chemistry vol 27 no 3 pp 752ndash761 2016
[146] K Philipp-Abbrederis K Herrmann S Knop et al ldquoIn vivomolecular imaging of chemokine receptor CXCR4 expressionin patients with advancedmultiple myelomardquo EMBOMolecularMedicine vol 7 no 4 pp 477ndash487 2015
[147] Z Wang M Zhang L Wang et al ldquoProspective study of 68Ga-NOTA-NFB Radiation dosimetry in healthy volunteers andfirst application in glioma patientsrdquo Theranostics vol 5 no 8pp 882ndash889 2015
[148] I M Jackson P J Scott and S Thompson ldquoClinical Applica-tions of Radiolabeled Peptides for PETrdquo Seminars in NuclearMedicine vol 47 no 5 pp 493ndash523 2017
[149] C Lapa T Reiter R A Werner et al ldquo[68Ga]Pentixafor-PETCT for Imaging of Chemokine Receptor 4 Expression afterMyocardial Infarctionrdquo JACC Cardiovascular Imaging vol 8no 12 pp 1466ndash1468 2015
[150] C Rischpler S G Nekolla H Kossmann et al ldquoUpregu-lated myocardial CXCR4-expression after myocardial infarc-tion assessed by simultaneous GA-68 pentixafor PETMRIrdquoJournal of Nuclear Cardiology vol 23 no 1 pp 131ndash133 2016
[151] F Hyafil J Pelisek I Laitinen et al ldquoImaging the CytokineReceptorCXCR4 in atherosclerotic plaqueswith the radiotracer68Ga-Pentixafor for PETrdquo Journal of Nuclear Medicine vol 58no 3 pp 499ndash506 2017
[152] Y Yi ldquoFolate receptor-targeted diagnostics and therapeutics forinflammatory diseasesrdquo ImmuneNetwork vol 16 no 6 pp 337ndash343 2016
[153] C M Paulos M J Turk G J Breur and P S Low ldquoFolatereceptor-mediated targeting of therapeutic and imaging agentsto activated macrophages in rheumatoid arthritisrdquo AdvancedDrug Delivery Reviews vol 56 no 8 pp 1205ndash1217 2004
[154] W Han R Zaynagetdinov F E Yull et al ldquoMolecular imagingof folate receptor 120573-positive macrophages during acute lunginflammationrdquo American Journal of Respiratory Cell and Molec-ular Biology vol 53 no 1 pp 50ndash59 2015
[155] B Kuhle C Muller and T L Ross ldquoA Novel 68Ga-Labeledpteroic acid-based PET tracer for tumor imaging via the folatereceptorrdquo Recent Results in Cancer Research vol 194 pp 257ndash267 2013
[156] C Brand V A Longo M Groaning W A Weber and TReiner ldquoDevelopment of a New Folate-Derived Ga-68-BasedPET Imaging AgentrdquoMolecular Imaging and Biology vol 19 no5 pp 754ndash761 2017
[157] M Fani XWang G Nicolas et al ldquoDevelopment of new folate-based PET radiotracers Preclinical evaluation of 68Ga-DOTA-folate conjugatesrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 38 no 1 pp 108ndash119 2011
[158] C J Mathias M R Lewis D E Reichert et al ldquoPreparationof 66Ga- and 68Ga-labeled Ga(III)-deferoxamine-folate aspotential folate-receptor-targeted PET radiopharmaceuticalsrdquoNuclear Medicine and Biology vol 30 no 7 pp 725ndash731 2003
[159] S-M Kim N Choi S Hwang et al ldquoFolate receptor-specific positron emission tomography imaging with folic acid-conjugated tissue inhibitor of metalloproteinase-2rdquo Bulletin ofthe Korean Chemical Society vol 34 no 11 pp 3243ndash3248 2013
[160] M Fani M-L Tamma G P Nicolas et al ldquoIn vivo imagingof folate receptor positive tumor xenografts using novel 68Ga-NODAGA-folate conjugatesrdquo Molecular Pharmaceutics vol 9no 5 pp 1136ndash1145 2012
[161] C Muller and R Schibli ldquoProspects in folate receptor-targetedradionuclide therapyrdquo Frontiers in Oncology vol 3 Article IDArticle 249 2013
[162] A Jain A Mathur U Pandey et al ldquoSynthesis and evaluationof a 68Ga labeled folic acid derivative for targeting folatereceptorsrdquo Applied Radiation and Isotopes vol 116 pp 77ndash842016
[163] W Xia A R Hilgenbrink E L Matteson M B Lockwood J-X Cheng and P S Low ldquoA functional folate receptor is inducedduring macrophage activation and can be used to target drugsto activated macrophagesrdquo Blood vol 113 no 2 pp 438ndash4462009
Contrast Media amp Molecular Imaging 21
[164] E P Krenning W A P Breeman P P M Kooij et alldquoLocalisation of endocrine-related tumours with radioiodi-nated analogue of somatostatinrdquoThe Lancet vol 1 no 8632 pp242ndash244 1989
[165] E P Krenning D J KwekkeboomWH Bakker et al ldquoSomato-statin receptor scintigraphy with [111In-DTPA-d-Phe1]- and[123I-Tyr3]-octreotide the Rotterdam experience with morethan 1000 patientsrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 20 no 8 pp 716ndash731 1993
[166] A Stahl G Meisetschlager M Schottelius et al ldquo[123I]Mtr-TOCA a radioiodinated and carbohydrated analogue ofoctreotide Scintigraphic comparison with [111In]octreotiderdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 33 no 1 pp 45ndash52 2006
[167] R Lebtahi J le Cloirec C Houzard et al ldquoDetection of neu-roendocrine tumors 99mTc-P829 scintigraphy compared with111In-pentetreotide scintigraphyrdquo Journal of Nuclear Medicinevol 43 no 7 pp 889ndash895 2002
[168] C Decristoforo T Maina B Nock M Gabriel P Cordopatisand R Moncayo ldquo99mTc-demotate 1 First data in tumourpatients - Results of a pilotphase I studyrdquo European Journal ofNuclearMedicine andMolecular Imaging vol 30 no 9 pp 1211ndash1219 2003
[169] C Decristoforo S J Mather W Cholewinski E DonnemillerG Riccabona and R Moncayo ldquo(99m)Tc-EDDAHYNIC-TOC A new (99m)Tc-labelled radiopharmaceutical forimaging somatostatin receptor-positive tumours First clinicalresults and intra-patient comparison with 111In-labelledoctreotide derivativesrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 27 no 9 pp 1318ndash1325 2000
[170] A Hubalewska-Dydejczyk K Fross-Baron R Mikołajczak etal ldquo99mTc-EDDAHYNIC-octreotate scintigraphy an efficientmethod for the detection and staging of carcinoid tumoursResults of 3 yearsrsquo experiencerdquo European Journal of NuclearMedicine and Molecular Imaging vol 33 no 10 pp 1123ndash11332006
[171] M Bangard M Behe S Guhlke et al ldquoDetection of somato-statin receptor-positive tumours using the new 99mC-tricine-HYNIC-D-Phe1-Tyr3-octreotide First results in patients andcomparison with 111In-DTPA-D-Phe1-octreotiderdquo EuropeanJournal of Nuclear Medicine and Molecular Imaging vol 27 no6 pp 628ndash637 2000
[172] A Helisch G J Forster H Reber et al ldquoPre-therapeuticdosimetry and biodistribution of 86Y-DOTA- Phe1-Tyr3-octreotide versus 111In-pentetreotide in patients with advancedneuroendocrine tumoursrdquo European Journal of NuclearMedicine and Molecular Imaging vol 31 no 10 pp 1386ndash13922004
[173] M Henze J Schuhmacher P Hipp et al ldquoPET imaging ofsomatostatin receptors using [68GA]DOTA-D-Phe1-Tyr3-Octreotide First results in patients with meningiomasrdquo Journalof Nuclear Medicine vol 42 no 7 pp 1053ndash1056 2001
[174] I Kayani J B Bomanji A Groves et al ldquoFunctional imaging ofneuroendocrine tumors with combined PETCT using 68Ga-DOTATATE (Dota-DPhe1 Tyr3-octreotate) and 18F-FDGrdquoCancer vol 112 no 11 pp 2447ndash2455 2008
[175] A Al-Nahhas ldquoNuclear medicine imaging of neuroendocrinetumoursrdquo Clinical Medicine vol 12 no 4 pp 377ndash380 2012
[176] V Ambrosini S Nicolini P Caroli et al ldquoPETCT imaging indifferent types of lung cancer an overviewrdquo European Journal ofRadiology vol 81 no 5 pp 988ndash1001 2012
[177] V Ambrosini D Campana P Tomassetti and S Fanti ldquo68Ga-labelled peptides for diagnosis of gastroenteropancreatic NETrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 39 no 1 pp S52ndashS60 2012
[178] K E Oberg J-C Reubi D J Kwekkeboom and E P KrenningldquoRole of somatostatins in gastroenteropancreatic neuroen-docrine tumor development and therapyrdquoGastroenterology vol139 no 3 pp 753-753 2010
[179] K Oberg ldquoGallium-68 somatostatin receptor PETCT Is ittime to replace 111Indium DTPA octreotide for patients withneuroendocrine tumorsrdquo Endocrine Journal vol 42 no 1 pp3-4 2012
[180] R Srirajaskanthan I Kayani A M Quigley J Soh M ECaplin and J Bomanji ldquoThe role of 68Ga-DOTATATE PET inpatients with neuroendocrine tumors and negative or equivocalfindings on 111In-DTPA-octreotide scintigraphyrdquo Journal ofNuclear Medicine vol 51 no 6 pp 875ndash882 2010
[181] A Kroiss D Putzer and C Uprimny ldquoFunctional imag-ing in phaeochromocytoma and neuroblastoma with 68Ga-DOTA-Tyr3-octreotide positron emission tomography and123I-metaiodobenzylguanidinerdquo European Journal of NuclearMedicine and Molecular Imaging vol 38 no 5 pp 865ndash8732011
[182] M Naji C Zhao S J Welsh et al ldquo68Ga-DOTA-TATE PETvs 123I-MIBG in identifying malignant neural crest tumoursrdquoMolecular Imaging and Biology vol 13 no 4 pp 769ndash775 2011
[183] V Ambrosini P Tomassetti P Castellucci et al ldquoComparisonbetween 68Ga-DOTA-NOC and 18F-DOPA PET for the detec-tion of gastro-entero-pancreatic and lung neuro-endocrinetumoursrdquo European Journal of Nuclear Medicine and MolecularImaging vol 35 no 8 pp 1431ndash1438 2008
[184] D Putzer M Gabriel B Henninger et al ldquoBone metastasesin patients with neuroendocrine tumor 68Ga- DOTA-Tyr3-octreotide PET in comparison to CT and bone scintigraphyrdquoJournal of Nuclear Medicine vol 50 no 8 pp 1214ndash1221 2009
[185] L K Anzola-Fuentes M Chianelli F Galli et al ldquoSomatostatinreceptor scintigraphy in patients with rheumatoid arthritis andsecondary Sjogrenrsquos syndrome treated with Infliximab a pilotstudyrdquo EJNMMI Research vol 6 no 1 article no 49 2016
[186] T Nobashi Y Nakamoto T Kubo et al ldquoThe utility of PETCTwith 68Ga-DOTATOC in sarcoidosis comparison with 67Ga-scintigraphyrdquoAnnals ofNuclearMedicine vol 30 no 8 pp 544ndash552 2016
[187] C Boy T A Heusner T D Poeppel et al ldquo68Ga-DOTATOCPETCT and somatostatin receptor (sst1-sst5) expression innormal human tissue Correlation of sst2mRNAand SUVmaxrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 38 no 7 pp 1224ndash1236 2011
[188] P Rinne S Hellberg M Kiugel et al ldquoComparison of Somato-statin Receptor 2-Targeting PET Tracers in the Detection ofMouse Atherosclerotic Plaquesrdquo Molecular Imaging and Biol-ogy vol 18 no 1 pp 99ndash108 2016
[189] M Asti E Ferrari S Croci et al ldquoSynthesis and characteri-zation of 68Ga-labeled curcumin and curcuminoid complexesas potential radiotracers for imaging of cancer and alzheimersdiseaserdquo Inorganic Chemistry vol 53 no 10 pp 4922ndash49332014
[190] A Signore I Santino and A W J M Glaudemans ldquoIn vivoimaging of microorganismsrdquo Clinical and Translational Imag-ing vol 4 no 3 pp 161-162 2016
[191] S Auletta F Galli C Lauri D Martinelli I Santino andA Signore ldquoImaging bacteria with radiolabelled quinolones
22 Contrast Media amp Molecular Imaging
cephalosporins and siderophores for imaging infection a sys-tematic reviewrdquo Clinical and Translational Imaging vol 4 no 4pp 229ndash252 2016
[192] X Ning S Lee Z Wang et al ldquoMaltodextrin-based imagingprobes detect bacteria in vivo with high sensitivity and speci-ficityrdquo Nature Materials vol 10 no 8 pp 602ndash607 2011
[193] J Ady andY Fong ldquoImaging for infection Fromvisualization ofinflammation to visualization of microbesrdquo Surgical Infectionsvol 15 no 6 pp 700ndash707 2014
[194] J M Sierra D Rodriguez-Puig A Soriano J Mensa C Pieraand J Vila ldquoAccumulation of 99mTc-ciprofloxacin in Staphy-lococcus aureus and Pseudomonas aeruginosardquo AntimicrobialAgents and Chemotherapy vol 52 no 7 pp 2691-2692 2008
[195] D I Andersson and D Hughes ldquoMicrobiological effects ofsublethal levels of antibioticsrdquoNature ReviewsMicrobiology vol12 no 7 pp 465ndash478 2014
[196] N Dumarey D Blocklet T Appelboom L Tant and ASchoutens ldquoInfecton is not specific for bacterial osteo-articularinfective pathologyrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 29 no 4 pp 530ndash535 2002
[197] K E Britton D W Wareham S S Das et al ldquoImaging bacte-rial infection with 99mTc-ciprofloxacin (Infecton)rdquo Journal ofClinical Pathology vol 55 no 11 pp 817ndash823 2002
[198] G Ferro-Flores M A Avila-Rodrıguez and F O Garcıa-PerezldquoImaging of bacteria with radiolabeled ubiquicidin by SPECTand PET techniquesrdquo Clinical and Translational Imaging vol 4no 3 pp 175ndash182 2016
[199] P S Hiemstra M T van den Barselaar M Roest P H Nibber-ing and R van Furth ldquoUbiquicidin a novel murine microbi-cidal protein present in the cytosolic fraction of macrophagesrdquoJournal of Leukocyte Biology vol 66 no 3 pp 423ndash428 1999
[200] M S Akhtar A Qaisar J Irfanullah et al ldquoAntimicrobialpeptide 99mTc-ubiquicidin 29ndash41 as human infection-imagingagent clinical trialrdquo Journal of Nuclear Medicne vol 46 no 4pp 567ndash573 2005
[201] M Assadi K Vahdat I Nabipour et al ldquoDiagnostic value of99mTc-ubiquicidin scintigraphy for osteomyelitis and compar-isons with 99mTc-methylene diphosphonate scintigraphy andmagnetic resonance imagingrdquo Nuclear Medicine Communica-tions vol 32 no 8 pp 716ndash723 2011
[202] T Emery ldquoExchange of Iron by Gallium in SiderophoresrdquoBiochemistry vol 25 no 16 pp 4629ndash4633 1986
[203] M Petrik C Zhai H Haas and C Decristoforo ldquoSiderophoresfor molecular imaging applicationsrdquo Clinical and TranslationalImaging vol 5 no 1 pp 15ndash27 2017
[204] H J Flint E A BayerM T Rincon R Lamed and B AWhiteldquoPolysaccharide utilization by gut bacteria potential for newinsights from genomic analysisrdquo Nature Reviews Microbiologyvol 6 no 2 pp 121ndash131 2008
[205] GGowrishankarMNamavari E B Jouannot et al ldquoInvestiga-tion of 6-[18F]-fluoromaltose as a novel PET tracer for imagingbacterial infectionrdquo PLoS ONE vol 9 no 9 Article ID e1079512014
[206] N Gholipour M Akhlaghi A M Kheirabadi et al ldquoChelator-free radiolabeling of dextran with 68Ga for PET studiesrdquoJournal of Radioanalytical and Nuclear Chemistry vol 311 no3 pp 1811ndash1817 2017
[207] C Bettegowda C A Foss I Cheong et al ldquoImaging bac-terial infections with radiolabeled 1-(21015840-deoxy-21015840- fluoro-120573-D-arabinofuranosyl)-5-iodouracilrdquo Proceedings of the NationalAcadamy of Sciences of the United States of America vol 102 no4 pp 1145ndash1150 2005
[208] S A Soghomonyan M Doubrovin J Pike et al ldquoPositronemission tomography (PET) imaging of tumor-localizedSalmonella expressing HSV1-TKrdquo Cancer GeneTherapy vol 12no 1 pp 101ndash108 2005
[209] C Palestro K Nichols S Sheikh-Fayyaz S Dewey P Singhaland K Bhargava ldquoCan Gallium-68 PET differentiate acuteinterstitial nephritis from acute tubular necrosisrdquo Journal ofNuclear Medicne vol 57 Supplement 2 p 551 2016
[210] A J Morguet D L Munz V Ivancevic et al ldquoImmunoscintig-raphy using technetium-99m-labeled anti-NCA-95 antigranu-locyte antibodies as an adjunct to echocardiography in subacuteinfective endocarditisrdquo Journal of the American College ofCardiology vol 23 no 5 pp 1171ndash1178 1994
[211] C van der Laken O Boerman W Oyen et al ldquoIn Vivo Expres-sion of Interleukin-1 Receptors during Various ExperimentallyInduced Inflammatory Conditionsrdquo The Journal of InfectiousDiseases vol 177 no 5 pp 1398ndash1401 1998
[212] C J Van Der Laken O C Boerman W J G Oyen M T PVan De Ven J W M Van Der Meer and F H M CorstensldquoScintigraphic detection of infection and inflammation Newdevelopments with special emphasis on receptor interactionrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 25 no 5 pp 535ndash546 1998
[213] C J van der LakenOC BoermanW J GOyenM T P van deVen J W M van der Meer and F H M Corstens ldquoImaging ofinfection in rabbits with radioiodinated interleukin-1 (120572 and 120573)its receptor antagonist and a chemotactic peptide a comparativestudyrdquo European Journal of Nuclear Medicine and MolecularImaging vol 25 no 4 pp 347ndash352 1998
[214] C J Van Der Laken O C BoermanW J G Oyen M T P VanDe Ven F H M Corstens and J W M Ven Der Meer ldquoThekinetics of radiolabelled interleukin-8 in infection and sterileinflammationrdquo Nuclear Medicine Communications vol 19 no3 pp 271ndash282 1998
[215] E Lazzeri P Erba M Perri et al ldquoScintigraphic imaging ofvertebral osteomyelitis with 111in-biotinrdquoThe Spine Journal vol33 no 7 pp E198ndashE204 2008
[216] E Blom B Langstrom and I Velikyan ldquo68Ga-labeling of biotinanalogues and their characterizationrdquo Bioconjugate Chemistryvol 20 no 6 pp 1146ndash1151 2009
[217] O Eriksson F Carlsson E Blom et al ldquoPreclinical evaluationof a 68Ga-labeled biotin analogue for applications in islettransplantationrdquo Nuclear Medicine and Biology vol 39 no 3pp 415ndash421 2012
[218] E A Weinstein A A Ordonez V P DeMarco et alldquoImaging Enterobacteriaceae infection in vivo with 18F-fluoro-deoxysorbitol positron emission tomographyrdquo Science Transla-tional Medicine vol 6 no 259 p 259ra146 2014
[219] K M Nielsen M H Kyneb A K O Alstrup et alldquo68Ga-labeled phage-display selected peptides as tracers forpositron emission tomography imaging of Staphylococcusaureus biofilm-associated infections Selection radiolabellingand preliminary biological evaluationrdquo Nuclear Medicine andBiology vol 43 no 10 pp 593ndash605 2016
[220] T J Makinen P Lankinen T Poyhonen J Jalava H T Aroand A Roivainen ldquoComparison of 18F-FDG and 68Ga PETimaging in the assessment of experimental osteomyelitis due toStaphylococcus aureusrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 32 no 11 pp 1259ndash1268 2005
[221] JMU Silvola I LaitinenH J Sipila et al ldquoUptake of 68galliumin atherosclerotic plaques in LDLRminusminusApoB100100micerdquo EJN-MMI Research vol 1 no 1 pp 1ndash8 2011
Contrast Media amp Molecular Imaging 23
[222] T A Wynn ldquoCellular and molecular mechanisms of fibrosisrdquoThe Journal of Pathology vol 214 no 2 pp 199ndash210 2008
[223] T Derlin D Jonigk J Bauersachs and FM Bengel ldquoMolecularImaging of Chemokine Receptor CXCR4 in NonndashSmall CellLung Cancer Using 68Ga-Pentixafor PETCT ComparisonWith 18F-FDGrdquo Clinical Nuclear Medicine 2016
[224] I Velikyan U Rosenstrom T N Bulenga O Eriksson andG Antoni ldquoFeasibility of multiple examinations using68ga-labelled collagelin analogues Organ distribution in rat forextrapolation to human organ and whole-body radiationdosimetryrdquo Pharmaceuticals vol 9 no 2 article no 31 2016
[225] S Jadhav M Kakela J Makila et al ldquoSynthesis and in VivoPET Imaging of Hyaluronan Conjugates of OligonucleotidesrdquoBioconjugate Chemistry vol 27 no 2 pp 391ndash403 2016
[226] A Autio A Saraste N Kudomi et al ldquoAssessment of bloodflow with (68) Ga-DOTA PET in experimental inflammation avalidation study using (15) O-waterrdquo American Journal ofNuclear Medicine and Molecular Imaging vol 4 no 6 pp 571ndash579 2014
[227] G Davies A Rolle A Maurer et al ldquoTowards translationalimmunoPETMR imaging of invasive pulmonary aspergillosisthe Humanised Monoclonal Antibody JF5 detects in vivordquoTheranostics vol 7 no 14 pp 3398ndash3414 2017
[228] DGoodwin CMeares GDavid et al ldquoMonoclonal antibodiesas reversible equilibrium carriers of radiopharmaceuticalsrdquoInternational Journal of Radiation Applications and Instrumen-tation Part B Nuclear Medicine and Biology vol 13 no 4 pp383ndash391 1986
[229] D A Goodwin C F Mears M McTigue and G S DavidldquoMonoclonal antibody hapten radiopharmaceutical deliveryrdquoNuclear Medicine Communications vol 7 no 8 pp 569ndash5801986
[230] S E Halpern and R O Dillman ldquoProblems associated withradioimmunodetection and possibilities for future solutionsrdquo JBiol Response Mod vol 6 no 3 pp 235ndash262 1987
[231] H Hong J Sun and W Cai ldquoRadionuclide-based cancerimaging targeting the carcinoembryonic antigenrdquo BiomarkerInsights vol 3 pp 435ndash451 2008
[232] G J Forster E B Santos P M Smith-Jones P Zanzonico andS M Larson ldquoPretargeted radioimmunotherapy with a single-chain antibodystreptavidin construct and radiolabeledDOTA-biotin Strategies for reduction of the renal doserdquo Journal ofNuclear Medicine vol 47 no 1 pp 140ndash149 2006
[233] Z Yao M Zhang H Kobayashi et al ldquoImproved targeting ofradiolabeled streptavidin in tumors pretargeted with biotiny-lated monoclonal antibodies through an avidin chaserdquo Journalof Nuclear Medicine vol 36 no 5 pp 837ndash841 1995
[234] C-H Chang R M Sharkey E A Rossi et al ldquoMolecularAdvances in Pretargeting Radioimunotherapy with BispecificAntibodies 1 Supported in part by USPHS Grant R01-CA-84379from the NIH and Department of Energy Grant DE-FG01-00NE22941 (both to R M S)1rdquo Mol Cancer Ther vol 1 no 7pp 553ndash563 2002
[235] R M Sharkey E A Rossi W J McBride C-H Chang andD M Goldenberg ldquoRecombinant Bispecific Monoclonal Anti-bodies Prepared by theDock-and-Lock Strategy for PretargetedRadioimmunotherapyrdquo Seminars in Nuclear Medicine vol 40no 3 pp 190ndash203 2010
[236] R M Sharkey E A Rossi C-H Chang and D M Golden-berg ldquoImproved cancer therapy and molecular imaging withmultivalent multispecific antibodiesrdquo Cancer Biotherapy andRadiopharmaceuticals vol 25 no 1 pp 1ndash12 2010
[237] D M Goldenberg R M Sharkey G Paganelli J Barbet andJ Chatal ldquoAntibody pretargeting advances cancer radioim-munodetection and radioimmunotherapyrdquo Journal of ClinicalOncology vol 24 no 5 pp 823ndash834 2006
[238] O C Boerman F G van Schaijk W J G Oyen and FH M Corstens ldquoPretargeted radioimmunotherapy of cancerprogress step by steprdquo Journal of Nuclear Medicine vol 44 no3 pp 400ndash411 2003
[239] J Schuhmacher S Kaul G Klivenyi et al ldquoImmunoscintigra-phy with positron emission tomography Gallium-68 chelateimaging of breast cancer pretargeted with bispecific anti-MUC1anti-Ga chelate antibodiesrdquo Cancer Research vol 61 no9 pp 3712ndash3717 2001
[240] J Schuhmacher G Klivenyi S Kaul et al ldquoPretargeting ofhuman mammary carcinoma xenografts with bispecific anti-MUC1anti-Ga chelate antibodies and immunoscintigraphywith PETrdquo Nuclear Medicine and Biology vol 28 no 7 pp 821ndash828 2001
[241] C Somasundaram S Matzku J Schuhmacher and M ZollerldquoDevelopment of a bispecific monoclonal antibody against agallium-67 chelate and the human melanoma-associated anti-gen p97 for potential use in pretargeted immunoscintigraphyrdquoCancer Immunology Immunotherapy vol 36 no 5 pp 337ndash3451993
[242] E A Rossi D L Rossi R Stein D M Goldenberg and C-H Chang ldquoA bispecific antibody-IFN1205722b immunocytokine tar-geting CD20 and HLA-DR is highly toxic to human lymphomaandmultiplemyeloma cellsrdquoCancer Research vol 70 no 19 pp7600ndash7609 2010
[243] R M Sharkey H Karacay S Litwin et al ldquoImproved ther-apeutic results by pretargeted radioimmunotherapy of non-Hodgkinrsquos lymphoma with a new recombinant trivalent anti-CD20 bispecific antibodyrdquo Cancer Research vol 68 no 13 pp5282ndash5290 2008
[244] G L Griffiths C-H Chang W J McBride et al ldquoReagentsandmethods for PETusing bispecific antibody pretargeting and68Ga-radiolabeled bivalent hapten-peptide-chelate conjugatesrdquoJournal of Nuclear Medicine vol 45 no 1 pp 30ndash39 2004
[245] J Watine M Miedouge and B Friedberg ldquoCarcinoembryonicantigen as an independent prognostic factor of recurrence andsurvival in patients resected for colorectal liver metastases Asystematic reviewrdquo Diseases of the Colon amp Rectum vol 44 no12 pp 1791ndash1799 2001
[246] M J Goldstein and E P Mitchell ldquoCarcinoembryonic antigenin the staging and follow-up of patients with colorectal cancerrdquoCancer Investigation vol 23 no 4 pp 338ndash351 2005
[247] D V Gold D M Goldenberg H Karacay et al ldquoA novelbispecific trivalent antibody construct for targeting pancreaticcarcinomardquo Cancer Research vol 68 no 12 pp 4819ndash48262008
[248] J Schuhmacher G Klivenyi R Matys et al ldquoMultistep tumortargeting in nudemice using bispecific antibodies and a galliumchelate suitable for immunoscintigraphy with positron emis-sion tomographyrdquo Cancer Research vol 55 no 1 pp 115ndash1231995
[249] G Klivenyi J Schuhmacher E Patzelt et al ldquoGallium-68chelate imaging of human colon carcinoma xenografts pre-targeted with bispecific anti-CD44(V6)anti-gallium chelateantibodiesrdquo Journal ofNuclearMedicine vol 39 no 10 pp 1769ndash1776 1998
[250] M Zoller J Schuhmacher J Reed W Maier-Borst and SMatzku ldquoEstablishment and characterization of monoclonal
24 Contrast Media amp Molecular Imaging
antibodies against an octahedral gallium chelate suitable forimmunoscintigraphy with PETrdquo Journal of Nuclear Medicinevol 33 no 7 pp 1366ndash1372 1992
[251] R M Sharkey T M Cardillo E A Rossi et al ldquoSignal ampli-fication in molecular imaging by pretargeting a multivalentbispecific antibodyrdquo Nature Medicine vol 11 no 11 pp 1250ndash1255 2005
[252] D M Goldenberg and R M Sharkey ldquoNovel radiolabeledantibody conjugatesrdquo Oncogene vol 26 no 25 pp 3734ndash37442007
[253] D M Goldenberg E A Rossi R M Sharkey W J McBrideand C-H Chang ldquoMultifunctional antibodies by the dock-and-lock method for improved cancer imaging and therapy bypretargetingrdquo Journal of NuclearMedicine vol 49 no 1 pp 158ndash163 2008
[254] R Schoffelen R M Sharkey D M Goldenberg et al ldquoPre-targeted immuno-positron emission tomography imaging ofcarcinoembryonic antigen-expressing tumors with a bispecificantibody and a68Ga- And18F-labeled hapten peptide in micewith human tumor xenograftsrdquoMolecular Cancer Therapeuticsvol 9 no 4 pp 1019ndash1027 2010
[255] E S Bos W H Kuijpers M Meesters-Winters et al ldquoIn vitroevaluation of DNA-DNA hybridization as a two-step approachin radioimmunotherapy of cancerrdquoCancer Research vol 54 no13 pp 3479ndash3486 1994
[256] G Paganelli M Bartolomei M Ferrari et al ldquoPre-TargetedLocoregional Radioimmunotherapy withrdquo Cancer biotherapyand radiopharmaceuticals vol 16 no 3 pp 227ndash235 2001
[257] A Forero P L Weiden J M Vose et al ldquoPhase 1 trial of a novelanti-CD20 fusion protein in pretargeted radioimmunotherapyfor B-cell non-Hodgkin lymphomardquo Blood vol 104 no 1 pp227ndash236 2004
[258] DM Goldenberg C-H Chang E A RossiW J McBride andR M Sharkey ldquoPretargeted molecular imaging and radioim-munotherapyrdquoTheranostics vol 2 no 5 pp 523ndash540 2012
[259] H Karacay R M Sharkey W J McBride E A Rossi C-HChang and D M Goldenberg ldquoOptimization of hapten-peptide labeling for pretargeted immunoPET of bispecificantibody using generator-produced 68Gardquo Journal of NuclearMedicine vol 52 no 4 pp 555ndash559 2011
[260] J R Oh and B C Ahn ldquoFalse-positive uptake on radioiodinewhole-body scintigraphy physiologic and pathologic variantsunrelated to thyroid cancerrdquo American Journal of NuclearMedicine and Molecular Imaging vol 2 no 2 pp 141ndash150 2012
[261] E Frampas C Rousseau C Bodet-Milin J Barbet J-F Chataland F Kraeber-Bodere ldquoImprovement of radioimmunotherapyusing pretargetingrdquo Frontiers in Oncology vol 3 Article ID00159 2013
[262] C S McKay and M G Finn ldquoClick chemistry in complexmixtures Bioorthogonal bioconjugationrdquo Chemistry amp Biologyvol 21 no 9 pp 1075ndash1101 2014
[263] B L Oliveira Z Guo and G J Bernardes ldquoInverse electrondemand DielsndashAlder reactions in chemical biologyrdquo ChemicalSociety Reviews vol 46 no 16 pp 4895ndash4950 2017
[264] B Nichols Z Qin J Yang D R Vera and N K Devaraj ldquo68Gachelating bioorthogonal tetrazine polymers for the multisteplabeling of cancer biomarkersrdquo Chemical Communications vol50 no 40 pp 5215ndash5217 2014
[265] R Rossin P R Verkerk S M van den Bosch et al ldquoInvivo chemistry for pretargeted tumor imaging in live micerdquoAngewandte Chemie International Edition vol 49 no 19 pp3375ndash3378 2010
[266] B M Zeglis K K Sevak T Reiner et al ldquoA pretargetedPET imaging strategy based on bioorthogonal diels-alder clickchemistryrdquo Journal of Nuclear Medicine vol 54 no 8 pp 1389ndash1396 2013
[267] J L Houghton R Membreno D Abdel-Atti et al ldquoEstablish-ment of the invivo efficacy of pretargeted radioimmunotherapyutilizing inverse electron demand diels-alder click chemistryrdquoMolecular Cancer Therapeutics vol 16 no 1 pp 124ndash133 2017
[268] J Funkhouser ldquoReinventing pharma the theranostic revolu-tionrdquo Current Drug Discovery pp 17ndash19 2002
[269] J Sorensen I Velikyan A Wennborg et al ldquoMeasuring HER2-expression in metastatic breast cancer using 68Ga-ABY025PETCTrdquo European Journal of Nuclear Medicine and MolecularImaging vol 41 pp S226ndashS226 2014
[270] I Velikyan A Wennborg J Feldwisch et al ldquoGMP compliantpreparation of a 68Gallium-labeled Affibody analogue forbreast cancer patient examination first-in-manrdquoEur JNuclMedMol Imaging vol 41 pp S228ndashS229 2014
[271] K Oberg ldquoMolecular imaging radiotherapy Theranostics forpersonalized patient management of neuroendocrine tumors(NETs)rdquoTheranostics vol 2 no 5 pp 448ndash458 2012
[272] I Velikyan AWennborg J FeldwischH Lindman J Carlssonand J Sorensen ldquoGood manufacturing practice production of [(68) Ga]Ga-ABY-025 for HER2 specific breast cancer imagingrdquoAmerican Journal of Nuclear Medicine and Molecular Imagingvol 6 no 2 pp 135ndash153 2016
[273] M Sandstrom K Lindskog I Velikyan et al ldquoBiodistributionand radiation dosimetry of the anti-HER2 Affibody molecule68Ga-ABY-025 in breast cancer patientsrdquo Journal of NuclearMedicine vol 57 no 6 pp 867ndash871 2016
[274] D Sandberg V Tolmachev I Velikyan et al ldquoIntra-imagereferencing for simplified assessment of HER2-expression inbreast cancer metastases using the Affibody molecule ABY-025with PET and SPECTrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 44 no 8 pp 1337ndash1346 2017
[275] H ZhangM AMoroz I Serganova et al ldquoImaging expressionof the human somatostatin receptor subtype-2 reporter genewith 68Ga-DOTATOCrdquo Journal ofNuclearMedicine vol 52 no1 pp 123ndash131 2011
[276] M Naji and A Al-Nahhas ldquo68Ga-labelled peptides in themanagement of neuroectodermal tumoursrdquo European Journalof Nuclear Medicine and Molecular Imaging vol 39 no 1 ppS61ndashS67 2012
[277] I Velikyan ldquoThe diversity of 68Ga-Based imaging agentsrdquoRecent Results in Cancer Research vol 194 pp 101ndash131 2013
[278] K Ferreira H-Y Hu V Fetz et al ldquoMultivalent siderophore-dotam conjugates as theranostics for imaging and treatment ofbacterial infectionsrdquo Angewandte Chemie International Editionvol 56 no 28 pp 8272ndash8276 2017
18F 110min 634 120573+ (97) Accelerator64Cu 128 h 656 120573+ (19) Accelerator68Ga 676min 1899 770 120573+ (89) Generator89Zr 784 h 900 120573+ (23) Accelerator124I 417 d 2100 120573+ (23) Accelerator
Gamma emitters67Ga 7826 h 91 93 185 296 388 120574 Accelerator99mTc 60 h 141 120574 Generator111In 679 h 245 172 (05ndash25) 120574 Auger electrons Accelerator123I 133 h 159 120574 Accelerator
Therapeutic radionuclides177Lu 671 d 113 2084 (598) 120574 (120573minus) Reactor
22 Unmet Medical Need Noninvasive and specific diag-nosis of many inflammatory diseases such as sarcoidosisosteomyelitis inflammatory bowel disease and rheumatoidarthritis as well as early and accurate diagnosis of deep-seated infectious diseases such as septic arthritis abscessesendocarditis and infections of prosthetics and implantswould benefit patients [20] Introduction of specific imagingagents disclosing cellular mechanisms of various diseaseson molecular level would allow improvement in patientmanagement and treatment outcome There is a strong needfor specific imaging agents not only for the accurate andquantitative diagnosis but also for the prognosis treatmentselection planning and adjustment as well as response mon-itoring as for example requirement for a certain antibioticand treatment duration Moreover the imaging could guidesurgical procedures and monitor implants of medical devicesor transplanted organs [43] Such imaging guided treatmentwould decrease the cost side effects and overtreatmentavoiding immune suppression effects in inflammation andpossibly reducing the problem of antimicrobial resistance bythe termination of an accomplished successful treatment asearly as possible There are potential challenges in targetingboth components of inflammatory response and microbesspecifically discrimination between infectious and sterileinflammation discrimination between acute and chronicinflammation discrimination between various infectiousmicroorganisms discrimination between pathogenic bac-teria and microbiota targeting specific types of bacteriadifficulty of accessing bacteria aggregated in a biofilm andquantification of reproducing bacteria
Health care requires further improvement of efficiencysafety and quality of treatment with patient personalizedapproach that would allow early diagnosis which is a crucialfactor in the reduction of mortality and patient managementcost [81] The concept of individualized patient managementon molecular level with regard to both diagnostics andtherapy is based on discoveries and success in genomicsproteomics and biotechnology Those achievements alsoaccelerate the development of various imaging agents and
the application of molecular imaging diagnostic techniquesis expanding very fast globally contributing considerably tothe realization of personalized medicine
3 Advantages of 68Ga NuclideProperties and Chemistry
Such radionuclides as 11C 18F 64Cu 68Ga 89Zr 99mTc 111Inand 124I are used in various radiopharmaceuticals for diag-nostic imaging with PET and SPECT (Table 1) With regardto PET 18F stands for 41 11C stands for 31 and 64Cu 68Ga89Zr and 124I stand for 28 of the radiopharmaceuticals [82]With regard to SPECT 99mTc and 111In stand respectivelyfor 42 and 29 of the radiopharmaceuticals As mentionedabove in the field of inflammation and infection gammaemitting 67Ga 99mTc 111In and positron-emitting 18F arecommonly in use The choice of a radionuclide depends onvarious aspects of production and application availabilityproduction mode and cost of the radionuclide nuclearcharacteristics and decay mode of the radionuclide labellingchemistry pathways and duration radiation dose to subjectsrelevance of the physical half-life of the radionuclide to thepharmacokinetic time frame of the imaging agentWithin thegroup of gamma emitters used for SPECT the productionvia generator system is an advantage that contributes to theleading position of 99mTc due to ready accessibility and lowercost Moreover the single and lower gamma energy of 99mTcresults in higher image resolution as compared to 67Ga and111In and shorter half-life of 99mTc reduces radiation dose tothe patient (Table 2)
The advantages of PET such as higher spatial resolutionsensitivity and accurate signal quantification are crucialespecially in the case of small size lesions Furthermoredynamic scanning allows modeling and investigation of themechanism of the interaction between the imaging agentand target Even though 68Ga has a relatively high positronenergy the resolution of the images is comparable to thatof 18F since it is the scanner detector resolution (4ndash6mm)
4 Contrast Media amp Molecular Imaging
Table 2 Effective doses for some PET and SPECT imaging agents Reproduced from [6]
Agent Examination time Effective dose [mSv][111In]In-DTPA-octreotideSPECT 24ndash48 h 108[68Ga]Ga-DOTA-TOCPET 30ndash60min 23[18F]FDGPET 60ndash120min 56[99mTc]-BPAMDSPECT 2ndash6 h 6[99mTc]-MDPSPECT 2ndash6 h 3-4[68Ga]Ga-BPAMDPET 30ndash60min 3-4
which is the limiting factor [4 83 84]The 68-min half-life of68Ga is not compatiblewith ligands of slowpharmacokineticsfor example antibodies Thus other positron emitters suchas 124I 89Zr and 64Cu with longer half-lives allowing 2ndash4days required for the clearance of the agent for the bloodcirculation and washout for the nontarget tissue are morerelevantThe relatively short half-life of 68Ga presents advan-tage in cases when repetitive examinations on the same dayare of interest [85] The high fraction of positron emission isanother advantage of 68Ga (89) as compared to 64Cu (19)and 124I (23) Comparison of some clinically used imagingagents demonstrates the lower effective dose that patient isexposed to when using 68Ga-based agent as compared tothe agents comprising 18F 99mTc and 111In (Table 2) [686 87] Moreover the duration of patient examinations isshorter for 68Ga-agents than that for SPECT agents and tosome extend for [18F]FDG In summary the use of 68Gawould be beneficial in terms of accessibility high sensitivityand resolution quantification dynamic scanning fast scan-ning protocol repetitive examinations and low radiationburden
The chemical form in aqueous solution is Ga(III)cation which provides robust coordination chemistry 68Ga-labelling can be direct or chelator mediated The directlabelling utilizes the chelating ability of macromolecules forexample lactoferrin and transferrin comprising Tyr His andAsp AA residues that can chelate Ga(III) in the presence ofsynergetic bicarbonate ion Lowmolecular weight ligands canform stable complexes of variable lipophilicity and charge fornontargeting imaging The chelator mediated 68Ga-labellingrequires presence of a bifunctional chelator (BFC) for the sub-sequent straightforward and side specific coordination withGa(III) Considerable number of chelators was successfullydeveloped [4 6 88ndash95]Themost commonly used are DOTAand NOTA based chelators The former requires heatingunder over 60∘C for the complexation with 68Ga while thelatter can chelate 68Ga at ambient temperature which mightbe crucial in case of temperature sensitive ligands and italso allows for cold kit type radiopharmaceutical prepara-tion under radiopharmacy practice [96] DOTA presents anadvantage in the context of radiotheranostics since it canform stable complexes with 68Ga for PET diagnostics and177Lu for radiotherapy
The chelator or prosthetic group mediated labellingmost commonly results in agents comprising biologicallyactive vectormolecule chelatorprosthetic groupmoiety and
radionuclide Very often pharmacokinetic modifiers (PKM)are incorporated in order to modulate pharmacokinetics andagent organ distribution and improve in vivo stability as wellas separate the binding site from the bulky chelatorprostheticgroup moiety which may deteriorate the biological activityof the vector molecule Considerable number of publicationsreveal strong influence of even slight modifications in any ofthe agent structural components and the accurate predictionof pharmacokinetics and pharmacodynamics of a new agentis not straightforward [97] Nevertheless vast experience andknowledge have been intensively gathered during last twodecades providing possibility for more efficient and effectivedevelopment The labelling chemistry of 68Ga is well charac-terized and is relevant to small molecules macromoleculesand particles
Ga(III) as a chemical element presents a unique advan-tage over other radionuclides as it has properties closelyresembling those of Fe(III) which is involved in manybiochemical processes including inflammation MoreoverFe(III) is an essential nutrient and limiting factor ofmicrobiallife [98] Stable Ga(III) has been used in treatment of variousdiseases including cancer infection and inflammation [99ndash101] The ability of Ga(III) to bind iron proteins for examplelactoferrin and transferrin as well as siderophores andenzymes can be utilized in the imaging agent development
4 Biomarkers andRadiopharmaceutical Development
The development of imaging agents relies strongly on theadvances experience and knowledge of the research ofbiomarkers for example receptors and antigens transportsystems substances involved in angiogenesis glycolysishypoxia proliferation and apoptosis and enzyme activityTargeting biomarkers that are specific for a given diseaseis one the major aims of an agent development for bothdiagnostic imaging and therapy The knowledge and accessto respective vector molecules have considerably expandeddue to the achievements in proteomics and genomics Infec-tion inflammation and fibrosis are closely interrelated pro-cesses and corresponding biomarkers might present practicalinterest in developing respective imaging agents Favorablecharacteristics of a target in general include expressionupregulation absence of expression in normal tissue andinternalization or stable binding of the respective ligand forthe longitudinal accumulation of the latter [102]
Contrast Media amp Molecular Imaging 5
5 Imaging Inflammation
Inflammatory response is a complex process involvingimmune system cells (T- and B-lymphocytes NK cellsmacrophages monocytes neutrophils eosinophils andmastcells) and products of their (patho)physiological activity forexample cytokines involved in the cell signaling Variousfunctions of the cells and their products as well as theirreceptors provide a broad range of potential imaging targets[103ndash107] Targeting the white blood cells of the immunesystem such as macrophages monocytes lymphocytes andneutrophils for the detection of their upregulation and traf-ficking secretion of cytokines and chemokines and phago-cytosis has been investigated both clinically and preclinicallyReceptors such as SSTRNCA-90 integrins folate bombesinvascular cell adhesion protein-1 and interleukins expressedby activated T-cells CXCR2 expressed on neutrophils andCXCR4 overexpressed by leukocytes have demonstratedpotential for in vivo targeted imaging [108] Respectiveligands and substrates can be considered for radiolabellingCytokines including interferons lymphokines interleukinsand chemokines bind to various receptors for example IL1and IL2 receptor types IFN CD40 CD37 CD30 CD4CCR5 and IL1-17R receptor family Folate CD64 NCA90and CD15 receptors expressed on macrophages leukocytesand granulocytes can serve as targets Not only do moleculesof such super families as chemokine integrin selectin andimmunoglobulin participate in the cell emigration cascadebut also enzymes on the surface of endothelia cells andleukocytes contribute to the leukocyte extravasation [109]Receptors on the endothelial wall for example for bindingof IL1 and TNF120572 are another category of the targets Theseare only few examples of targets for potential imaging agentdevelopment (Table 3) Many targets were utilized in oncol-ogy [28] and their translation to inflammation is feasible
51 Targeting Cell Receptors with Antibodies Radiolabelled(99mTc 111In and 123I) anti-CD2 anti-CD5 anti-CD25 anti-CD45 antibodies and their fragments were used for the imag-ing of T-lymphocyte infiltration in various inflammatorydiseases [110] Typically for antibody slow pharmacokineticsthe time delay between the administration and examina-tion stretches up to 24 hours Interleukin-8 labelled with99mTc was studied in rabbits with induced acute pyogenicosteomyelitis [111] and induced acute colitis [112] The agentwas found suitable for the scintigraphic evaluation of therespective diseases CD163 receptor expressed in monocytesand activated macrophages was targeted with an anti-CD163antibody labelled with 68Ga in rats with acute collagen-induced arthritis [45]The agent demonstrated specific bind-ing and thus potential for studies of inflammatory diseases
52 Targeting Angiogenesis Angiogenesis plays an importantrole in wound healing chronic inflammation and tumourgrowth [113] The family of vascular endothelial growthfactors (VEGF) and integrins play crucial role in the angio-genesis cascade Integrin receptors are overexpressed on thesurface of vascular endothelial cells during angiogenesis inmalignances tissue healing and inflammation The largest
group is radiolabelled peptide ligands comprising arginine-glycine-aspartic acid (RGD) sequence and peptidomimeticstargeting 120572v1205733 integrin receptors Various analogues weredeveloped introducing cyclization andmultimerization vari-ety of chelatecoligand moieties PKM such as carbohy-drate and polyethylene glycol chains [114ndash121] Various RGDanalogues labelled with 18F 68Ga and 99mTc were usedin oncological clinical trials [122] The majority of themcomprised 18F however advantages of 68Ga such as accessi-bility of the radionuclide more straightforward and efficientlabelling chemistry lower radiation dose and better imagecontrast renderedmore extensive development of 68Ga-basedanalogues [123ndash127]
The imaging agents tested in cancer systems can berelevant for the imaging of inflammation related diseasesTheimaging and evaluation of synovial angiogenesis in patientswith rheumatoid arthritis was accomplished using [68Ga]Ga-PRGD2 [46] The elevated agent uptake was detected inthe sites of active inflammation rich neovasculature andphysiological integrin receptor expression while no traceraccumulationwas detected in axillary lymphnodeswith reac-tive hyperplasia and strenuous skeletal muscles [68Ga]Ga-PRGD2PET-CT was found useful for the evaluation of syn-ovial angiogenesis and follow-up of the treatment response
[68Ga]Ga-NOTA-c(RGDyK)was developed for the imag-ing of myocardial infarction (MI) and follow-up of theresponse to the therapeutic intervention and demonstratedpromising results preclinically [47] The uptake in the MIlesions was enhanced and correlated with the vascularendothelial growth factor expression Dynamic [68Ga]Ga-NOTA-c(RGDyK)PET scanning with subsequent kineticmodeling studies in rats with forelimb ischemia showedhigher uptake and distribution volume in the ischemicarea as compared to that of sham operation and controlregions [48] Monitoring myocardial repair and angiogenesisafter ischemic injury was found plausible using [68Ga]Ga-NODAGA-RGD and [68Ga]Ga-TRAP-(RGD)3 in rat model[49] Elevated uptake of [68Ga]Ga-DOTA-E-[c(RGDfK)]2was observed in the infarcted area while no accumulationwas detected in the noninfarcted myocardium of the samerats [50]The uptake of [68Ga]Ga-DOTA-RGD in atheroscle-rotic plaques was studied in vivo in atherosclerotic micewith promising results [52] Elevated uptake of [68Ga]Ga-NODAGA-RGD in injured myocardium as compared toviable ischemic areas in pig model presumably indicatedincreased expression of 120572V1205733 receptors associated with injuryrepair in the presence of coronary stenosis [51]
Although targeting VEGF receptors were studied in thecontext of cancerous diseases chronic inflammation can alsobe considered A ligand consisting of a single chain (scVEGF3ndash112 amino acids of human VEGF121) [128 129] was labelledwith 68Ga and the resulting agent showed distinct uptake inthe tumour xenografts in mice however high kidney uptakeneeded to be addressed [130 131]
53 Targeting Selectins P-selectin is expressed on the activeendothelium surface and platelets and operates the migra-tion of leukocytes in response to inflammatory cytokines
6 Contrast Media amp Molecular Imaging
Table 3 68Ga-based imaging agents for inflammation and infection investigated preclinically and clinically
E-selectin binding peptide labelled with 99mTc accumu-lated in acute osteomyelitic lesions in rats presumably byinteraction with activated vascular endothelium [132] Ananalogue of P-selectin natural ligand fucoidan labelled with68Ga could discriminate active and inactive atheroschleroticplaques in mice [44]
54 Targeting Vascular Adhesion Protein-1 Vascular adhe-sion protein-1 (VAP-1) and CD73 are endothelial surfaceenzymes involved in the recruitment of leukocytes and theirmovement from the blood into the tissue [109] Endothelialactivation that takes place during inflammation can be uti-lized for specific targeting imaging Several peptide analogues
Contrast Media amp Molecular Imaging 7
300
250
200
150
100
50
0
(kBq
ml)
Inflammation
Kidneys
Muscle
Inflammation
Kidneys
Muscle
Figure 1 PET images of the distribution of [68Ga]Ga-DOTAVAP-P1 [68Ga]Ga-DOTAVAP-PEG-P1 and [68Ga]Ga-DOTA-Siglec-9 inturpentine-induced rat model of sterile inflammation All three peptide analogues showed target-to-nontarget ratio above 6 with rapidaccumulation in the inflammation site and renal clearance Adapted from [57]
labelledwith 68Gawere designed for the visualization ofVAP-1 and showed promising results in animals with inducedinfection and sterile inflammation [7ndash13 133] The bindingwas proven specific and it was possible to differentiate inflam-mation from infection [68Ga]Ga-Siglec targeting VAP-1demonstrated preclinical potential for imaging of synovialinflammation in patients with rheumatic diseases [53] Thesame agent was utilized for respiratory distress syndrome(ARDS an inflammatory lung injury) imaging in a porcinemodel [54] Imaging VAP-1 with [68Ga]Ga-Siglec was foundpromising also for the detection of inflamed atheroscle-rotic lesions [55] and inflammatory response induced bycatheter implantation and staphylococcal infection [56]68Ga-Siglec and two more peptide analogues with affinityto VAP-1 ([68Ga]Ga-DOTAVAP-P1 [68Ga]Ga-DOTAVAP-PEG-P1 and [68Ga]Ga-DOTA-Siglec-9) were investigated inrat model of sterile skinmuscle inflammation (Figure 1) [57]They showed distinct uptake in the affected sites
55 Targeting Chemokines Cytokines are produced bymacrophages B-lymphocytes T-lymphocytes and mast cellsand act through receptors modulating for example immuneresponse to infection and inflammation Cytokines includechemokines interleukins interferons and lymphokines thatcan be classified in broad families exhibiting diverse func-tions for example IL-1 and IL-6 superfamilies and TNFTNFreceptor superfamily Therapeutics targeting cytokines are inclinical use for example inhibiting TNF or IL-6 in rheumaticdiseases
Chemokine receptors are physiologically expressed onB-lymphocytes T-lymphocytes macrophages neutrophilseosinophils monocytes and hematopoietic stem cells [134]Imaging agents targeting CXCR4 are based on inhibitors(AMD3100) or small peptides (NFB T140 pentixafor andTN14003) and comprise 18F 67Ga 68Ga or 64Cu [135ndash148] They were developed and studied for the imaging of
various cancerous diseases lung breast prostate cancersacute myeloid leukemia and glioblastoma
The application of CXCR4 targeting agents was extendedbeyond oncology Clinical caseimage reports [149 150]were published on the utilization of [68Ga]Ga-pentixafor fordetection and quantification of CXCR4 receptor density inischemic heart diseases reflecting the role of the receptorin inflammatory and progenitor cell recruitment [58 59]The same agent was successfully used in the assessment ofmacrophage infiltration in atherosclerotic plaques in rabbitdisease model [151]
56 Targeting Folate Receptors Folate receptors (FRs) areoverexpressed on a variety of cancer cells and activatedmacrophages but not on normal cells [152 153] Theenhanced expression of FR was found in lung macrophagesduring acute inflammation [154] The majority of the nuclearimaging agents based on folic acid or pteroic acid [155] weredeveloped for diagnosis of cancers overexpressing FR recep-tors such as breast cervical ovarian colorectal nasopharyn-geal renal and endometrial cancers Various 68Ga-labelledagents demonstrated accumulation in cell cultures and micebearing folate-receptor positive human nasopharyngeal car-cinoma cell line (KB) xenografts [6 156ndash162] [68Ga]Ga-DOTA-PEG-FA comprising folic acid was investigated forthe detection and quantification of inflammatory response tomedical implants using mice with subcutaneously implantedpolylactic acid and poly(N-isopropylacrylamide) particles asa model [60] The agent was accumulated in the area of theimplant most probably reflecting interaction of [68Ga]Ga-DOTA-PEG-FA with folate receptor expressed on activatedmacrophages Another folic acid based agent [68Ga]Ga-DOTA-folate was successfully tested in an inflammatory pawrat model (Figure 2) [61] Distinct accumulation in inflamedhand and foot joints of rheumatoid arthritis of a 99mTc-labelled folate analogue was observed in a patient while no
8 Contrast Media amp Molecular Imaging
NH ONHONH
OOO
HOHN O
HN
NN
N N
HO
O
N
N
O
O
N
N
O
O
O
Ga+
minus
（3
(a)
2
15
1
05
0
(b)
Figure 2 Accumulation of [68Ga]Ga-DOTA-folate (a) in the site of inflammation of rat inflammatory pawmodel induced by subcutaneouslyinjected Complete Freundrsquos Adjuvant (b) Adapted from [61]
4
2
0
Figure 3 Intense atherosclerotic inflammation (white arrows) was detected by [68Ga]Ga-DOTA-TATE in a patient with acute coronarysyndrome Adapted from [65]
uptake was detected in a nonarthritis patientrsquos hands and feet[163]
57 Targeting Somatostatin Receptors Somatostatin receptor(SSTR) ligand analogues have found an extensive appli-cation in diagnosis and radiotherapy of neuroendocrinetumours The elevated expression of SSTRs is known also insmall cell lung cancer breast cancer renal cell carcinomaprostate cancer and malignant lymphoma A number ofsomatostatin ligand analogues labelled with gamma- andpositron-emitting radionuclides were used clinically foroncological cases [85 164ndash174] 68Ga-labelled somatostatinanalogues demonstrated superior performance in terms ofhigher specificity and sensitivity detection rate shorterexamination time and quantification possibility and havebecome a golden standard for the detection of neuroen-docrine tumours (NETs) taking over that title from [111In]-pentetreotide (OctreoScan) and demonstrating specificityand sensitivity of over 90 [27 175ndash180] 68Ga-labelledagents for the imaging of NETs demonstrated advantages
also over other radionuclides and tracers such as [18F]FDG[174] 123I-metaiodobenzylguanidine ([123I]MIBG) [181 182][18F]DOPA [183] [99mTc]-dicarboxy propane diphosphonate[184] and [18F]NaF
SSTR are also overexpressed on activated macrophagesand T-lymphocytes 68Ga-labelled analogues were used ininflammation related diseases such as idiopathic pulmonaryfibrosis [62] Gravesrsquo and Hashimotorsquos diseases [63] coro-nary artery plaque imaging and characterization [64] andatherosclerotic inflammation with excellent macrophagespecificity (Figure 3) [65] Promising diagnostic potential ofa 99mTc-labelled analogue was demonstrated in patients withrheumatoid arthritis and secondary Sjogrenrsquos syndrome andthe method was suggested for the assistance in anti-TNFalpha antibody treatment planning [185] [68Ga]Ga-DOTA-TOCPET-CT was found superior to 67Ga-CitrateSPECT indetection of sarcoidosis lesions [186] A clinical study demon-strated correlation between uptake of [68Ga]Ga-DOTA-TOCand SST2 mRNA expression and recorded the information ina database [187] providing tools for accurate quantification
Contrast Media amp Molecular Imaging 9
and evaluation of disease progression and treatment responsein cancerous and inflammatory diseases involving SSTRsPreclinical study using atherosclerotic mice demonstratedsuperior targeting properties of [68Ga]Ga-DOTA-NOC ascompared to [18F]FDR-NOC [188] overall confirming thepotential of SSTR targeting for atherosclerotic plaque imag-ing
58 Imaging Neuroinflammation Despite difficulty ofdesigning 68Ga-labelled molecules capable of blood-brainbarrier penetration several agents were suggested for theimaging of neuroinflammation in particular A120573 plaquesdeposited on blood vessels [67ndash69] Bivalent styrylpyridineslabelled with 68Ga demonstrated high specificity and affinityfor A120573 plaques using postmortem Alzheimerrsquos disease (AD)brain sections [67] Benzofuran derivative comprising 68Gashowed promising results in terms of binding specificityand affinity investigated in vitro in sections of Tg2576mice [68] Although the synthesis of a 68Ga-labelledPittsburgh compound analogue was successful the in vitrobinding to amyloid deposits was limited [69] The commondisadvantage of these agents is poor blood-brain barrierpenetration nevertheless the exploration of more successfulanalogues continues Curcumin functions as an antioxidantantimicrobial anti-inflammatory and anticancer agentDiacetyl-curcumin and bis(dehydroxy)curcumin labelledwith 68Ga demonstrated in vitro binding to 120573-amyloid fibrilsand lung cancer cells [189] Potential application of the agentscould include diagnostic imaging of Alzheimerrsquos disease andvarious cancers
6 Imaging Infection
Infection imaging can be indirect utilizing targets involvedin the immune response namely inflammation as presentedin the inflammation targets section above or direct utilizingpathogen related targets The direct imaging is especiallycrucial in cases where inflammatory response is absent Thedifference in biochemistry and structure between bacterialand human cells might exclude physiological uptake byhuman tissuemaking it easier tomeet the favorable character-istics of an imaging agent However discrimination betweenthe various infectious microorganisms pathogenic bacteriaand microbiota targeting specific bacteria type as well asdifficulty of accessing bacteria aggregated in a biofilm makesthe task very challenging [190 191] The specific targetingof infection would require accumulation of the radioactivesignal in the pathogen The radiolabelled targeting agentsfor infection can be roughly divided into several groupsantibiotics based antimicrobial protein and peptide basedsiderophore and other metabolisable compound based andantigen-specific antibodies and antibody fragments (Table 3)
61 Radiolabelled Antibiotics Antimicrobials act on the pro-cesses that are specific to microbes for example bacteria andfungi and thus corresponding imaging agents might distin-guish infection from inflammation [191] They might requireinternalization or may bind to the cell surface dependent on
their biological action mechanism [191ndash193] The possibilityof antibiotic resistance development exists also in the case ofimaging agents even though the amount of such agents wouldbe subnanomolar [194 195] Another complication is possiblenonspecific uptake of antibiotics based agents by leucocytes[196] Considerable number of various antibiotic analogueshave been labelled with 99mTc 111In 131I 11C and 18F[102] and evaluated preclinically and clinically with 99mTc-ciprofloxacin becoming a commercial product (Infecton) [21197 198] However the further improvement of specificityis desirable [191] Antibiotics are accessible and cheap andthey demonstrate high sensitivity [102 191] making thedevelopment of 68Ga-labelled analogues very attractive giventhe earlier mentioned advantages that 68Ga as a radionu-clide in combination with PET provides Two 68Ga-labelledanalogues based on ciprofloxacin demonstrated potential fordiscrimination between bacterial infection and inflammationin rats infected with Staphylococcus aureus [70]
62 Radiolabelled Antimicrobial Proteins and Peptides Anti-microbial proteins and peptides for example serprocidinscathelicidins and defensins produced by the cells of immunesystem target microbial membrane lipids and impose micro-bicidal effect [35 43] They present a large group of poten-tial candidates for microbial imaging including bacteriafungi parasites and viruses Antimicrobial peptides havedemonstrated higher specificity for infection than antibioticanalogues They accumulate at infection but not sterileinflammation sites The most thoroughly studied antimicro-bial peptide ubiquicidin UBI [29ndash41] labelled with 99mTc[199] demonstrated promising results in human clinical trials[200 201] It has the potential for quantification of viableinfecting microorganisms and consequently for monitoringthe efficacy of antimicrobial therapy in patients
Fragments of an antimicrobial peptide ubiquicidin con-jugated to NOTA and labelled with 68Ga [68Ga]Ga-NOTA-UBI29-41 and [68Ga]Ga-NOTA-UBI30-41 demonstratedpossibility for the distinction between infection and inflam-mation in a rabbit model [71 72] Antimicrobial peptidefragments GF-17 and RAWVAWR-NH2 of respectivelyhuman cathelicidin LL-37 andhuman lysozyme active againstE coli and S aureus were labelled with 68Ga and theirbiodistribution in normal rats demonstrated fast clearancefrom liver [75] Antimicrobial depsipeptide based agent[68Ga]Ga-DOTA-TBIA101 targeting bacterial lipopolysac-charides detected muscular E coli-infection in mice (Fig-ure 4) [73] The agent was also studied in healthy rabbitsand various disease model rabbits such as sterile inflam-mation Staphylococcus aureus infection andMycobacteriumtuberculosis [74] The clearance of [68Ga]Ga-DOTA-TBIA101from blood and normal tissue was fast and enhanced uptakein sterile inflammation and Mycobacterium tuberculosis siteswas observed The improvement of the bacterial selectivitywill require modification of the agent structure
63 Radiolabelled Siderophores Bacteria and fungi producevarious siderophores for harvesting iron which is essentialfor their survival and growth [34 98 191] Siderophores
10 Contrast Media amp Molecular Imaging
(a)
(b)
(c) (d)
(e)
Figure 4 Left panel presents maximum intensity projection images of [68Ga]Ga-DOTA-TBIA101 distribution in a healthy mouse (a) and amouse with muscular infection site (MIS) in the right hind muscle tissue (white arrows) Right panel presents coronal (c) sagittal (d) andaxial (e) images with uptake in theMIS (white arrow) and absence of the uptake in the contralateralmuscle tissue Ki and Bl stand respectivelyfor kidney and bladder Reproduced from [73]
can also play a critical role in the development of biofilmsby microbes They are low molecular weight compoundsspecifically chelating Fe(III) and Ga(III) can form stablecomplexes with them mimicking Fe(III) [202 203]
Desferri-triacetylfusarinine C (TAFC) and desferri-ferricrocin (FC) labelled with 68Ga were used for theimaging of invasive pulmonary aspergillosis (IPA) caused byAspergillus fumigatus [15] [68Ga]Ga-TAFC demonstratedsuperior characteristics in terms of specific target bindingmetabolic stability and fast blood clearance in a rat modelof A fumigatus infection Seven analogues were developedin another study with TAFC and ferrioxamine E (FOXE)showing favorable binding clearance elimination andstability characteristics [16] as well as lung uptake inrat of invasive aspergillosis model wherein the uptakeextent was correlated with disease severity [17] [68Ga]Ga-triacetylfusarinine C and [68Ga]Ga-ferrioxamine E wereinvestigated in rat model of A fumigatus and demonstratedrapid uptake in the lungs (Figure 5) [76]
64 Radiolabelled Metabolisable Agents Mammalian micro-biota consumes (poly)saccharides in particular maltose andmaltodextrins [204] The transport mechanism is specific
to bacteria and is absent in mammalian cells making itpossible to utilize these (poly)saccharides for imaging agentdevelopment Maltodextrin functionalized with a fluorescentdye was internalized through the bacteria-specific maltodex-trin transport pathway and discriminated between activebacteria and inflammation in vivo [192] Maltose labelledwith 18F localized specifically bacterial infection in mice[205] Potential to label polysaccharides directly with 68Gamight be utilized extensively
As mentioned above the chemical properties of Ga(III)provide the potential for direct labelling of polysaccharidesDextran was labelled directly and resulting complex demon-strated sufficient stability in human serum however thefeasibility of the bacterial imaging was not demonstrated[206]
Trapping of nucleosides that are substrates of thymidinekinase occurring within bacteria was explored using 18Fand 125I labelled analogues of uracil [207] Promising resultswere obtained in seven bacterial species in mice Anotherstudy in the context of therapeutic bacteria developmentdemonstrated possibility of detecting Salmonella vectorswithin tumours using 18F-labelled uracil [208] However
Contrast Media amp Molecular Imaging 11
N
O
N
ON
HN
O
O
O
OO O
NH
O
O
O
O
NH
O
OGa
（3
（3
（3
（3
（3
（3
（2
(a) (b) (c)
Figure 5 Molecular structure of [68Ga]Ga-triacetylfusarinine C (a) used for the in vivo imaging of a rat with Aspergillus fumigatus infection(b) and negative control of noninfected rat (c) White arrows point at the infected (b) and normal (c) lungs Adapted from [76]
the development of 68Ga-labelled nucleosides that wouldmaintain their biological activity is challenging and fewexamples known from the literature confirm that [4 6]
7 68Ga-Citrate
As mentioned above 68GaPET provides a number of advan-tages over 67GaSPECT and following publications demon-strate it in clinical and preclinical studies [68Ga]Ga-citratedemonstrated high diagnostic accuracy of 90of osteomyeli-tis and diskitis in clinical studies (Figure 6) [18 19] Thisstudy demonstrates that [68Ga]Ga-citrate can be employedfor monitoring the response to treatment [68Ga]Ga-citratewas used clinically to follow-up surgical intervention inpatients with acute osteomyelitis and intra-abdominal infec-tion [77] The agent was also used to successfully visualizelungmalignancy and tuberculosis in patients however in caseof high prevalence of granulomatous diseases the distinctionbetween malignant and benign lung lesions was unclear [7879] Another clinical study conducted head-to-head compar-ison of [68Ga]Ga-citrate (Figure 7) and [18F]FDG in patientswith Staphylococcus aureus bacteremia [80] The detectionrate of osteomyelitis was similar and further investigationof [68Ga]Ga-citrate applicability in cases of osteomyelitisinduced by other pathogens as well as for monitoring healingprocess is warranted
Comparative study of [68Ga]Ga-citrate and [67Ga]Ga-citrate was performed in healthy and infection model rats[77] The performance of [68Ga]Ga-citrate was found supe-rior in terms of image contrast in the lower abdomen and
extremities Potential of [68Ga]Ga-citrate for the differentia-tion of acute interstitial nephritis from acute tubular necrosiswas studied in rat model of the disease and it was demon-strated that the kidney uptake correlated with the extentof mononuclear cell infiltration accompanying inflammation[209] 68Ga-labelled Apo-transferrin demonstrated bacterialinfection detection capacity in rat model with Staphylococcusaureus wherein the infection site was visualized 1 h afteradministration of the agent [14]
71 Radiolabelled Antibodies and Antibody FragmentsHuman immunoglobulin (HIG) binds to bacteria but alsoaccumulates at the sites of fungal and viral infection aswell as sterile inflammation due to binding to leukocytesThe improved specificity for bacteria was achieved for thefragments of HIG It is feasible to develop specific antibodiesto various antigens present on the bacterial cell surface [102]Monoclonal antibodies labelled with 99mTc were used forinfection imaging via granulocytes targeting NCA-95 [210]Various cytokines of interleukin family (IL-1 IL-8) labelledwith 123I or 99mTc demonstrated accumulation in the sitesof infection in various animal models [111 112 211ndash214]Registered antigranulocyte radiopharmaceuticals suchas LeuTech Scintimun and Leukoscan are based on99mTc-labelled antibodies This experience can be translatedto 68Ga however either the size of the antibodies mustbe reduced or pretargeting techniques must be appliedin order to overcome the discrepancy between the shortphysical half-life of 68Ga and slow pharmacokinetics ofantibodies
12 Contrast Media amp Molecular Imaging
(a) (b) (c) (d)
Figure 6 [68Ga]Ga-citrate PETCT examination of a patient affected by acute osteomyelitis before (left panel) and after (right panel) surgicalcurettage showing uptake in the transaxial (a c) and 3D reconstruction images (b d red area) Absence of the uptake after the therapyconfirms complete response to the treatment Adapted from [19]
Figure 7 Vertebral osteomyelitis (spondylodiscitis red arrow-heads) and abscesses in the iliopsoas and paravertebral area (redarrows) were detected by [68Ga]Ga-citrate in a patient admittedto the hospital with back pain and general symptoms The PETacquisition was performed 88min after administration of 245MBqof [68Ga]Ga-citrate Adapted from [80]
72 Radiolabelled Biotin Biotin is a growth factor utilizedin many bacteria An 111In-labelled analogue of biotin wassuccessfully utilized for diagnosis of vertebral infections ina clinical study [215] It would be rational to explore therelevance of 68Ga-labelled analogues given the advantagesof 68Ga over 111In and promising [68Ga]Ga-DOTA-Biotinanalogues [216 217] developed for monitoring survival oftransplanted avidin-coated islets
8 Miscellaneous
Stable Ga(III) complex with thiosemicarbazones demon-strated antimicrobial effect against P aeruginosa and Calbicans due to most probably both displacement of essentialFe(III) with Ga(III) and thiosemicarbazones [101] Substitu-tion of the stable Ga(III) by radioactive 68Ga might result ina specific infection imaging agent
Selective imaging of Enterobacteriaceae using 2-[18F]-fluorodeoxysorbitol (18F-FDS)was demonstrated in amurine
myositis model [218] The uptake of 18F-FDS was correlatedwith bacterial burden moreover the agent differentiatedinfection from sterile inflammation Given the potential of68Ga for the labelling of small biologically active molecules[4] it might be plausible to develop a respective analoguewith added value of the advantages that 68Ga offers includingsimpler production chemistry lowered radiation dose repet-itive examination and accessibility at clinical centers withoutcyclotrons and remote from [18F]-FDG distribution sites Asmentioned above the poor access to bacteria aggregated ina biofilm might make the imaging task challenging Severalpeptide candidates with affinity for S aureus biofilm weredesigned and labelled with 68Ga [219] The resulting agentsdemonstrated binding in vitro however it was not possible toblock the binding with excess of the cold peptide
Ionic 68Ga was found superior to [18F]-FDG in infectiondetection in the rat model with diffuse osteomyelitis [220] Inanother study the uptake of ionic 68Ga was observed in theaortic plaques of atherosclerotic mice specifically at the sitesrich inmacrophages [221] However the slow blood clearanceof ionic 68Ga presents a limitation
Chronic inflammation is the major reason of fibro-sis [222] 68Ga-labelled SST analogue ([68Ga]Ga-DOTA-NOC) demonstrated uptake in pathogenic areas in patientsaffected by idiopathic pulmonary fibrosis with potentialfor monitoring response to treatment and drug develop-ment [62] Another clinical study using [68Ga]Ga-pentixaforalso showed potential of the agent for monitoring dis-ease activity and response to treatment in idiopathic pul-monary fibrosis [223] Peptide based agents CNO2A-PEG2-c[CPGRVMHGLHLGDDEGPC] and [68Ga]Ga-NODAGA-PEG2-c[CPGRVMHGLHLGDDEGPC] for the imaging andquantification of fibrosis by PET were developed and char-acterized preclinically showing fast clearance from normal
Contrast Media amp Molecular Imaging 13
tissue and blood and binding specificity [89] Dosimetrycalculations demonstrated possibility of six examinations peryear in humans assuring disease monitoring in longitudinalstudies and routine clinical setup [224]
Several hyaluronan conjugates of oligonucleotides target-ing CD44 positive cells were developed and tested in healthyrats sham-operated rats and rats with myocardial infarction[225]The uptake of the agents was higher for the latter groupand varied dependent on the difference in the oligonucleotidestructure
TLR2 and TLR4 expression levels in neutrophils werefound higher in individuals with bacterial and viral infectionsthan those in control samples There is a possibility that IL-4IL-8 IL-10 IL-12 and TNF-a might serve as biomarkers forinfections and that IL-2 IL-8 or IL-10 is potentially able todistinguish between bacterial and viral infections [22]
Mannosylated human serum albumin labelled with 68Gavia NOTA chelator moiety ([68Ga]Ga-NOTA-MSA) wastested in a rat model of myocarditis targetingmannose recep-tors expressed onmacrophages infiltratingmyocardium [66]The uptake in the diseased myocardium was considerablyhigher than that of the normal one and it was precludedby administration of excess of nonlabelled MSA indicatingbinding specificity The tracer build-up was also observed inthe organs of macrophage accumulation
[68Ga]Ga-DOTA was investigated for the quantificationof increased blood flow which is one of the key events ininflammation [226] The uptake kinetics of [68Ga]Ga-DOTAin the site of inflammation in rats with induced inflamma-tion correlated well with that of 15O-water suggesting highrelevance [68Ga]Ga-DOTA
9 Pretargeted Imaging
The half-life of 68Ga is shorter than that of 64Cu 67Ga 99mTc89Zr 111In and 123124125I and thus in contrast to the latterit is not compatible with slow pharmacokinetics of largemolecules such as antibodies and glycoproteins The rangeof antigen-specific antibodies relevant to inflammation andinfection is broad and a number of 99mTc-labelled antibodieswere used clinically [20 21 227] The respective range of68Ga-based agents could be similarThe solution to overcomethe incompatibility of half-life time frames could be eitherthe reduction of the antibody size or the application of thepretargeting concept
The history of the pretargeting concept spans threedecades predominantly in the field of oncology [228ndash230]It was developed to improve image contrast and dosimetryin immunoimaging and radioimmunotherapy when usingradiolabelled antibody ligands with slow pharmacokinetics[231] The arsenal of antibodies is vast and diverse encourag-ing extensive investment into development of techniques thatwould allow their exploration to the fullest Pretargeting con-siders at least two major steps wherein a functionalized anti-body is first administered for target localization and clearancefrom blood and normal tissue and thereafter a radiolabelledsmall molecule capable of binding to the functionalized
antibody due to high affinity or covalent interaction is admin-istered The key properties of the radiolabelled molecules arefast pharmacokinetic and clearance Several techniques havebeen developed for the realization of pretargeting conceptincluding avidinstreptavidin-biotin systems [216 217 232233] bispecific antibodies (bsmAb) with haptens [232 234ndash254] antibody-oligonucleotide conjugates with complemen-tary oligonucleotides [255] biorthogonal systems allowingcovalent chemical reactions in vivo (Figure 8)
The high affinity of biotin to avidin and streptavidinproteins was utilized clinically and preclinically in pretar-geting approach for the imaging and therapy of pancreaticadenocarcinoma [232] glioblastoma [256] and lymphoma[257] However this pretargeting technique may requirethree steps in order to eliminate the excess of antibody-(strept)avidin conjugate circulating in the blood and notbound to the target by adding clearing agent Anotherapplication of the technique was monitoring transplantationof islets of Langerhans in the treatment for type 1 diabetesmellitus wherein the cells or cellmimetics were conjugated to(strept)avidin prior to the transplantation [216 217] Severalanalogues of biotin comprising DOTA chelate moiety forlabelling with 68Ga and ethylene glycol linker of variouslength demonstrated the influence of the latter on the affinitytowards avidin
Particular example of hapten molecules is the ones com-prising histamine-succinyl-glycine (HSG) motif and chelatemoiety [251ndash253 258] for the complexationwith 68Ga Severalanalogues were developed for the imaging of carcinoem-bryonic antigen (CEA) pretargeted with anti-CEA bsmAb[254 259 260] and two clinical studies of medullary thyroidcarcinoma and breast carcinoma positive for CEA using68Ga-labelled hapten molecules and bsmAb were initiated[261]
Bioorthogonal reactions are fast regioselective requiringsmall reagent concentration and occurring under mild con-ditions often in aqueous solution and temperature below 37∘C[262 263] Amongst various biorthogonal reaction types thecycloaddition of tetrazines and various dienophiles referredto as inverse-electron-demandDiels-Alder (IEDDA) reactionis themost successful in the context of pretargeting Antibod-ies functionalized with trans-cyclooctene (TCO) and a radi-olabelled tetrazine that can interact in vivo based on IEDDAreaction were studied [264ndash267] In particular 68Ga-labelledtetrazine dextran demonstrated favorable pharmacokineticsin a healthy mouse [264] However the proof of concept is tobe performed in a xenografted animal Accumulation of anti-TAG72 [265] and anti-A33 [266] antibodies functionalizedwith TCO in mouse xenografts was visualized respectivelyby an 111In and 64Cu-labelled tetrazine analogues Anti-CA199 antibody-TCO in combination with 177Lu-labelledtetrazine demonstrated radiotherapeutic effect in pancreaticcancer murine model [267]
Thepretargeted imaging techniquesmay contribute to theexpansion of immuno-PET with 68Ga providing the intrinsicadvantages of 68Ga and PET As mentioned above mostof the developed radiolabelled counterparts of pretargetingtechniques have demonstrated promising results There are
14 Contrast Media amp Molecular Imaging
H
ON
NN
O
OO
OO
NH
NS
NH
ONH
O
HO
ONH
O
Ga
HN
NH
NH
O
OO
HNN
HN
NH
NH
O
OO
HNN
（2
(a)
NH
O
O
NH
N
NNGa
O O
O O
O
O
O
N N
NN
OO
（2
(b)
N
N
O
O
N
N
O
O
O
NH
O
O
ONH
NHS
O
H
HO
NH
+
minus
(c)
Figure 8 Schematic presentation of pretargeting techniques (a) bispecific antibodies engineered to specifically bind with radiolabelledhapten molecules (b) bioorthogonal click chemistry for fast and specific covalent binding between for example a trans-cyclooctenefunctionalized antibody and a radiolabelled tetrazine (c) interaction between antibody-(strept)avidin conjugate and radiolabelled biotinutilizing extremely high affinity of (strept)avidin and biotin
Contrast Media amp Molecular Imaging 15
a considerable number of potential antibody biomarkersthat could be considered for the imaging of infection andinflammation
10 Theranostics Potential
Theranostics [268] embraces realization of personalizedmedicine by conducting diagnosis on individual basis andproviding possibility of predicting the efficacy of a specifictreatment and following up the response to the treatmentenabling adjustment of the latter very early in the processIn the context of nuclear medicine wherein the radiophar-maceuticals targeted at biomarkers specific to a disease cancarry either diagnostic radionuclides or therapeutic ones theconcept can be denoted as radiotheranostics [28] The tar-geted molecular imaging such as PET can offer noninvasivediagnosis specific to the disease for example tumour-typespecific and provide accurate localization of the lesions Thestrongest advantage of PET is the potential for quantificationof the target for example receptor expression investigationof the uptake kinetics and estimation of the dosimetryThesecharacteristics of PET allow for individualized treatmentselection and planning monitoring of treatment responseand detection of recurrent diseaseThe individualized patientmanagement provides such advantages as optimization ofthe treatment regimen for the improved response and exclu-sion of futile treatments minimization of risks and toxicitywith overall outcome of reduced cost and patient distressThe importance of individualized patient management wasdemonstrated by clinical studies wherein the influence ofdose of the administered radiopharmaceutical targeted atreceptors overexpressed in cancer lesions on the diagnosticoutcome was investigated in the same patient [85 269270] 68Ga-labelled SST analogues [26ndash28 271] and Affibodymolecules [5 272ndash274] used respectively in NENs andbreast cancer patients are the most prominent examplesof (radio)theranostics involving 68GaPET wherein 68Ga-labelled analogues were used not only for localization of thelesions but also for staging patient stratification prognosistherapy selection and monitoring of the response to thetreatment of NETs and other cancer types [2ndash4 6 85 176275ndash277]
The methodology can be translated to inflammationand infection allowing for accurate and specific selection oftreatment regimen and for follow-up and evaluation of theresponse to therapy resulting in improved treatment efficacyand decreased cost and side effects The accommodation ofboth imaging function and antibiotic function in the samemolecule is a novel example of a theranostic agent [278]A series of siderophores conjugated with DOTA moiety forthe radiolabelling and with antibiotics for the treatmentof bacterial infection were investigated preclinically Theaccumulation of the intravenously administered ampicillinconjugate in the site of subcutaneously injected P aeruginosain mice was clearly and focally visualized within 06 h withretention for at least 24 h These results obtained usinganalogues carrying dye for optical imaging can be translatedto 68Ga-labelled counterparts for PET
11 Conclusions
The medical need for specific agents for noninvasive quan-titative and whole-body imaging of inflammation and infec-tion has not been met yet despite decades of research How-ever the prerequisites in terms of identification of potentialtargets design and synthesis of the respective ligands andimaging technologies are evolving very fast The potentialof accurate and quantitative lesion localization as well asmonitoring of the treatment response promises personalizedpatient management
The use of 68Ga in oncology is established proving thestrong potential of 68Ga for the promotion of PET technol-ogy for effective and efficient diagnostics and personalizedmedicineThe experience of oncological 68Ga-based agents isgetting translated to inflammation and infection Pretargetedimaging technology opens wide possibilities based on anti-body biomarkers
Conflicts of Interest
The author declares that there are no conflicts of interestregarding the publication of this article
References
[1] I Velikyan ldquoContinued rapid growth inGa applications update2013 to June 2014rdquo Journal of Labelled CompoundsampRadiophar-maceuticals pp 99ndash121 2015
[2] I Velikyan ldquo 68Ga-based radiopharmaceuticals Production andapplication relationshiprdquo Molecules vol 20 no 7 pp 12913ndash12943 2015
[3] M Fani P Peitl and I Velikyan ldquoCurrent status of radiophar-maceuticals for the theranostics of neuroendocrine neoplasmsrdquoPharmaceuticals vol 10 no 1 article no 30 2017
[4] I Velikyan ldquoPositron emitting [68Ga]Ga-based imaging agentsChemistry and diversityrdquoMedicinal Chemistry vol 7 no 5 pp345ndash379 2011
[5] J Sorensen I Velikyan D Sandberg et al ldquoMeasuringHER2-receptor expression in metastatic breast cancer using[68Ga]ABY-025 Affibody PETCTrdquo Theranostics vol 6 no 2pp 262ndash271 2016
[6] I Velikyan ldquoProspective of 68Ga-Radiopharmaceutical devel-opmentrdquoTheranostics vol 4 no 1 pp 47ndash80 2014
[7] P Lankinen T J Makinen T A Poyhonen et al ldquo68Ga-DOTAVAP-P1 PET imaging capable of demonstrating the phaseof inflammation in healing bones and the progress of infectionin osteomyelitic bonesrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 35 no 2 pp 352ndash364 2008
[8] T UjulaMHuttunen P Luoto et al ldquoMatrixmetalloproteinase9 targeting peptides Syntheses 68Ga-labeling and preliminaryevaluation in a rat melanoma xenograft modelrdquo BioconjugateChemistry vol 21 no 9 pp 1612ndash1621 2010
[9] A Autio T Ujula P Luoto S Salomaki S Jalkanen and ARoivainen ldquoPET imaging of inflammation and adenocarcinomaxenografts using vascular adhesion protein 1 targeting peptide68Ga-DOTAVAP-P1 Comparison with 18F-FDGrdquo EuropeanJournal of Nuclear Medicine and Molecular Imaging vol 37 no10 pp 1918ndash1925 2010
16 Contrast Media amp Molecular Imaging
[10] J Silvola A Autio P Luoto S Jalkanen andA Roivainen ldquoPre-liminary evaluation of novel 68Ga-DOTAVAP-PEG-P2 peptidetargeting vascular adhesion protein-1rdquo Clinical Physiology andFunctional Imaging vol 30 no 1 pp 75ndash78 2010
[11] T Ujula S Salomaki P Virsu et al ldquoSynthesis 68Ga labelingand preliminary evaluation of DOTA peptide binding vascularadhesion protein-1 a potential PET imaging agent for diagnos-ing osteomyelitisrdquo Nuclear Medicine and Biology vol 36 no 6pp 631ndash641 2009
[12] A Autio T Henttinen H J Sipila S Jalkanen and ARoivainen ldquoMini-PEG spacering of VAP-1-targeting 68Ga-DOTAVAP-P1 peptide improves PET imaging of inflamma-tionrdquo EJNMMI Research vol 1 no 1 pp 1ndash7 2011
[13] K Aalto A Autio E A Kiss et al ldquoSiglec-9 is a novel leukocyteligand for vascular adhesion protein-1 and can be used in PETimaging of inflammation and cancerrdquo Blood vol 118 no 13 pp3725ndash3733 2011
[14] V Kumar D K Boddeti S G Evans F Roesch and RHowman-Giles ldquoPotential use of 68Ga-apo-transferrin as a PETimaging agent for detecting Staphylococcus aureus infectionrdquoNuclear Medicine and Biology vol 38 no 3 pp 393ndash398 2011
[15] M Petrik H Haas G Dobrozemsky et al ldquo68Ga-siderophoresfor PET imaging of invasive pulmonary aspergillosis Proof ofprinciplerdquo Journal of Nuclear Medicine vol 51 no 4 pp 639ndash645 2010
[16] M Petrik H Haas M Schrettl A Helbok M Blatzer and CDecristoforo ldquoIn vitro and in vivo evaluation of selected 68Ga-siderophores for infection imagingrdquo Nuclear Medicine andBiology vol 39 no 3 pp 361ndash369 2012
[17] M Petrik GM Franssen H Haas et al ldquoPreclinical evaluationof two 68Ga-siderophores as potential radiopharmaceuticals forAspergillus fumigatus infection imagingrdquo European Journal ofNuclearMedicine andMolecular Imaging vol 39 no 7 pp 1175ndash1183 2012
[18] A Rizzello D Di Pierro F Lodi et al ldquoSynthesis and qualitycontrol of 68Ga citrate for routine clinical PETrdquo NuclearMedicine Communications vol 30 no 7 pp 542ndash545 2009
[19] C Nanni C Errani and L Boriani ldquo 68Ga-citrate PETCT forevaluating patients with infections of the bone preliminaryresultsrdquo Journal of Nuclear Medicine vol 51 no 12 pp 1932ndash1936 2010
[20] S S Das A V Hall D W Wareham and K E Britton ldquoInfec-tion imaging with radiopharmaceuticals in the 21st centuryrdquoBrazilian Archives of Biology and Technology vol 45 no spepp 25ndash37 2002
[21] A Signore and A W J M Glaudemans ldquoThe molecularimaging approach to image infections and inflammation bynuclear medicine techniquesrdquo Annals of Nuclear Medicine vol25 no 10 pp 681ndash700 2011
[22] T Yusa K Tateda A Ohara and S Miyazaki ldquoNew possiblebiomarkers for diagnosis of infections and diagnostic distinc-tion between bacterial and viral infections in childrenrdquo Journalof Infection and Chemotherapy vol 23 no 2 pp 96ndash100 2017
[23] A Signore A W J M Glaudemans O Gheysens C Lauriand O A Catalano ldquoNuclear Medicine Imaging in PediatricInfection or Chronic Inflammatory Diseasesrdquo Seminars inNuclear Medicine vol 47 no 3 pp 286ndash303 2017
[24] I Velikyan ldquoMolecular imaging and radiotherapyTheranosticsfor personalized patient managementrdquo Theranostics vol 2 no5 pp 424ndash426 2012
[25] F Rosch and R P Baum ldquoGenerator-based PET radiophar-maceuticals for molecular imaging of tumours On the way
to THERANOSTICSrdquo Dalton Transactions vol 40 no 23 pp6104ndash6111 2011
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[29] J Czernin andWAWeber ldquoIssues and controversies in nuclearmedicine Introductionrdquo Journal of Nuclear Medicine vol 52no Supplement 2 pp 1Sndash2S 2011
[30] S J Goldsmith and S Vallabhajosula ldquoClinically proven radio-pharmaceuticals for infection imaging mechanisms and appli-cationsrdquo Seminars in Nuclear Medicine vol 39 no 1 pp 2ndash102009
[31] M F Tsan ldquoMechanism of gallium-67 accumulation in inflam-matory lesionsrdquo Journal of Nuclear Medicine vol 26 no 1 pp88ndash92 1985
[32] S L Kipper ldquoRadiolabelled leukocyte imaging of the abdomenrdquoin Nuclear Medicine Annual J Freeman Ed pp 81ndash126 RavenPress New York NY USA 1995
[33] F Jamar J Buscombe A Chiti et al ldquoEANMSNMMI guidelinefor 18F-FDG use in inflammation and infectionrdquo Journal ofNuclear Medicine vol 54 no 4 pp 647ndash658 2013
[34] C J Palestro ldquoThe current role of gallium imaging in infectionrdquoSeminars in Nuclear Medicine vol 24 no 2 pp 128ndash141 1994
[35] M S Akhtar M B Imran M A Nadeem and A ShahidldquoAntimicrobial peptides as infection imaging agents better thanradiolabeled antibioticsrdquo International Journal of Peptides vol2012 Article ID 965238 19 pages 2012
[36] D Delbeke and G M Segall ldquoStatus of and trends in nuclearmedicine in the United Statesrdquo Journal of Nuclear Medicine vol52 no 2 2011
[37] S S Gambhir J Czernin J Schwimmer D H Silverman R EColeman and M E Phelps ldquoA tabulated summary of the FDGPET literaturerdquo Journal of Nuclear Medicine vol 42 pp 1Sndash93S2001
[38] M J Lindsay B A Siegel S R Tunis et al ldquoThe NationalOncologic PET Registry ExpandedMedicare coverage for PETunder coverage with evidence developmentrdquo American Journalof Roentgenology vol 188 no 4 pp 1109ndash1113 2007
[39] F Gemmel H Van Den Wyngaert C Love M M Welling PGemmel and C J Palestro ldquoProsthetic joint infectionsradionuclide state-of-the-art imagingrdquo European Journal ofNuclearMedicine andMolecular Imaging vol 39 no 5 pp 892ndash909 2012
[40] J Sorensen ldquoHow does the patient benefit from clinical PETrdquoTheranostics vol 2 no 5 pp 427ndash436 2012
[41] S L Rice C A Roney P Daumar and J S Lewis ldquoThe nextgeneration of positron emission tomography radiopharmaceu-ticals in oncologyrdquo Seminars in Nuclear Medicine vol 41 no 4pp 265ndash282 2011
[42] R LWahl JMHerman and E Ford ldquoThePromise and Pitfallsof Positron Emission Tomography and Single-Photon EmissionComputed Tomography Molecular Imaging-Guided RadiationTherapyrdquo Seminars in Radiation Oncology vol 21 no 2 pp 88ndash100 2011
Contrast Media amp Molecular Imaging 17
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[44] X Li W Bauer I Israel et al ldquoTargeting p-selectin by gallium-68-labeled fucoidan positron emission tomography for nonin-vasive characterization of vulnerable plaques Correlation within vivo 176t mrirdquo Arteriosclerosis Thrombosis and VascularBiology vol 34 no 8 pp 1661ndash1667 2014
[45] S Eichendorff P Svendsen D Bender et al ldquoBiodistributionand PET Imaging of a Novel [68Ga]-Anti-CD163-AntibodyConjugate in Rats with Collagen-Induced Arthritis and inControlsrdquoMolecular Imaging and Biology vol 17 no 1 pp 87ndash93 2014
[46] Z Zhu Y Yin K Zheng et al ldquoEvaluation of synovial angiogen-esis in patients with rheumatoid arthritis using 68Ga-PRGD2PETCT A prospective proof-of-concept cohort studyrdquo Annalsof the Rheumatic Diseases vol 73 no 6 pp 1269ndash1272 2014
[47] J S Eo J C Paeng S Lee et al ldquoAngiogenesis imaging inmyocardial infarction using 68Ga-NOTA- RGD PET Charac-terization and application to therapeutic efficacy monitoring inratsrdquo Coronary Artery Disease vol 24 no 4 pp 303ndash311 2013
[48] J H Kim Y-H Kim Y J Kim et al ldquoQuantitative positronemission tomography imaging of angiogenesis in rats with fore-limb ischemia using 68Ga-NOTA-c(RGDyK)rdquo Angiogenesisvol 16 no 4 pp 837ndash846 2013
[49] I Laitinen J Notni K Pohle et al ldquoComparison of cyclicRGD peptides for 120572v1205733 integrin detection in a rat model ofmyocardial infarctionrdquo EJNMMI Research vol 3 no 1 pp 1ndash9 2013
[50] M Kiugel I Dijkgraaf V Kyto et al ldquoDimeric [68Ga]DOTA-RGD Peptide Targeting 120572 ltinfgtvltinfgt 120573 ltinfgt3ltinfgt Inte-grin Reveals Extracellular Matrix Alterations after MyocardialInfarctionrdquo Molecular Imaging and Biology vol 16 no 6 pp793ndash801 2014
[51] M Gronman M Tarkia T Kiviniemi et al ldquoImaging of 120572v1205733integrin expression in experimental myocardial ischemia with[68Ga]NODAGA-RGD positron emission tomographyrdquo Jour-nal of Translational Medicine vol 15 no 1 p 144 2017
[52] J Haukkala I Laitinen P Luoto et al ldquo68Ga-DOTA-RGDpep-tide Biodistribution and binding into atherosclerotic plaquesin micerdquo European Journal of Nuclear Medicine and MolecularImaging vol 36 no 12 pp 2058ndash2067 2009
[53] H Virtanen A Autio R Siitonen et al ldquo68Ga-DOTA-Siglec-9- a new imaging tool to detect synovitisrdquo Arthritis Research ampTherapy vol 17 no 1 article no 308 2015
[54] J Retamal J Sorensen M Lubberink et al ldquoFeasibility of(68) Ga-labeled Siglec-9 peptide for the imaging of acutelung inflammation a pilot study in a porcine model of acuterespiratory distress syndromerdquoAm JNuclMedMol Imaging vol6 no 1 pp 18ndash31 2016
[55] J M U Silvola H Virtanen R Siitonen et al ldquoLeukocytetrafficking-associated vascular adhesion protein 1 is expressedand functionally active in atherosclerotic plaquesrdquo ScientificReports vol 6 Article ID 35089 2016
[56] H Ahtinen J Kulkova L Lindholm et al ldquo68Ga-DOTA-Siglec-9 PETCT imaging of peri-implant tissue responses andstaphylococcal infectionsrdquo EJNMMI Research vol 4 no 1article no 45 pp 1ndash11 2014
[57] A Autio S Jalkanen and A Roivainen ldquoNuclear imaging ofinflammation Homing-associated molecules as targetsrdquo EJN-MMI Research vol 3 no 1 pp 1ndash7 2013
[58] J TThackeray T Derlin AHaghikia et al ldquoMolecular Imagingof the Chemokine Receptor CXCR4 after Acute MyocardialInfarctionrdquo JACC Cardiovascular Imaging vol 8 no 12 pp1417ndash1426 2015
[59] J S Schmid A Schirbel A K Buck S Kropf H-J Westerand C Lapa ldquoPentixafor-Positron Emission TomographyComputed Tomography Detects Chemokine Receptor CXCR4Expression after Ischemic Strokerdquo Circulation CardiovascularImaging vol 9 no 9 Article ID e005217 2016
[60] J Zhou G Hao H Weng et al ldquoIn vivo evaluation ofmedical device-associated inflammation using a macrophage-specific positron emission tomography (PET) imaging proberdquoBioorganic amp Medicinal Chemistry Letters vol 23 no 7 pp2044ndash2047 2013
[61] S A Kularatne M-J Belanger X Meng et al ldquoComparativeanalysis of folate derived PET imaging agents with [ 18F]-2-fluoro-2-deoxy-d-glucose using a rodent inflammatory pawmodelrdquo Molecular Pharmaceutics vol 10 no 8 pp 3103ndash31112013
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[63] T Lincke J Singer R Kluge O Sabri and R Paschke ldquoRela-tive quantification of indium-111 pentetreotide and gallium-68DOTATOC uptake in the thyroid gland and association withthyroid pathologiesrdquoThyroid vol 19 no 4 pp 381ndash389 2009
[64] A Rominger T Saam E Vogl et al ldquoIn vivo imaging ofmacrophage activity in the coronary arteries using 68Ga-DOTATATE PETCT correlation with coronary calcium bur-den and risk factorsrdquo Journal of Nuclear Medicine vol 51 no 2pp 193ndash197 2010
[65] J M Tarkin F R Joshi N R Evans et al ldquoDetection ofAtherosclerotic Inflammation by 68Ga-DOTATATE PET Com-pared to [18F]FDG PET Imagingrdquo Journal of the AmericanCollege of Cardiology vol 69 no 14 pp 1774ndash1791 2017
[66] S-P Lee H-J Im S Kang et al ldquoNoninvasive imaging ofmyocardial inflammation in myocarditis using 68Ga-taggedmannosylated human serum albumin positron emissiontomographyrdquoTheranostics vol 7 no 2 pp 413ndash424 2017
[67] Z Zha J Song S R Choi et al ldquo68Ga-Bivalent PolypegylatedStyrylpyridine Conjugates for Imaging A120573 Plaques in CerebralAmyloid Angiopathyrdquo Bioconjugate Chemistry vol 27 no 5 pp1314ndash1323 2016
[68] H Watanabe M Ono S Iikuni et al ldquoA 68Ga complex basedon benzofuran scaffold for the detection of 120573-amyloid plaquesrdquoBioorganic amp Medicinal Chemistry Letters vol 24 no 20 pp4834ndash4837 2014
[69] D Cressier M Dhilly T T Cao Pham et al ldquoGallium-68 Com-plexes Conjugated to Pittsburgh Compound B Radiolabelingand Biological EvaluationrdquoMolecular Imaging and Biology vol18 no 3 pp 334ndash343 2016
[70] D Satpati CArjun R KrishnamohanG Samuel and S Baner-jee ldquo68Ga-labeledCiprofloxacinConjugates as Radiotracers forTargeting Bacterial InfectionrdquoChemical Biology ampDrug Designvol 87 no 5 pp 680ndash686 2016
[71] T Ebenhan N Chadwick and M M Sathekge ldquoPeptidesynthesis characterization and 68Ga-radiolabeling of NOTA-conjugated ubiquicidin fragments for prospective infectionimaging with PETCTrdquo Nuclear Medicine and Biology vol 41no 5 pp 390ndash400 2014
18 Contrast Media amp Molecular Imaging
[72] T Ebenhan J R Zeevaart and J D Venter ldquoPreclinicalevaluation of 68Ga-labeled 1 4 7-triazacyclononane-1 4 7-triacetic acid-ubiquicidin as a radioligand for PET infectionimagingrdquo Journal of Nuclear Medicine vol 55 no 2 pp 308ndash314 2014
[73] B B Mokaleng T Ebenhan S Ramesh et al ldquoSynthesis 68Ga-radiolabeling and preliminary in vivo assessment of adepsipeptide-derived compound as a potential PETCTinfection imaging agentrdquo BioMed Research International vol2015 Article ID 284354 2015
[74] T Ebenhan B Mokaleng J Venter H Kruger J Zeevaart andM Sathekge ldquoPreclinical Assessment of a 68Ga-DOTA-Functionalized Depsipeptide as a Radiodiagnostic InfectionImaging AgentrdquoMolecules vol 22 no 9 p 1403 2017
[75] S Chopra B Singh A Koul A Mishra and H Wester ldquoSyn-thesis of DOTA conjugated GF-17 and RAWVAWR-NH2 andradiolabeling with 68Ga as a potential PET tracer for infectionimagingrdquo J Nucl Med vol 57 Supplement 2 p 1115 2016
[76] M Petrik HHaas P Laverman et al ldquo 68Ga-triacetylfusarinineC and 68Ga-ferrioxamine e for aspergillus infection imaginguptake specificity in various microorganismsrdquoMolecular Imag-ing and Biology vol 16 no 1 pp 102ndash108 2014
[77] V Kumar and D K Boddeti ldquo 68Ga-radiopharmaceuticals forPET imaging of infection and inflammationrdquo Recent Results inCancer Research vol 194 pp 189ndash219 2013
[78] M Vorster A Maes A Jacobs et al ldquoEvaluating the possiblerole of 68Ga-citrate PETCT in the characterization of indeter-minate lung lesionsrdquo Annals of Nuclear Medicine vol 28 no 6pp 523ndash530 2014
[79] M Vorster B Mokaleng M M Sathekge and T Ebenhan ldquoAmodified technique for efficient radiolabeling of 68Ga-citratefrom a SnO2-based 68Ge68Ga generator for better infectionimagingrdquoHellenic Journal of Nuclear Medicine vol 16 no 3 pp193ndash198 2013
[80] S Salomaeki J Kemppainen U Hohenthal et al ldquoHead-to-head comparison of 68Ga-Citrate and 18F-FDG PETCT fordetection of infectious foci in patients with staphylococcusaureus bacteraemiardquo Contrast Media amp Molecular Imaging vol2017 p 8 2017
[81] L Fass ldquoImaging and cancer a reviewrdquoMolecular Oncology vol2 no 2 pp 115ndash152 2008
[82] A Chopra L Shan W C Eckelman et al ldquoMolecular imagingand contrast agent database (MICAD) Evolution and progressrdquoMolecular Imaging and Biology vol 14 no 1 pp 4ndash13 2012
[83] A Sanchez-Crespo P Andreo and S A Larsson ldquoPositronflight in human tissues and its influence on PET image spatialresolutionrdquo European Journal of Nuclear Medicine and Molecu-lar Imaging vol 31 no 1 pp 44ndash51 2004
[84] H W A M De Jong L Perk G W M Visser R Boellaard GAM S Van Dongen and A A Lammertsma ldquoHigh resolutionPET imaging characteristics of68Ga 124i and89Zr comparedto18Frdquo in Proceedings of the Nuclear Science Symposium Con-ference Record 2005 IEEE pp 1624ndash1627 Puerto Rico October2005
[85] I Velikyan A Sundin B Eriksson et al ldquoIn vivo bindingof [68Ga]-DOTATOC to somatostatin receptors in neuroen-docrine tumours - impact of peptide massrdquo Nuclear Medicineand Biology vol 37 no 3 pp 265ndash275 2010
[86] U Eberlein and M Lassmann ldquoDosimetry of [68Ga]-labeledcompoundsrdquo Applied Radiation and Isotopes vol 76 pp 70ndash742013
[87] C PettinatoA SarnelliMDiDonna et al ldquo68Ga-DOTANOCBiodistribution and dosimetry in patients affected by neuroen-docrine tumorsrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 35 no 1 pp 72ndash79 2008
[88] B P Burke G S Clemente and S J Archibald ldquoRecentadvances in chelator design and labelling methodology for68Ga radiopharmaceuticalsrdquo Journal of Labelled Compoundsand Radiopharmaceuticals vol 57 no 4 pp 239ndash243 2014
[89] I Velikyan U Rosenstrom S Estrada et al ldquoSynthesis andpreclinical evaluation of 68Ga-labeled collagelin analogs forimaging and quantification of fibrosisrdquo Nuclear Medicine andBiology vol 41 no 9 pp 728ndash736 2014
[90] M F Ferreira G Pereira J P Andre and etal C ldquoGa[NO2A-N-(120572-amino)propionate] chelates Synthesis and evaluation aspotential tracers for 68Ga PETrdquoDalton Transactions vol 43 no21 pp 8037ndash8047 2014
[91] J Notni J Simecek and H-J Wester ldquoPhosphinic acid func-tionalized polyazacycloalkane chelators for radiodiagnosticsand radiotherapeutics Unique characteristics and applicationsrdquoChemMedChem vol 9 no 6 pp 1107ndash1115 2014
[92] J Simecek O Zemek P Hermann J Notni and H J WesterldquoTailored gallium( III) chelator NOPO synthesis characteriza-tion bioconjugation and application in preclinical Ga-68-PETimagingrdquoMolecular Pharmaceutics 2013
[93] D Parker B P Waldron and D S Yufit ldquoCrystallographicand solution NMR structural analyses of four hexacoordinatedgallium(iii) complexes based on ligands derived from 6-amino-perhydro-14-diazepinerdquo Dalton Transactions vol 42 no 22pp 8001ndash8008 2013
[94] B P Waldron D Parker C Burchardt D S Yufit M ZimnyandF Roesch ldquoStructure and stability of hexadentate complexesof ligands based on AAZTA for efficient PET labelling withgallium-68rdquo Chemical Communications vol 49 no 6 pp 579ndash581 2013
[95] D Parker and B PWaldron ldquoConformational analysis and syn-thetic approaches to polydentate perhydro-diazepine ligandsfor the complexation of gallium(iii)rdquo Organic amp BiomolecularChemistry vol 11 no 17 pp 2827ndash2838 2013
[96] I Velikyan H Maecke and B Langstrom ldquoConvenient prepa-ration of 68Ga-based PET-radiopharmaceuticals at room tem-peraturerdquo Bioconjugate Chemistry vol 19 no 2 pp 569ndash5732008
[97] J Erchegyi R Cescato B Waser J E Rivier and J C ReubildquoN-Imidazolebenzyl-histidine substitution in somatostatin andin its octapeptide analogue modulates receptor selectivity andfunctionrdquo Journal of Medicinal Chemistry vol 54 no 17 pp5981ndash5987 2011
[98] R Saha N Saha R S Donofrio and L L Bestervelt ldquoMicrobialsiderophores Amini reviewrdquo Journal of Basic Microbiology vol53 no 4 pp 303ndash317 2013
[99] V Nikolova S Angelova N Markova and T Dudev ldquoGalliumas a Therapeutic Agent A Thermodynamic Evaluation of theCompetition between Ga3+ and Fe3+ Ions in MetalloproteinsrdquoThe Journal of Physical Chemistry B vol 120 no 9 pp 2241ndash2248 2016
[100] C R Chitambar ldquoGallium and its competing roles with ironin biological systemsrdquo Biochimica et Biophysica Acta (BBA) -Molecular Cell Research vol 1863 no 8 pp 2044ndash2053 2016
[101] J A Lessa M A Soares and R G dos Santos ldquoGallium(III)complexes with 2-acetylpyridine-derived thiosemicarbazonesantimicrobial and cytotoxic effects and investigation on theinteractions with tubulinrdquo BioMetals vol 26 pp 151ndash165 2013
Contrast Media amp Molecular Imaging 19
[102] M van Oosten M Hahn L M A Crane et al ldquoTargetedimaging of bacterial infections Advances hurdles and hopesrdquoFEMS Microbiology Reviews vol 39 no 6 pp 892ndash916 2015
[103] M Vorster AMaes C V DWiele andM Sathekge ldquoGallium-68 PET A Powerful Generator-based Alternative to Infectionand Inflammation Imagingrdquo Seminars in Nuclear Medicine vol46 no 5 pp 436ndash447 2016
[104] M Kircher and C Lapa ldquoNovel Noninvasive Nuclear MedicineImaging Techniques for Cardiac Inflammationrdquo Current Car-diovascular Imaging Reports vol 10 no 2 article no 6 2017
[105] D AHammoud ldquoMolecular imaging of inflammation Currentstatusrdquo Journal of Nuclear Medicine vol 57 no 8 pp 1161ndash11652016
[106] D R Brenner D Scherer K Muir et al ldquoA review of the appli-cation of inflammatory biomarkers in epidemiologic cancerresearchrdquo Cancer Epidemiology Biomarkers amp Prevention vol23 no 9 pp 1729ndash1751 2014
[107] M D Turner B Nedjai T Hurst and D J PenningtonldquoCytokines and chemokines at the crossroads of cell signallingand inflammatory diseaserdquo Biochimica et Biophysica Acta (BBA)- Molecular Cell Research vol 1843 no 11 pp 2563ndash2582 2014
[108] L Werner H Guzner-Gur and I Dotan ldquoInvolvement ofCXCR4CXCR7CXCL12 interactions in inflammatory boweldiseaserdquoTheranostics vol 3 no 1 pp 40ndash46 2013
[109] S Jalkanen and M Salmi ldquoVAP-1 and CD73 endothelial cellsurface enzymes in leukocyte extravasationrdquo ArteriosclerosisThrombosis and Vascular Biology vol 28 no 1 pp 18ndash26 2008
[110] G Malviya F Galli I Sonni and A Signore ldquoImaging T-lymphocytes in inflammatory diseases A nuclear medicineapproachrdquo The Quarterly Journal of Nuclear Medicine andMolecular Imaging vol 58 no 3 pp 237ndash257 2014
[111] S Gratz H J RennenO C BoermanW J Oyen and P Burmaldquo(99m)Tc-interleukin-8 for imaging acute osteomyelitisrdquo Jour-nal of Nuclear Medicine vol 42 no 8 pp 1257ndash1264 2001
[112] S Gratz H J Rennen O C Boerman W J Oyen andF H Corstens ldquoRapid imaging of experimental colitis with(99m)Tc-interleukin-8 in rabbitsrdquo Journal of Nuclear Medicnevol 42 no 6 pp 917ndash923 2001
[113] C Alkim H Alkim A R Koksal S Boga and I SenldquoAngiogenesis in inflammatory bowel diseaserdquo InternationalJournal of Inflammation vol 2015 Article ID 970890 2015
[114] I S Alam T H Witney G Tomasi et al ldquoRadiolabeled RGDtracer kinetics annotates differential 120572v1205733 integrin expressionlinked to cell intrinsic and vessel expressionrdquoMolecular Imagingand Biology vol 16 no 4 pp 558ndash566 2014
[115] J Notni K Pohle and H-J Wester ldquoBe spoilt for choice withradiolabelled RGD peptides Preclinical evaluation of 68Ga-TRAP(RGD)3rdquoNuclear Medicine and Biology vol 40 no 1 pp33ndash41 2013
[116] J Oxboel M Brandt-Larsen C Schjoeth-Eskesen et al ldquoCom-parison of two new angiogenesis PET tracers 68Ga-NODAGA-E[c(RGDyK)]2 and 64Cu-NODAGA-E[c(RGDyK)]2 in vivoimaging studies in human xenograft tumorsrdquo Nuclear Medicineand Biology vol 41 no 3 pp 259ndash267 2014
[117] J Simecek J Notni T G Kapp H Kessler and H-J WesterldquoBenefits of NOPO as chelator in gallium-68 peptides exempli-fied by preclinical characterization of 68Ga-NOPO-c(RGDfK)rdquoMolecular Pharmaceutics vol 11 no 5 pp 1687ndash1695 2014
[118] M Trajkovic-Arsic P Mohajerani A Sarantopoulos et alldquoMultimodal molecular imaging of integrin avb3 for in vivodetection of pancreatic cancerrdquo Journal of NuclearMedicine vol55 no 3 pp 446ndash451 2014
[119] H Cai and P S Conti ldquoRGD-based PET tracers for imagingreceptor integrin 120572 v1205733 expressionrdquo Journal of Labelled Com-pounds and Radiopharmaceuticals vol 56 no 5 pp 264ndash2792013
[120] I Dijkgraaf S Y A Terry W J Mcbride et al ldquoImagingintegrin alpha-v-beta-3 expression in tumors with an 18F-labeled dimeric RGD peptiderdquo Contrast Media amp MolecularImaging vol 8 no 3 pp 238ndash245 2013
[121] P A Knetsch M Petrik C Rangger et al ldquo[68Ga]NS3-RGD and [68Ga] Oxo-DO3A-RGD for imaging 120572v1205733 integrinexpression Synthesis evaluation and comparisonrdquo NuclearMedicine and Biology vol 40 no 1 pp 65ndash72 2013
[122] Z Liu and F Wang ldquoDevelopment of RGD-based radiotracersfor tumor imaging and therapy Translating from bench tobedsiderdquo Current Molecular Medicine vol 13 no 10 pp 1487ndash1505 2013
[123] H Choi J H Phi J C Paeng et al ldquoImaging of integrin 120572v1205733expression using 68Ga-RGD positron emission tomography inpediatric cerebral infarctrdquoMolecular Imaging vol 12 no 4 pp213ndash217 2013
[124] H-J Yoon K W Kang I K Chun et al ldquoCorrelation of breastcancer subtypes based on estrogen receptor progesteronereceptor and HER2 with functional imaging parameters from68Ga-RGD PETCT and 18F-FDG PETCTrdquo European Journalof Nuclear Medicine and Molecular Imaging vol 41 no 8 pp1534ndash1543 2014
[125] R P Baum H R Kulkarni D Muller et al ldquoFirst-in-human study demonstrating tumor-angiogenesis by PETCTimaging with 68Ga-NODAGA-THERANOST a high-affinitypeptidomimetic for 120572v1205733 integrin receptor targetingrdquo CancerBiotherapy andRadiopharmaceuticals vol 30 no 4 pp 152ndash1592015
[126] R Haubner A Finkenstedt A Stegmayr et alldquo[68Ga]NODAGA-RGD ndash Metabolic stability biodistributionand dosimetry data from patients with hepatocellularcarcinoma and liver cirrhosisrdquo European Journal of NuclearMedicine and Molecular Imaging vol 43 no 11 pp 2005ndash20132016
[127] V Lopez-Rodrıguez C Galindo-Sarco F O Garcıa-Perez GFerro-Flores O Arrieta and M A Avila-Rodrıguez ldquoPET-based human dosimetry of the dimeric 120572v1205733 integrin ligand68Ga-DOTA-E-[c(RGDfK)]2 a potential tracer for imagingtumor angiogenesisrdquo Journal of Nuclear Medicine vol 57 no 3pp 404ndash409 2016
[128] M V Backer Z Levashova V Patel et al ldquoMolecular imagingof VEGF receptors in angiogenic vasculature with single-chainVEGF-based probesrdquo Nature Medicine vol 13 no 4 pp 504ndash509 2007
[129] MV Backer Z Levashova R Levenson F G Blankenberg andJ M Backer ldquoCysteine-containing fusion tag for site-specificconjugation of therapeutic and imaging agents to targetingproteinsrdquoMethods in Molecular Biology (Clifton NJ) vol 494pp 275ndash294 2008
[130] M Eder A V Krivoshein M Backer J M Backer UHaberkorn and M Eisenhut ldquoScVEGF-PEG-HBED-CC andscVEGF-PEG-NOTA conjugates comparison of easy-to-labelrecombinant proteins for [68Ga]PET imaging of VEGF recep-tors in angiogenic vasculaturerdquo Nuclear Medicine and Biologyvol 37 no 4 pp 405ndash412 2010
[131] E Blom I Velikyan A Monazzam P Razifar et al ldquoSynthe-sis and characterization of scVEGF-PEG-[ 68Ga]NOTA andscVEGF-PEG-[ 68Ga]DOTA PET tracersrdquo Journal of Labelled
20 Contrast Media amp Molecular Imaging
Compounds and Radiopharmaceuticals vol 54 no 11 pp 685ndash692 2011
[132] S Gratz M Behe and O C Boerman ldquo 99119898Tc-E-selectinbinding peptide for imaging acute osteomyelitis in a novel ratmodelrdquo Nuclear Medicine Communications vol 22 no 9 pp1003ndash1013 2001
[133] S B Jensen M Kakela L Joslashdal et al ldquoExploring the radiosyn-thesis and in vitro characteristics of [68Ga]Ga-DOTA-Siglec-9rdquoJournal of Labelled Compounds and Radiopharmaceuticals vol60 no 9 pp 439ndash449 2017
[134] B A Teicher and S P Fricker ldquoCXCL12 (SDF-1)CXCR4pathway in cancerrdquo Clinical Cancer Research vol 16 no 11 pp2927ndash2931 2010
[135] O Jacobson I D Weiss D O Kiesewetter J M Farber andX Chen ldquoPET of tumor CXCR4 expression with 4-18F-T140rdquoJournal of Nuclear Medicine vol 51 no 11 pp 1796ndash1804 2010
[136] A Aghanejad A R Jalilian Y Fazaeli et al ldquoSynthesis andevaluation of [67Ga]-AMD3100 A novel imaging agent fortargeting the chemokine receptorCXCR4rdquo Scientia Pharmaceu-tica vol 82 no 1 pp 29ndash42 2014
[137] O Jacobson I D Weiss L P Szajek et al ldquoPET imaging ofCXCR4 using copper-64 labeled peptide antagonistrdquoTheranos-tics vol 1 pp 251ndash262 2011
[138] O Jacobson I D Weiss L P Szajek et al ldquoImprovement ofCXCR4 tracer specificity for PET imagingrdquo Journal of Con-trolled Release vol 157 no 2 pp 216ndash223 2012
[139] H J Wester U Keller M Schottelius et al ldquoDisclosing theCXCR4 expression in lymphoproliferative diseases by targetedmolecular imagingrdquo Theranostics vol 5 no 6 pp 618ndash6302015
[140] E Gourni O Demmer M Schottelius et al ldquoPET of CXCR4expression by a 68Ga-labeled highly specific targeted contrastagentrdquo Journal of NuclearMedicine vol 52 no 11 pp 1803ndash18102011
[141] O Demmer I Dijkgraaf U Schumacher et al ldquoDesignsynthesis and functionalization of dimeric peptides targetingchemokine receptor CXCR4rdquo Journal of Medicinal Chemistryvol 54 no 21 pp 7648ndash7662 2011
[142] O Demmer E Gourni U Schumacher H Kessler and H-JWester ldquoPET Imaging of CXCR4 Receptors in Cancer by a NewOptimized Ligandrdquo ChemMedChem vol 6 no 10 pp 1789ndash1791 2011
[143] U Hennrich L Seyler M Schafer et al ldquoSynthesis and invitro evaluation of 68Ga-DOTA-4-FBn-TN14003 a novel tracerfor the imaging of CXCR4 expressionrdquo Bioorganic amp MedicinalChemistry vol 20 no 4 pp 1502ndash1510 2012
[144] G P C George E Stevens O Aberg et al ldquoPreclinical evalua-tion of a CXCR4-specific 68Ga-labelled TN14003 derivative forcancer PET imagingrdquo Bioorganic amp Medicinal Chemistry vol22 no 2 pp 796ndash803 2014
[145] S Poty E Gourni P Desogere et al ldquoAMD3100 A VersatilePlatform for CXCR4 Targeting 68Ga-Based Radiopharmaceu-ticalsrdquo Bioconjugate Chemistry vol 27 no 3 pp 752ndash761 2016
[146] K Philipp-Abbrederis K Herrmann S Knop et al ldquoIn vivomolecular imaging of chemokine receptor CXCR4 expressionin patients with advancedmultiple myelomardquo EMBOMolecularMedicine vol 7 no 4 pp 477ndash487 2015
[147] Z Wang M Zhang L Wang et al ldquoProspective study of 68Ga-NOTA-NFB Radiation dosimetry in healthy volunteers andfirst application in glioma patientsrdquo Theranostics vol 5 no 8pp 882ndash889 2015
[148] I M Jackson P J Scott and S Thompson ldquoClinical Applica-tions of Radiolabeled Peptides for PETrdquo Seminars in NuclearMedicine vol 47 no 5 pp 493ndash523 2017
[149] C Lapa T Reiter R A Werner et al ldquo[68Ga]Pentixafor-PETCT for Imaging of Chemokine Receptor 4 Expression afterMyocardial Infarctionrdquo JACC Cardiovascular Imaging vol 8no 12 pp 1466ndash1468 2015
[150] C Rischpler S G Nekolla H Kossmann et al ldquoUpregu-lated myocardial CXCR4-expression after myocardial infarc-tion assessed by simultaneous GA-68 pentixafor PETMRIrdquoJournal of Nuclear Cardiology vol 23 no 1 pp 131ndash133 2016
[151] F Hyafil J Pelisek I Laitinen et al ldquoImaging the CytokineReceptorCXCR4 in atherosclerotic plaqueswith the radiotracer68Ga-Pentixafor for PETrdquo Journal of Nuclear Medicine vol 58no 3 pp 499ndash506 2017
[152] Y Yi ldquoFolate receptor-targeted diagnostics and therapeutics forinflammatory diseasesrdquo ImmuneNetwork vol 16 no 6 pp 337ndash343 2016
[153] C M Paulos M J Turk G J Breur and P S Low ldquoFolatereceptor-mediated targeting of therapeutic and imaging agentsto activated macrophages in rheumatoid arthritisrdquo AdvancedDrug Delivery Reviews vol 56 no 8 pp 1205ndash1217 2004
[154] W Han R Zaynagetdinov F E Yull et al ldquoMolecular imagingof folate receptor 120573-positive macrophages during acute lunginflammationrdquo American Journal of Respiratory Cell and Molec-ular Biology vol 53 no 1 pp 50ndash59 2015
[155] B Kuhle C Muller and T L Ross ldquoA Novel 68Ga-Labeledpteroic acid-based PET tracer for tumor imaging via the folatereceptorrdquo Recent Results in Cancer Research vol 194 pp 257ndash267 2013
[156] C Brand V A Longo M Groaning W A Weber and TReiner ldquoDevelopment of a New Folate-Derived Ga-68-BasedPET Imaging AgentrdquoMolecular Imaging and Biology vol 19 no5 pp 754ndash761 2017
[157] M Fani XWang G Nicolas et al ldquoDevelopment of new folate-based PET radiotracers Preclinical evaluation of 68Ga-DOTA-folate conjugatesrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 38 no 1 pp 108ndash119 2011
[158] C J Mathias M R Lewis D E Reichert et al ldquoPreparationof 66Ga- and 68Ga-labeled Ga(III)-deferoxamine-folate aspotential folate-receptor-targeted PET radiopharmaceuticalsrdquoNuclear Medicine and Biology vol 30 no 7 pp 725ndash731 2003
[159] S-M Kim N Choi S Hwang et al ldquoFolate receptor-specific positron emission tomography imaging with folic acid-conjugated tissue inhibitor of metalloproteinase-2rdquo Bulletin ofthe Korean Chemical Society vol 34 no 11 pp 3243ndash3248 2013
[160] M Fani M-L Tamma G P Nicolas et al ldquoIn vivo imagingof folate receptor positive tumor xenografts using novel 68Ga-NODAGA-folate conjugatesrdquo Molecular Pharmaceutics vol 9no 5 pp 1136ndash1145 2012
[161] C Muller and R Schibli ldquoProspects in folate receptor-targetedradionuclide therapyrdquo Frontiers in Oncology vol 3 Article IDArticle 249 2013
[162] A Jain A Mathur U Pandey et al ldquoSynthesis and evaluationof a 68Ga labeled folic acid derivative for targeting folatereceptorsrdquo Applied Radiation and Isotopes vol 116 pp 77ndash842016
[163] W Xia A R Hilgenbrink E L Matteson M B Lockwood J-X Cheng and P S Low ldquoA functional folate receptor is inducedduring macrophage activation and can be used to target drugsto activated macrophagesrdquo Blood vol 113 no 2 pp 438ndash4462009
Contrast Media amp Molecular Imaging 21
[164] E P Krenning W A P Breeman P P M Kooij et alldquoLocalisation of endocrine-related tumours with radioiodi-nated analogue of somatostatinrdquoThe Lancet vol 1 no 8632 pp242ndash244 1989
[165] E P Krenning D J KwekkeboomWH Bakker et al ldquoSomato-statin receptor scintigraphy with [111In-DTPA-d-Phe1]- and[123I-Tyr3]-octreotide the Rotterdam experience with morethan 1000 patientsrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 20 no 8 pp 716ndash731 1993
[166] A Stahl G Meisetschlager M Schottelius et al ldquo[123I]Mtr-TOCA a radioiodinated and carbohydrated analogue ofoctreotide Scintigraphic comparison with [111In]octreotiderdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 33 no 1 pp 45ndash52 2006
[167] R Lebtahi J le Cloirec C Houzard et al ldquoDetection of neu-roendocrine tumors 99mTc-P829 scintigraphy compared with111In-pentetreotide scintigraphyrdquo Journal of Nuclear Medicinevol 43 no 7 pp 889ndash895 2002
[168] C Decristoforo T Maina B Nock M Gabriel P Cordopatisand R Moncayo ldquo99mTc-demotate 1 First data in tumourpatients - Results of a pilotphase I studyrdquo European Journal ofNuclearMedicine andMolecular Imaging vol 30 no 9 pp 1211ndash1219 2003
[169] C Decristoforo S J Mather W Cholewinski E DonnemillerG Riccabona and R Moncayo ldquo(99m)Tc-EDDAHYNIC-TOC A new (99m)Tc-labelled radiopharmaceutical forimaging somatostatin receptor-positive tumours First clinicalresults and intra-patient comparison with 111In-labelledoctreotide derivativesrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 27 no 9 pp 1318ndash1325 2000
[170] A Hubalewska-Dydejczyk K Fross-Baron R Mikołajczak etal ldquo99mTc-EDDAHYNIC-octreotate scintigraphy an efficientmethod for the detection and staging of carcinoid tumoursResults of 3 yearsrsquo experiencerdquo European Journal of NuclearMedicine and Molecular Imaging vol 33 no 10 pp 1123ndash11332006
[171] M Bangard M Behe S Guhlke et al ldquoDetection of somato-statin receptor-positive tumours using the new 99mC-tricine-HYNIC-D-Phe1-Tyr3-octreotide First results in patients andcomparison with 111In-DTPA-D-Phe1-octreotiderdquo EuropeanJournal of Nuclear Medicine and Molecular Imaging vol 27 no6 pp 628ndash637 2000
[172] A Helisch G J Forster H Reber et al ldquoPre-therapeuticdosimetry and biodistribution of 86Y-DOTA- Phe1-Tyr3-octreotide versus 111In-pentetreotide in patients with advancedneuroendocrine tumoursrdquo European Journal of NuclearMedicine and Molecular Imaging vol 31 no 10 pp 1386ndash13922004
[173] M Henze J Schuhmacher P Hipp et al ldquoPET imaging ofsomatostatin receptors using [68GA]DOTA-D-Phe1-Tyr3-Octreotide First results in patients with meningiomasrdquo Journalof Nuclear Medicine vol 42 no 7 pp 1053ndash1056 2001
[174] I Kayani J B Bomanji A Groves et al ldquoFunctional imaging ofneuroendocrine tumors with combined PETCT using 68Ga-DOTATATE (Dota-DPhe1 Tyr3-octreotate) and 18F-FDGrdquoCancer vol 112 no 11 pp 2447ndash2455 2008
[175] A Al-Nahhas ldquoNuclear medicine imaging of neuroendocrinetumoursrdquo Clinical Medicine vol 12 no 4 pp 377ndash380 2012
[176] V Ambrosini S Nicolini P Caroli et al ldquoPETCT imaging indifferent types of lung cancer an overviewrdquo European Journal ofRadiology vol 81 no 5 pp 988ndash1001 2012
[177] V Ambrosini D Campana P Tomassetti and S Fanti ldquo68Ga-labelled peptides for diagnosis of gastroenteropancreatic NETrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 39 no 1 pp S52ndashS60 2012
[178] K E Oberg J-C Reubi D J Kwekkeboom and E P KrenningldquoRole of somatostatins in gastroenteropancreatic neuroen-docrine tumor development and therapyrdquoGastroenterology vol139 no 3 pp 753-753 2010
[179] K Oberg ldquoGallium-68 somatostatin receptor PETCT Is ittime to replace 111Indium DTPA octreotide for patients withneuroendocrine tumorsrdquo Endocrine Journal vol 42 no 1 pp3-4 2012
[180] R Srirajaskanthan I Kayani A M Quigley J Soh M ECaplin and J Bomanji ldquoThe role of 68Ga-DOTATATE PET inpatients with neuroendocrine tumors and negative or equivocalfindings on 111In-DTPA-octreotide scintigraphyrdquo Journal ofNuclear Medicine vol 51 no 6 pp 875ndash882 2010
[181] A Kroiss D Putzer and C Uprimny ldquoFunctional imag-ing in phaeochromocytoma and neuroblastoma with 68Ga-DOTA-Tyr3-octreotide positron emission tomography and123I-metaiodobenzylguanidinerdquo European Journal of NuclearMedicine and Molecular Imaging vol 38 no 5 pp 865ndash8732011
[182] M Naji C Zhao S J Welsh et al ldquo68Ga-DOTA-TATE PETvs 123I-MIBG in identifying malignant neural crest tumoursrdquoMolecular Imaging and Biology vol 13 no 4 pp 769ndash775 2011
[183] V Ambrosini P Tomassetti P Castellucci et al ldquoComparisonbetween 68Ga-DOTA-NOC and 18F-DOPA PET for the detec-tion of gastro-entero-pancreatic and lung neuro-endocrinetumoursrdquo European Journal of Nuclear Medicine and MolecularImaging vol 35 no 8 pp 1431ndash1438 2008
[184] D Putzer M Gabriel B Henninger et al ldquoBone metastasesin patients with neuroendocrine tumor 68Ga- DOTA-Tyr3-octreotide PET in comparison to CT and bone scintigraphyrdquoJournal of Nuclear Medicine vol 50 no 8 pp 1214ndash1221 2009
[185] L K Anzola-Fuentes M Chianelli F Galli et al ldquoSomatostatinreceptor scintigraphy in patients with rheumatoid arthritis andsecondary Sjogrenrsquos syndrome treated with Infliximab a pilotstudyrdquo EJNMMI Research vol 6 no 1 article no 49 2016
[186] T Nobashi Y Nakamoto T Kubo et al ldquoThe utility of PETCTwith 68Ga-DOTATOC in sarcoidosis comparison with 67Ga-scintigraphyrdquoAnnals ofNuclearMedicine vol 30 no 8 pp 544ndash552 2016
[187] C Boy T A Heusner T D Poeppel et al ldquo68Ga-DOTATOCPETCT and somatostatin receptor (sst1-sst5) expression innormal human tissue Correlation of sst2mRNAand SUVmaxrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 38 no 7 pp 1224ndash1236 2011
[188] P Rinne S Hellberg M Kiugel et al ldquoComparison of Somato-statin Receptor 2-Targeting PET Tracers in the Detection ofMouse Atherosclerotic Plaquesrdquo Molecular Imaging and Biol-ogy vol 18 no 1 pp 99ndash108 2016
[189] M Asti E Ferrari S Croci et al ldquoSynthesis and characteri-zation of 68Ga-labeled curcumin and curcuminoid complexesas potential radiotracers for imaging of cancer and alzheimersdiseaserdquo Inorganic Chemistry vol 53 no 10 pp 4922ndash49332014
[190] A Signore I Santino and A W J M Glaudemans ldquoIn vivoimaging of microorganismsrdquo Clinical and Translational Imag-ing vol 4 no 3 pp 161-162 2016
[191] S Auletta F Galli C Lauri D Martinelli I Santino andA Signore ldquoImaging bacteria with radiolabelled quinolones
22 Contrast Media amp Molecular Imaging
cephalosporins and siderophores for imaging infection a sys-tematic reviewrdquo Clinical and Translational Imaging vol 4 no 4pp 229ndash252 2016
[192] X Ning S Lee Z Wang et al ldquoMaltodextrin-based imagingprobes detect bacteria in vivo with high sensitivity and speci-ficityrdquo Nature Materials vol 10 no 8 pp 602ndash607 2011
[193] J Ady andY Fong ldquoImaging for infection Fromvisualization ofinflammation to visualization of microbesrdquo Surgical Infectionsvol 15 no 6 pp 700ndash707 2014
[194] J M Sierra D Rodriguez-Puig A Soriano J Mensa C Pieraand J Vila ldquoAccumulation of 99mTc-ciprofloxacin in Staphy-lococcus aureus and Pseudomonas aeruginosardquo AntimicrobialAgents and Chemotherapy vol 52 no 7 pp 2691-2692 2008
[195] D I Andersson and D Hughes ldquoMicrobiological effects ofsublethal levels of antibioticsrdquoNature ReviewsMicrobiology vol12 no 7 pp 465ndash478 2014
[196] N Dumarey D Blocklet T Appelboom L Tant and ASchoutens ldquoInfecton is not specific for bacterial osteo-articularinfective pathologyrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 29 no 4 pp 530ndash535 2002
[197] K E Britton D W Wareham S S Das et al ldquoImaging bacte-rial infection with 99mTc-ciprofloxacin (Infecton)rdquo Journal ofClinical Pathology vol 55 no 11 pp 817ndash823 2002
[198] G Ferro-Flores M A Avila-Rodrıguez and F O Garcıa-PerezldquoImaging of bacteria with radiolabeled ubiquicidin by SPECTand PET techniquesrdquo Clinical and Translational Imaging vol 4no 3 pp 175ndash182 2016
[199] P S Hiemstra M T van den Barselaar M Roest P H Nibber-ing and R van Furth ldquoUbiquicidin a novel murine microbi-cidal protein present in the cytosolic fraction of macrophagesrdquoJournal of Leukocyte Biology vol 66 no 3 pp 423ndash428 1999
[200] M S Akhtar A Qaisar J Irfanullah et al ldquoAntimicrobialpeptide 99mTc-ubiquicidin 29ndash41 as human infection-imagingagent clinical trialrdquo Journal of Nuclear Medicne vol 46 no 4pp 567ndash573 2005
[201] M Assadi K Vahdat I Nabipour et al ldquoDiagnostic value of99mTc-ubiquicidin scintigraphy for osteomyelitis and compar-isons with 99mTc-methylene diphosphonate scintigraphy andmagnetic resonance imagingrdquo Nuclear Medicine Communica-tions vol 32 no 8 pp 716ndash723 2011
[202] T Emery ldquoExchange of Iron by Gallium in SiderophoresrdquoBiochemistry vol 25 no 16 pp 4629ndash4633 1986
[203] M Petrik C Zhai H Haas and C Decristoforo ldquoSiderophoresfor molecular imaging applicationsrdquo Clinical and TranslationalImaging vol 5 no 1 pp 15ndash27 2017
[204] H J Flint E A BayerM T Rincon R Lamed and B AWhiteldquoPolysaccharide utilization by gut bacteria potential for newinsights from genomic analysisrdquo Nature Reviews Microbiologyvol 6 no 2 pp 121ndash131 2008
[205] GGowrishankarMNamavari E B Jouannot et al ldquoInvestiga-tion of 6-[18F]-fluoromaltose as a novel PET tracer for imagingbacterial infectionrdquo PLoS ONE vol 9 no 9 Article ID e1079512014
[206] N Gholipour M Akhlaghi A M Kheirabadi et al ldquoChelator-free radiolabeling of dextran with 68Ga for PET studiesrdquoJournal of Radioanalytical and Nuclear Chemistry vol 311 no3 pp 1811ndash1817 2017
[207] C Bettegowda C A Foss I Cheong et al ldquoImaging bac-terial infections with radiolabeled 1-(21015840-deoxy-21015840- fluoro-120573-D-arabinofuranosyl)-5-iodouracilrdquo Proceedings of the NationalAcadamy of Sciences of the United States of America vol 102 no4 pp 1145ndash1150 2005
[208] S A Soghomonyan M Doubrovin J Pike et al ldquoPositronemission tomography (PET) imaging of tumor-localizedSalmonella expressing HSV1-TKrdquo Cancer GeneTherapy vol 12no 1 pp 101ndash108 2005
[209] C Palestro K Nichols S Sheikh-Fayyaz S Dewey P Singhaland K Bhargava ldquoCan Gallium-68 PET differentiate acuteinterstitial nephritis from acute tubular necrosisrdquo Journal ofNuclear Medicne vol 57 Supplement 2 p 551 2016
[210] A J Morguet D L Munz V Ivancevic et al ldquoImmunoscintig-raphy using technetium-99m-labeled anti-NCA-95 antigranu-locyte antibodies as an adjunct to echocardiography in subacuteinfective endocarditisrdquo Journal of the American College ofCardiology vol 23 no 5 pp 1171ndash1178 1994
[211] C van der Laken O Boerman W Oyen et al ldquoIn Vivo Expres-sion of Interleukin-1 Receptors during Various ExperimentallyInduced Inflammatory Conditionsrdquo The Journal of InfectiousDiseases vol 177 no 5 pp 1398ndash1401 1998
[212] C J Van Der Laken O C Boerman W J G Oyen M T PVan De Ven J W M Van Der Meer and F H M CorstensldquoScintigraphic detection of infection and inflammation Newdevelopments with special emphasis on receptor interactionrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 25 no 5 pp 535ndash546 1998
[213] C J van der LakenOC BoermanW J GOyenM T P van deVen J W M van der Meer and F H M Corstens ldquoImaging ofinfection in rabbits with radioiodinated interleukin-1 (120572 and 120573)its receptor antagonist and a chemotactic peptide a comparativestudyrdquo European Journal of Nuclear Medicine and MolecularImaging vol 25 no 4 pp 347ndash352 1998
[214] C J Van Der Laken O C BoermanW J G Oyen M T P VanDe Ven F H M Corstens and J W M Ven Der Meer ldquoThekinetics of radiolabelled interleukin-8 in infection and sterileinflammationrdquo Nuclear Medicine Communications vol 19 no3 pp 271ndash282 1998
[215] E Lazzeri P Erba M Perri et al ldquoScintigraphic imaging ofvertebral osteomyelitis with 111in-biotinrdquoThe Spine Journal vol33 no 7 pp E198ndashE204 2008
[216] E Blom B Langstrom and I Velikyan ldquo68Ga-labeling of biotinanalogues and their characterizationrdquo Bioconjugate Chemistryvol 20 no 6 pp 1146ndash1151 2009
[217] O Eriksson F Carlsson E Blom et al ldquoPreclinical evaluationof a 68Ga-labeled biotin analogue for applications in islettransplantationrdquo Nuclear Medicine and Biology vol 39 no 3pp 415ndash421 2012
[218] E A Weinstein A A Ordonez V P DeMarco et alldquoImaging Enterobacteriaceae infection in vivo with 18F-fluoro-deoxysorbitol positron emission tomographyrdquo Science Transla-tional Medicine vol 6 no 259 p 259ra146 2014
[219] K M Nielsen M H Kyneb A K O Alstrup et alldquo68Ga-labeled phage-display selected peptides as tracers forpositron emission tomography imaging of Staphylococcusaureus biofilm-associated infections Selection radiolabellingand preliminary biological evaluationrdquo Nuclear Medicine andBiology vol 43 no 10 pp 593ndash605 2016
[220] T J Makinen P Lankinen T Poyhonen J Jalava H T Aroand A Roivainen ldquoComparison of 18F-FDG and 68Ga PETimaging in the assessment of experimental osteomyelitis due toStaphylococcus aureusrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 32 no 11 pp 1259ndash1268 2005
[221] JMU Silvola I LaitinenH J Sipila et al ldquoUptake of 68galliumin atherosclerotic plaques in LDLRminusminusApoB100100micerdquo EJN-MMI Research vol 1 no 1 pp 1ndash8 2011
Contrast Media amp Molecular Imaging 23
[222] T A Wynn ldquoCellular and molecular mechanisms of fibrosisrdquoThe Journal of Pathology vol 214 no 2 pp 199ndash210 2008
[223] T Derlin D Jonigk J Bauersachs and FM Bengel ldquoMolecularImaging of Chemokine Receptor CXCR4 in NonndashSmall CellLung Cancer Using 68Ga-Pentixafor PETCT ComparisonWith 18F-FDGrdquo Clinical Nuclear Medicine 2016
[224] I Velikyan U Rosenstrom T N Bulenga O Eriksson andG Antoni ldquoFeasibility of multiple examinations using68ga-labelled collagelin analogues Organ distribution in rat forextrapolation to human organ and whole-body radiationdosimetryrdquo Pharmaceuticals vol 9 no 2 article no 31 2016
[225] S Jadhav M Kakela J Makila et al ldquoSynthesis and in VivoPET Imaging of Hyaluronan Conjugates of OligonucleotidesrdquoBioconjugate Chemistry vol 27 no 2 pp 391ndash403 2016
[226] A Autio A Saraste N Kudomi et al ldquoAssessment of bloodflow with (68) Ga-DOTA PET in experimental inflammation avalidation study using (15) O-waterrdquo American Journal ofNuclear Medicine and Molecular Imaging vol 4 no 6 pp 571ndash579 2014
[227] G Davies A Rolle A Maurer et al ldquoTowards translationalimmunoPETMR imaging of invasive pulmonary aspergillosisthe Humanised Monoclonal Antibody JF5 detects in vivordquoTheranostics vol 7 no 14 pp 3398ndash3414 2017
[228] DGoodwin CMeares GDavid et al ldquoMonoclonal antibodiesas reversible equilibrium carriers of radiopharmaceuticalsrdquoInternational Journal of Radiation Applications and Instrumen-tation Part B Nuclear Medicine and Biology vol 13 no 4 pp383ndash391 1986
[229] D A Goodwin C F Mears M McTigue and G S DavidldquoMonoclonal antibody hapten radiopharmaceutical deliveryrdquoNuclear Medicine Communications vol 7 no 8 pp 569ndash5801986
[230] S E Halpern and R O Dillman ldquoProblems associated withradioimmunodetection and possibilities for future solutionsrdquo JBiol Response Mod vol 6 no 3 pp 235ndash262 1987
[231] H Hong J Sun and W Cai ldquoRadionuclide-based cancerimaging targeting the carcinoembryonic antigenrdquo BiomarkerInsights vol 3 pp 435ndash451 2008
[232] G J Forster E B Santos P M Smith-Jones P Zanzonico andS M Larson ldquoPretargeted radioimmunotherapy with a single-chain antibodystreptavidin construct and radiolabeledDOTA-biotin Strategies for reduction of the renal doserdquo Journal ofNuclear Medicine vol 47 no 1 pp 140ndash149 2006
[233] Z Yao M Zhang H Kobayashi et al ldquoImproved targeting ofradiolabeled streptavidin in tumors pretargeted with biotiny-lated monoclonal antibodies through an avidin chaserdquo Journalof Nuclear Medicine vol 36 no 5 pp 837ndash841 1995
[234] C-H Chang R M Sharkey E A Rossi et al ldquoMolecularAdvances in Pretargeting Radioimunotherapy with BispecificAntibodies 1 Supported in part by USPHS Grant R01-CA-84379from the NIH and Department of Energy Grant DE-FG01-00NE22941 (both to R M S)1rdquo Mol Cancer Ther vol 1 no 7pp 553ndash563 2002
[235] R M Sharkey E A Rossi W J McBride C-H Chang andD M Goldenberg ldquoRecombinant Bispecific Monoclonal Anti-bodies Prepared by theDock-and-Lock Strategy for PretargetedRadioimmunotherapyrdquo Seminars in Nuclear Medicine vol 40no 3 pp 190ndash203 2010
[236] R M Sharkey E A Rossi C-H Chang and D M Golden-berg ldquoImproved cancer therapy and molecular imaging withmultivalent multispecific antibodiesrdquo Cancer Biotherapy andRadiopharmaceuticals vol 25 no 1 pp 1ndash12 2010
[237] D M Goldenberg R M Sharkey G Paganelli J Barbet andJ Chatal ldquoAntibody pretargeting advances cancer radioim-munodetection and radioimmunotherapyrdquo Journal of ClinicalOncology vol 24 no 5 pp 823ndash834 2006
[238] O C Boerman F G van Schaijk W J G Oyen and FH M Corstens ldquoPretargeted radioimmunotherapy of cancerprogress step by steprdquo Journal of Nuclear Medicine vol 44 no3 pp 400ndash411 2003
[239] J Schuhmacher S Kaul G Klivenyi et al ldquoImmunoscintigra-phy with positron emission tomography Gallium-68 chelateimaging of breast cancer pretargeted with bispecific anti-MUC1anti-Ga chelate antibodiesrdquo Cancer Research vol 61 no9 pp 3712ndash3717 2001
[240] J Schuhmacher G Klivenyi S Kaul et al ldquoPretargeting ofhuman mammary carcinoma xenografts with bispecific anti-MUC1anti-Ga chelate antibodies and immunoscintigraphywith PETrdquo Nuclear Medicine and Biology vol 28 no 7 pp 821ndash828 2001
[241] C Somasundaram S Matzku J Schuhmacher and M ZollerldquoDevelopment of a bispecific monoclonal antibody against agallium-67 chelate and the human melanoma-associated anti-gen p97 for potential use in pretargeted immunoscintigraphyrdquoCancer Immunology Immunotherapy vol 36 no 5 pp 337ndash3451993
[242] E A Rossi D L Rossi R Stein D M Goldenberg and C-H Chang ldquoA bispecific antibody-IFN1205722b immunocytokine tar-geting CD20 and HLA-DR is highly toxic to human lymphomaandmultiplemyeloma cellsrdquoCancer Research vol 70 no 19 pp7600ndash7609 2010
[243] R M Sharkey H Karacay S Litwin et al ldquoImproved ther-apeutic results by pretargeted radioimmunotherapy of non-Hodgkinrsquos lymphoma with a new recombinant trivalent anti-CD20 bispecific antibodyrdquo Cancer Research vol 68 no 13 pp5282ndash5290 2008
[244] G L Griffiths C-H Chang W J McBride et al ldquoReagentsandmethods for PETusing bispecific antibody pretargeting and68Ga-radiolabeled bivalent hapten-peptide-chelate conjugatesrdquoJournal of Nuclear Medicine vol 45 no 1 pp 30ndash39 2004
[245] J Watine M Miedouge and B Friedberg ldquoCarcinoembryonicantigen as an independent prognostic factor of recurrence andsurvival in patients resected for colorectal liver metastases Asystematic reviewrdquo Diseases of the Colon amp Rectum vol 44 no12 pp 1791ndash1799 2001
[246] M J Goldstein and E P Mitchell ldquoCarcinoembryonic antigenin the staging and follow-up of patients with colorectal cancerrdquoCancer Investigation vol 23 no 4 pp 338ndash351 2005
[247] D V Gold D M Goldenberg H Karacay et al ldquoA novelbispecific trivalent antibody construct for targeting pancreaticcarcinomardquo Cancer Research vol 68 no 12 pp 4819ndash48262008
[248] J Schuhmacher G Klivenyi R Matys et al ldquoMultistep tumortargeting in nudemice using bispecific antibodies and a galliumchelate suitable for immunoscintigraphy with positron emis-sion tomographyrdquo Cancer Research vol 55 no 1 pp 115ndash1231995
[249] G Klivenyi J Schuhmacher E Patzelt et al ldquoGallium-68chelate imaging of human colon carcinoma xenografts pre-targeted with bispecific anti-CD44(V6)anti-gallium chelateantibodiesrdquo Journal ofNuclearMedicine vol 39 no 10 pp 1769ndash1776 1998
[250] M Zoller J Schuhmacher J Reed W Maier-Borst and SMatzku ldquoEstablishment and characterization of monoclonal
24 Contrast Media amp Molecular Imaging
antibodies against an octahedral gallium chelate suitable forimmunoscintigraphy with PETrdquo Journal of Nuclear Medicinevol 33 no 7 pp 1366ndash1372 1992
[251] R M Sharkey T M Cardillo E A Rossi et al ldquoSignal ampli-fication in molecular imaging by pretargeting a multivalentbispecific antibodyrdquo Nature Medicine vol 11 no 11 pp 1250ndash1255 2005
[252] D M Goldenberg and R M Sharkey ldquoNovel radiolabeledantibody conjugatesrdquo Oncogene vol 26 no 25 pp 3734ndash37442007
[253] D M Goldenberg E A Rossi R M Sharkey W J McBrideand C-H Chang ldquoMultifunctional antibodies by the dock-and-lock method for improved cancer imaging and therapy bypretargetingrdquo Journal of NuclearMedicine vol 49 no 1 pp 158ndash163 2008
[254] R Schoffelen R M Sharkey D M Goldenberg et al ldquoPre-targeted immuno-positron emission tomography imaging ofcarcinoembryonic antigen-expressing tumors with a bispecificantibody and a68Ga- And18F-labeled hapten peptide in micewith human tumor xenograftsrdquoMolecular Cancer Therapeuticsvol 9 no 4 pp 1019ndash1027 2010
[255] E S Bos W H Kuijpers M Meesters-Winters et al ldquoIn vitroevaluation of DNA-DNA hybridization as a two-step approachin radioimmunotherapy of cancerrdquoCancer Research vol 54 no13 pp 3479ndash3486 1994
[256] G Paganelli M Bartolomei M Ferrari et al ldquoPre-TargetedLocoregional Radioimmunotherapy withrdquo Cancer biotherapyand radiopharmaceuticals vol 16 no 3 pp 227ndash235 2001
[257] A Forero P L Weiden J M Vose et al ldquoPhase 1 trial of a novelanti-CD20 fusion protein in pretargeted radioimmunotherapyfor B-cell non-Hodgkin lymphomardquo Blood vol 104 no 1 pp227ndash236 2004
[258] DM Goldenberg C-H Chang E A RossiW J McBride andR M Sharkey ldquoPretargeted molecular imaging and radioim-munotherapyrdquoTheranostics vol 2 no 5 pp 523ndash540 2012
[259] H Karacay R M Sharkey W J McBride E A Rossi C-HChang and D M Goldenberg ldquoOptimization of hapten-peptide labeling for pretargeted immunoPET of bispecificantibody using generator-produced 68Gardquo Journal of NuclearMedicine vol 52 no 4 pp 555ndash559 2011
[260] J R Oh and B C Ahn ldquoFalse-positive uptake on radioiodinewhole-body scintigraphy physiologic and pathologic variantsunrelated to thyroid cancerrdquo American Journal of NuclearMedicine and Molecular Imaging vol 2 no 2 pp 141ndash150 2012
[261] E Frampas C Rousseau C Bodet-Milin J Barbet J-F Chataland F Kraeber-Bodere ldquoImprovement of radioimmunotherapyusing pretargetingrdquo Frontiers in Oncology vol 3 Article ID00159 2013
[262] C S McKay and M G Finn ldquoClick chemistry in complexmixtures Bioorthogonal bioconjugationrdquo Chemistry amp Biologyvol 21 no 9 pp 1075ndash1101 2014
[263] B L Oliveira Z Guo and G J Bernardes ldquoInverse electrondemand DielsndashAlder reactions in chemical biologyrdquo ChemicalSociety Reviews vol 46 no 16 pp 4895ndash4950 2017
[264] B Nichols Z Qin J Yang D R Vera and N K Devaraj ldquo68Gachelating bioorthogonal tetrazine polymers for the multisteplabeling of cancer biomarkersrdquo Chemical Communications vol50 no 40 pp 5215ndash5217 2014
[265] R Rossin P R Verkerk S M van den Bosch et al ldquoInvivo chemistry for pretargeted tumor imaging in live micerdquoAngewandte Chemie International Edition vol 49 no 19 pp3375ndash3378 2010
[266] B M Zeglis K K Sevak T Reiner et al ldquoA pretargetedPET imaging strategy based on bioorthogonal diels-alder clickchemistryrdquo Journal of Nuclear Medicine vol 54 no 8 pp 1389ndash1396 2013
[267] J L Houghton R Membreno D Abdel-Atti et al ldquoEstablish-ment of the invivo efficacy of pretargeted radioimmunotherapyutilizing inverse electron demand diels-alder click chemistryrdquoMolecular Cancer Therapeutics vol 16 no 1 pp 124ndash133 2017
[268] J Funkhouser ldquoReinventing pharma the theranostic revolu-tionrdquo Current Drug Discovery pp 17ndash19 2002
[269] J Sorensen I Velikyan A Wennborg et al ldquoMeasuring HER2-expression in metastatic breast cancer using 68Ga-ABY025PETCTrdquo European Journal of Nuclear Medicine and MolecularImaging vol 41 pp S226ndashS226 2014
[270] I Velikyan A Wennborg J Feldwisch et al ldquoGMP compliantpreparation of a 68Gallium-labeled Affibody analogue forbreast cancer patient examination first-in-manrdquoEur JNuclMedMol Imaging vol 41 pp S228ndashS229 2014
[271] K Oberg ldquoMolecular imaging radiotherapy Theranostics forpersonalized patient management of neuroendocrine tumors(NETs)rdquoTheranostics vol 2 no 5 pp 448ndash458 2012
[272] I Velikyan AWennborg J FeldwischH Lindman J Carlssonand J Sorensen ldquoGood manufacturing practice production of [(68) Ga]Ga-ABY-025 for HER2 specific breast cancer imagingrdquoAmerican Journal of Nuclear Medicine and Molecular Imagingvol 6 no 2 pp 135ndash153 2016
[273] M Sandstrom K Lindskog I Velikyan et al ldquoBiodistributionand radiation dosimetry of the anti-HER2 Affibody molecule68Ga-ABY-025 in breast cancer patientsrdquo Journal of NuclearMedicine vol 57 no 6 pp 867ndash871 2016
[274] D Sandberg V Tolmachev I Velikyan et al ldquoIntra-imagereferencing for simplified assessment of HER2-expression inbreast cancer metastases using the Affibody molecule ABY-025with PET and SPECTrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 44 no 8 pp 1337ndash1346 2017
[275] H ZhangM AMoroz I Serganova et al ldquoImaging expressionof the human somatostatin receptor subtype-2 reporter genewith 68Ga-DOTATOCrdquo Journal ofNuclearMedicine vol 52 no1 pp 123ndash131 2011
[276] M Naji and A Al-Nahhas ldquo68Ga-labelled peptides in themanagement of neuroectodermal tumoursrdquo European Journalof Nuclear Medicine and Molecular Imaging vol 39 no 1 ppS61ndashS67 2012
[277] I Velikyan ldquoThe diversity of 68Ga-Based imaging agentsrdquoRecent Results in Cancer Research vol 194 pp 101ndash131 2013
[278] K Ferreira H-Y Hu V Fetz et al ldquoMultivalent siderophore-dotam conjugates as theranostics for imaging and treatment ofbacterial infectionsrdquo Angewandte Chemie International Editionvol 56 no 28 pp 8272ndash8276 2017
Computational and Mathematical Methods in Medicine
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Research and TreatmentAIDS
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Evidence-Based Complementary andAlternative Medicine
Volume 2018Hindawiwwwhindawicom
Submit your manuscripts atwwwhindawicom
4 Contrast Media amp Molecular Imaging
Table 2 Effective doses for some PET and SPECT imaging agents Reproduced from [6]
Agent Examination time Effective dose [mSv][111In]In-DTPA-octreotideSPECT 24ndash48 h 108[68Ga]Ga-DOTA-TOCPET 30ndash60min 23[18F]FDGPET 60ndash120min 56[99mTc]-BPAMDSPECT 2ndash6 h 6[99mTc]-MDPSPECT 2ndash6 h 3-4[68Ga]Ga-BPAMDPET 30ndash60min 3-4
which is the limiting factor [4 83 84]The 68-min half-life of68Ga is not compatiblewith ligands of slowpharmacokineticsfor example antibodies Thus other positron emitters suchas 124I 89Zr and 64Cu with longer half-lives allowing 2ndash4days required for the clearance of the agent for the bloodcirculation and washout for the nontarget tissue are morerelevantThe relatively short half-life of 68Ga presents advan-tage in cases when repetitive examinations on the same dayare of interest [85] The high fraction of positron emission isanother advantage of 68Ga (89) as compared to 64Cu (19)and 124I (23) Comparison of some clinically used imagingagents demonstrates the lower effective dose that patient isexposed to when using 68Ga-based agent as compared tothe agents comprising 18F 99mTc and 111In (Table 2) [686 87] Moreover the duration of patient examinations isshorter for 68Ga-agents than that for SPECT agents and tosome extend for [18F]FDG In summary the use of 68Gawould be beneficial in terms of accessibility high sensitivityand resolution quantification dynamic scanning fast scan-ning protocol repetitive examinations and low radiationburden
The chemical form in aqueous solution is Ga(III)cation which provides robust coordination chemistry 68Ga-labelling can be direct or chelator mediated The directlabelling utilizes the chelating ability of macromolecules forexample lactoferrin and transferrin comprising Tyr His andAsp AA residues that can chelate Ga(III) in the presence ofsynergetic bicarbonate ion Lowmolecular weight ligands canform stable complexes of variable lipophilicity and charge fornontargeting imaging The chelator mediated 68Ga-labellingrequires presence of a bifunctional chelator (BFC) for the sub-sequent straightforward and side specific coordination withGa(III) Considerable number of chelators was successfullydeveloped [4 6 88ndash95]Themost commonly used are DOTAand NOTA based chelators The former requires heatingunder over 60∘C for the complexation with 68Ga while thelatter can chelate 68Ga at ambient temperature which mightbe crucial in case of temperature sensitive ligands and italso allows for cold kit type radiopharmaceutical prepara-tion under radiopharmacy practice [96] DOTA presents anadvantage in the context of radiotheranostics since it canform stable complexes with 68Ga for PET diagnostics and177Lu for radiotherapy
The chelator or prosthetic group mediated labellingmost commonly results in agents comprising biologicallyactive vectormolecule chelatorprosthetic groupmoiety and
radionuclide Very often pharmacokinetic modifiers (PKM)are incorporated in order to modulate pharmacokinetics andagent organ distribution and improve in vivo stability as wellas separate the binding site from the bulky chelatorprostheticgroup moiety which may deteriorate the biological activityof the vector molecule Considerable number of publicationsreveal strong influence of even slight modifications in any ofthe agent structural components and the accurate predictionof pharmacokinetics and pharmacodynamics of a new agentis not straightforward [97] Nevertheless vast experience andknowledge have been intensively gathered during last twodecades providing possibility for more efficient and effectivedevelopment The labelling chemistry of 68Ga is well charac-terized and is relevant to small molecules macromoleculesand particles
Ga(III) as a chemical element presents a unique advan-tage over other radionuclides as it has properties closelyresembling those of Fe(III) which is involved in manybiochemical processes including inflammation MoreoverFe(III) is an essential nutrient and limiting factor ofmicrobiallife [98] Stable Ga(III) has been used in treatment of variousdiseases including cancer infection and inflammation [99ndash101] The ability of Ga(III) to bind iron proteins for examplelactoferrin and transferrin as well as siderophores andenzymes can be utilized in the imaging agent development
4 Biomarkers andRadiopharmaceutical Development
The development of imaging agents relies strongly on theadvances experience and knowledge of the research ofbiomarkers for example receptors and antigens transportsystems substances involved in angiogenesis glycolysishypoxia proliferation and apoptosis and enzyme activityTargeting biomarkers that are specific for a given diseaseis one the major aims of an agent development for bothdiagnostic imaging and therapy The knowledge and accessto respective vector molecules have considerably expandeddue to the achievements in proteomics and genomics Infec-tion inflammation and fibrosis are closely interrelated pro-cesses and corresponding biomarkers might present practicalinterest in developing respective imaging agents Favorablecharacteristics of a target in general include expressionupregulation absence of expression in normal tissue andinternalization or stable binding of the respective ligand forthe longitudinal accumulation of the latter [102]
Contrast Media amp Molecular Imaging 5
5 Imaging Inflammation
Inflammatory response is a complex process involvingimmune system cells (T- and B-lymphocytes NK cellsmacrophages monocytes neutrophils eosinophils andmastcells) and products of their (patho)physiological activity forexample cytokines involved in the cell signaling Variousfunctions of the cells and their products as well as theirreceptors provide a broad range of potential imaging targets[103ndash107] Targeting the white blood cells of the immunesystem such as macrophages monocytes lymphocytes andneutrophils for the detection of their upregulation and traf-ficking secretion of cytokines and chemokines and phago-cytosis has been investigated both clinically and preclinicallyReceptors such as SSTRNCA-90 integrins folate bombesinvascular cell adhesion protein-1 and interleukins expressedby activated T-cells CXCR2 expressed on neutrophils andCXCR4 overexpressed by leukocytes have demonstratedpotential for in vivo targeted imaging [108] Respectiveligands and substrates can be considered for radiolabellingCytokines including interferons lymphokines interleukinsand chemokines bind to various receptors for example IL1and IL2 receptor types IFN CD40 CD37 CD30 CD4CCR5 and IL1-17R receptor family Folate CD64 NCA90and CD15 receptors expressed on macrophages leukocytesand granulocytes can serve as targets Not only do moleculesof such super families as chemokine integrin selectin andimmunoglobulin participate in the cell emigration cascadebut also enzymes on the surface of endothelia cells andleukocytes contribute to the leukocyte extravasation [109]Receptors on the endothelial wall for example for bindingof IL1 and TNF120572 are another category of the targets Theseare only few examples of targets for potential imaging agentdevelopment (Table 3) Many targets were utilized in oncol-ogy [28] and their translation to inflammation is feasible
51 Targeting Cell Receptors with Antibodies Radiolabelled(99mTc 111In and 123I) anti-CD2 anti-CD5 anti-CD25 anti-CD45 antibodies and their fragments were used for the imag-ing of T-lymphocyte infiltration in various inflammatorydiseases [110] Typically for antibody slow pharmacokineticsthe time delay between the administration and examina-tion stretches up to 24 hours Interleukin-8 labelled with99mTc was studied in rabbits with induced acute pyogenicosteomyelitis [111] and induced acute colitis [112] The agentwas found suitable for the scintigraphic evaluation of therespective diseases CD163 receptor expressed in monocytesand activated macrophages was targeted with an anti-CD163antibody labelled with 68Ga in rats with acute collagen-induced arthritis [45]The agent demonstrated specific bind-ing and thus potential for studies of inflammatory diseases
52 Targeting Angiogenesis Angiogenesis plays an importantrole in wound healing chronic inflammation and tumourgrowth [113] The family of vascular endothelial growthfactors (VEGF) and integrins play crucial role in the angio-genesis cascade Integrin receptors are overexpressed on thesurface of vascular endothelial cells during angiogenesis inmalignances tissue healing and inflammation The largest
group is radiolabelled peptide ligands comprising arginine-glycine-aspartic acid (RGD) sequence and peptidomimeticstargeting 120572v1205733 integrin receptors Various analogues weredeveloped introducing cyclization andmultimerization vari-ety of chelatecoligand moieties PKM such as carbohy-drate and polyethylene glycol chains [114ndash121] Various RGDanalogues labelled with 18F 68Ga and 99mTc were usedin oncological clinical trials [122] The majority of themcomprised 18F however advantages of 68Ga such as accessi-bility of the radionuclide more straightforward and efficientlabelling chemistry lower radiation dose and better imagecontrast renderedmore extensive development of 68Ga-basedanalogues [123ndash127]
The imaging agents tested in cancer systems can berelevant for the imaging of inflammation related diseasesTheimaging and evaluation of synovial angiogenesis in patientswith rheumatoid arthritis was accomplished using [68Ga]Ga-PRGD2 [46] The elevated agent uptake was detected inthe sites of active inflammation rich neovasculature andphysiological integrin receptor expression while no traceraccumulationwas detected in axillary lymphnodeswith reac-tive hyperplasia and strenuous skeletal muscles [68Ga]Ga-PRGD2PET-CT was found useful for the evaluation of syn-ovial angiogenesis and follow-up of the treatment response
[68Ga]Ga-NOTA-c(RGDyK)was developed for the imag-ing of myocardial infarction (MI) and follow-up of theresponse to the therapeutic intervention and demonstratedpromising results preclinically [47] The uptake in the MIlesions was enhanced and correlated with the vascularendothelial growth factor expression Dynamic [68Ga]Ga-NOTA-c(RGDyK)PET scanning with subsequent kineticmodeling studies in rats with forelimb ischemia showedhigher uptake and distribution volume in the ischemicarea as compared to that of sham operation and controlregions [48] Monitoring myocardial repair and angiogenesisafter ischemic injury was found plausible using [68Ga]Ga-NODAGA-RGD and [68Ga]Ga-TRAP-(RGD)3 in rat model[49] Elevated uptake of [68Ga]Ga-DOTA-E-[c(RGDfK)]2was observed in the infarcted area while no accumulationwas detected in the noninfarcted myocardium of the samerats [50]The uptake of [68Ga]Ga-DOTA-RGD in atheroscle-rotic plaques was studied in vivo in atherosclerotic micewith promising results [52] Elevated uptake of [68Ga]Ga-NODAGA-RGD in injured myocardium as compared toviable ischemic areas in pig model presumably indicatedincreased expression of 120572V1205733 receptors associated with injuryrepair in the presence of coronary stenosis [51]
Although targeting VEGF receptors were studied in thecontext of cancerous diseases chronic inflammation can alsobe considered A ligand consisting of a single chain (scVEGF3ndash112 amino acids of human VEGF121) [128 129] was labelledwith 68Ga and the resulting agent showed distinct uptake inthe tumour xenografts in mice however high kidney uptakeneeded to be addressed [130 131]
53 Targeting Selectins P-selectin is expressed on the activeendothelium surface and platelets and operates the migra-tion of leukocytes in response to inflammatory cytokines
6 Contrast Media amp Molecular Imaging
Table 3 68Ga-based imaging agents for inflammation and infection investigated preclinically and clinically
E-selectin binding peptide labelled with 99mTc accumu-lated in acute osteomyelitic lesions in rats presumably byinteraction with activated vascular endothelium [132] Ananalogue of P-selectin natural ligand fucoidan labelled with68Ga could discriminate active and inactive atheroschleroticplaques in mice [44]
54 Targeting Vascular Adhesion Protein-1 Vascular adhe-sion protein-1 (VAP-1) and CD73 are endothelial surfaceenzymes involved in the recruitment of leukocytes and theirmovement from the blood into the tissue [109] Endothelialactivation that takes place during inflammation can be uti-lized for specific targeting imaging Several peptide analogues
Contrast Media amp Molecular Imaging 7
300
250
200
150
100
50
0
(kBq
ml)
Inflammation
Kidneys
Muscle
Inflammation
Kidneys
Muscle
Figure 1 PET images of the distribution of [68Ga]Ga-DOTAVAP-P1 [68Ga]Ga-DOTAVAP-PEG-P1 and [68Ga]Ga-DOTA-Siglec-9 inturpentine-induced rat model of sterile inflammation All three peptide analogues showed target-to-nontarget ratio above 6 with rapidaccumulation in the inflammation site and renal clearance Adapted from [57]
labelledwith 68Gawere designed for the visualization ofVAP-1 and showed promising results in animals with inducedinfection and sterile inflammation [7ndash13 133] The bindingwas proven specific and it was possible to differentiate inflam-mation from infection [68Ga]Ga-Siglec targeting VAP-1demonstrated preclinical potential for imaging of synovialinflammation in patients with rheumatic diseases [53] Thesame agent was utilized for respiratory distress syndrome(ARDS an inflammatory lung injury) imaging in a porcinemodel [54] Imaging VAP-1 with [68Ga]Ga-Siglec was foundpromising also for the detection of inflamed atheroscle-rotic lesions [55] and inflammatory response induced bycatheter implantation and staphylococcal infection [56]68Ga-Siglec and two more peptide analogues with affinityto VAP-1 ([68Ga]Ga-DOTAVAP-P1 [68Ga]Ga-DOTAVAP-PEG-P1 and [68Ga]Ga-DOTA-Siglec-9) were investigated inrat model of sterile skinmuscle inflammation (Figure 1) [57]They showed distinct uptake in the affected sites
55 Targeting Chemokines Cytokines are produced bymacrophages B-lymphocytes T-lymphocytes and mast cellsand act through receptors modulating for example immuneresponse to infection and inflammation Cytokines includechemokines interleukins interferons and lymphokines thatcan be classified in broad families exhibiting diverse func-tions for example IL-1 and IL-6 superfamilies and TNFTNFreceptor superfamily Therapeutics targeting cytokines are inclinical use for example inhibiting TNF or IL-6 in rheumaticdiseases
Chemokine receptors are physiologically expressed onB-lymphocytes T-lymphocytes macrophages neutrophilseosinophils monocytes and hematopoietic stem cells [134]Imaging agents targeting CXCR4 are based on inhibitors(AMD3100) or small peptides (NFB T140 pentixafor andTN14003) and comprise 18F 67Ga 68Ga or 64Cu [135ndash148] They were developed and studied for the imaging of
various cancerous diseases lung breast prostate cancersacute myeloid leukemia and glioblastoma
The application of CXCR4 targeting agents was extendedbeyond oncology Clinical caseimage reports [149 150]were published on the utilization of [68Ga]Ga-pentixafor fordetection and quantification of CXCR4 receptor density inischemic heart diseases reflecting the role of the receptorin inflammatory and progenitor cell recruitment [58 59]The same agent was successfully used in the assessment ofmacrophage infiltration in atherosclerotic plaques in rabbitdisease model [151]
56 Targeting Folate Receptors Folate receptors (FRs) areoverexpressed on a variety of cancer cells and activatedmacrophages but not on normal cells [152 153] Theenhanced expression of FR was found in lung macrophagesduring acute inflammation [154] The majority of the nuclearimaging agents based on folic acid or pteroic acid [155] weredeveloped for diagnosis of cancers overexpressing FR recep-tors such as breast cervical ovarian colorectal nasopharyn-geal renal and endometrial cancers Various 68Ga-labelledagents demonstrated accumulation in cell cultures and micebearing folate-receptor positive human nasopharyngeal car-cinoma cell line (KB) xenografts [6 156ndash162] [68Ga]Ga-DOTA-PEG-FA comprising folic acid was investigated forthe detection and quantification of inflammatory response tomedical implants using mice with subcutaneously implantedpolylactic acid and poly(N-isopropylacrylamide) particles asa model [60] The agent was accumulated in the area of theimplant most probably reflecting interaction of [68Ga]Ga-DOTA-PEG-FA with folate receptor expressed on activatedmacrophages Another folic acid based agent [68Ga]Ga-DOTA-folate was successfully tested in an inflammatory pawrat model (Figure 2) [61] Distinct accumulation in inflamedhand and foot joints of rheumatoid arthritis of a 99mTc-labelled folate analogue was observed in a patient while no
8 Contrast Media amp Molecular Imaging
NH ONHONH
OOO
HOHN O
HN
NN
N N
HO
O
N
N
O
O
N
N
O
O
O
Ga+
minus
（3
(a)
2
15
1
05
0
(b)
Figure 2 Accumulation of [68Ga]Ga-DOTA-folate (a) in the site of inflammation of rat inflammatory pawmodel induced by subcutaneouslyinjected Complete Freundrsquos Adjuvant (b) Adapted from [61]
4
2
0
Figure 3 Intense atherosclerotic inflammation (white arrows) was detected by [68Ga]Ga-DOTA-TATE in a patient with acute coronarysyndrome Adapted from [65]
uptake was detected in a nonarthritis patientrsquos hands and feet[163]
57 Targeting Somatostatin Receptors Somatostatin receptor(SSTR) ligand analogues have found an extensive appli-cation in diagnosis and radiotherapy of neuroendocrinetumours The elevated expression of SSTRs is known also insmall cell lung cancer breast cancer renal cell carcinomaprostate cancer and malignant lymphoma A number ofsomatostatin ligand analogues labelled with gamma- andpositron-emitting radionuclides were used clinically foroncological cases [85 164ndash174] 68Ga-labelled somatostatinanalogues demonstrated superior performance in terms ofhigher specificity and sensitivity detection rate shorterexamination time and quantification possibility and havebecome a golden standard for the detection of neuroen-docrine tumours (NETs) taking over that title from [111In]-pentetreotide (OctreoScan) and demonstrating specificityand sensitivity of over 90 [27 175ndash180] 68Ga-labelledagents for the imaging of NETs demonstrated advantages
also over other radionuclides and tracers such as [18F]FDG[174] 123I-metaiodobenzylguanidine ([123I]MIBG) [181 182][18F]DOPA [183] [99mTc]-dicarboxy propane diphosphonate[184] and [18F]NaF
SSTR are also overexpressed on activated macrophagesand T-lymphocytes 68Ga-labelled analogues were used ininflammation related diseases such as idiopathic pulmonaryfibrosis [62] Gravesrsquo and Hashimotorsquos diseases [63] coro-nary artery plaque imaging and characterization [64] andatherosclerotic inflammation with excellent macrophagespecificity (Figure 3) [65] Promising diagnostic potential ofa 99mTc-labelled analogue was demonstrated in patients withrheumatoid arthritis and secondary Sjogrenrsquos syndrome andthe method was suggested for the assistance in anti-TNFalpha antibody treatment planning [185] [68Ga]Ga-DOTA-TOCPET-CT was found superior to 67Ga-CitrateSPECT indetection of sarcoidosis lesions [186] A clinical study demon-strated correlation between uptake of [68Ga]Ga-DOTA-TOCand SST2 mRNA expression and recorded the information ina database [187] providing tools for accurate quantification
Contrast Media amp Molecular Imaging 9
and evaluation of disease progression and treatment responsein cancerous and inflammatory diseases involving SSTRsPreclinical study using atherosclerotic mice demonstratedsuperior targeting properties of [68Ga]Ga-DOTA-NOC ascompared to [18F]FDR-NOC [188] overall confirming thepotential of SSTR targeting for atherosclerotic plaque imag-ing
58 Imaging Neuroinflammation Despite difficulty ofdesigning 68Ga-labelled molecules capable of blood-brainbarrier penetration several agents were suggested for theimaging of neuroinflammation in particular A120573 plaquesdeposited on blood vessels [67ndash69] Bivalent styrylpyridineslabelled with 68Ga demonstrated high specificity and affinityfor A120573 plaques using postmortem Alzheimerrsquos disease (AD)brain sections [67] Benzofuran derivative comprising 68Gashowed promising results in terms of binding specificityand affinity investigated in vitro in sections of Tg2576mice [68] Although the synthesis of a 68Ga-labelledPittsburgh compound analogue was successful the in vitrobinding to amyloid deposits was limited [69] The commondisadvantage of these agents is poor blood-brain barrierpenetration nevertheless the exploration of more successfulanalogues continues Curcumin functions as an antioxidantantimicrobial anti-inflammatory and anticancer agentDiacetyl-curcumin and bis(dehydroxy)curcumin labelledwith 68Ga demonstrated in vitro binding to 120573-amyloid fibrilsand lung cancer cells [189] Potential application of the agentscould include diagnostic imaging of Alzheimerrsquos disease andvarious cancers
6 Imaging Infection
Infection imaging can be indirect utilizing targets involvedin the immune response namely inflammation as presentedin the inflammation targets section above or direct utilizingpathogen related targets The direct imaging is especiallycrucial in cases where inflammatory response is absent Thedifference in biochemistry and structure between bacterialand human cells might exclude physiological uptake byhuman tissuemaking it easier tomeet the favorable character-istics of an imaging agent However discrimination betweenthe various infectious microorganisms pathogenic bacteriaand microbiota targeting specific bacteria type as well asdifficulty of accessing bacteria aggregated in a biofilm makesthe task very challenging [190 191] The specific targetingof infection would require accumulation of the radioactivesignal in the pathogen The radiolabelled targeting agentsfor infection can be roughly divided into several groupsantibiotics based antimicrobial protein and peptide basedsiderophore and other metabolisable compound based andantigen-specific antibodies and antibody fragments (Table 3)
61 Radiolabelled Antibiotics Antimicrobials act on the pro-cesses that are specific to microbes for example bacteria andfungi and thus corresponding imaging agents might distin-guish infection from inflammation [191] They might requireinternalization or may bind to the cell surface dependent on
their biological action mechanism [191ndash193] The possibilityof antibiotic resistance development exists also in the case ofimaging agents even though the amount of such agents wouldbe subnanomolar [194 195] Another complication is possiblenonspecific uptake of antibiotics based agents by leucocytes[196] Considerable number of various antibiotic analogueshave been labelled with 99mTc 111In 131I 11C and 18F[102] and evaluated preclinically and clinically with 99mTc-ciprofloxacin becoming a commercial product (Infecton) [21197 198] However the further improvement of specificityis desirable [191] Antibiotics are accessible and cheap andthey demonstrate high sensitivity [102 191] making thedevelopment of 68Ga-labelled analogues very attractive giventhe earlier mentioned advantages that 68Ga as a radionu-clide in combination with PET provides Two 68Ga-labelledanalogues based on ciprofloxacin demonstrated potential fordiscrimination between bacterial infection and inflammationin rats infected with Staphylococcus aureus [70]
62 Radiolabelled Antimicrobial Proteins and Peptides Anti-microbial proteins and peptides for example serprocidinscathelicidins and defensins produced by the cells of immunesystem target microbial membrane lipids and impose micro-bicidal effect [35 43] They present a large group of poten-tial candidates for microbial imaging including bacteriafungi parasites and viruses Antimicrobial peptides havedemonstrated higher specificity for infection than antibioticanalogues They accumulate at infection but not sterileinflammation sites The most thoroughly studied antimicro-bial peptide ubiquicidin UBI [29ndash41] labelled with 99mTc[199] demonstrated promising results in human clinical trials[200 201] It has the potential for quantification of viableinfecting microorganisms and consequently for monitoringthe efficacy of antimicrobial therapy in patients
Fragments of an antimicrobial peptide ubiquicidin con-jugated to NOTA and labelled with 68Ga [68Ga]Ga-NOTA-UBI29-41 and [68Ga]Ga-NOTA-UBI30-41 demonstratedpossibility for the distinction between infection and inflam-mation in a rabbit model [71 72] Antimicrobial peptidefragments GF-17 and RAWVAWR-NH2 of respectivelyhuman cathelicidin LL-37 andhuman lysozyme active againstE coli and S aureus were labelled with 68Ga and theirbiodistribution in normal rats demonstrated fast clearancefrom liver [75] Antimicrobial depsipeptide based agent[68Ga]Ga-DOTA-TBIA101 targeting bacterial lipopolysac-charides detected muscular E coli-infection in mice (Fig-ure 4) [73] The agent was also studied in healthy rabbitsand various disease model rabbits such as sterile inflam-mation Staphylococcus aureus infection andMycobacteriumtuberculosis [74] The clearance of [68Ga]Ga-DOTA-TBIA101from blood and normal tissue was fast and enhanced uptakein sterile inflammation and Mycobacterium tuberculosis siteswas observed The improvement of the bacterial selectivitywill require modification of the agent structure
63 Radiolabelled Siderophores Bacteria and fungi producevarious siderophores for harvesting iron which is essentialfor their survival and growth [34 98 191] Siderophores
10 Contrast Media amp Molecular Imaging
(a)
(b)
(c) (d)
(e)
Figure 4 Left panel presents maximum intensity projection images of [68Ga]Ga-DOTA-TBIA101 distribution in a healthy mouse (a) and amouse with muscular infection site (MIS) in the right hind muscle tissue (white arrows) Right panel presents coronal (c) sagittal (d) andaxial (e) images with uptake in theMIS (white arrow) and absence of the uptake in the contralateralmuscle tissue Ki and Bl stand respectivelyfor kidney and bladder Reproduced from [73]
can also play a critical role in the development of biofilmsby microbes They are low molecular weight compoundsspecifically chelating Fe(III) and Ga(III) can form stablecomplexes with them mimicking Fe(III) [202 203]
Desferri-triacetylfusarinine C (TAFC) and desferri-ferricrocin (FC) labelled with 68Ga were used for theimaging of invasive pulmonary aspergillosis (IPA) caused byAspergillus fumigatus [15] [68Ga]Ga-TAFC demonstratedsuperior characteristics in terms of specific target bindingmetabolic stability and fast blood clearance in a rat modelof A fumigatus infection Seven analogues were developedin another study with TAFC and ferrioxamine E (FOXE)showing favorable binding clearance elimination andstability characteristics [16] as well as lung uptake inrat of invasive aspergillosis model wherein the uptakeextent was correlated with disease severity [17] [68Ga]Ga-triacetylfusarinine C and [68Ga]Ga-ferrioxamine E wereinvestigated in rat model of A fumigatus and demonstratedrapid uptake in the lungs (Figure 5) [76]
64 Radiolabelled Metabolisable Agents Mammalian micro-biota consumes (poly)saccharides in particular maltose andmaltodextrins [204] The transport mechanism is specific
to bacteria and is absent in mammalian cells making itpossible to utilize these (poly)saccharides for imaging agentdevelopment Maltodextrin functionalized with a fluorescentdye was internalized through the bacteria-specific maltodex-trin transport pathway and discriminated between activebacteria and inflammation in vivo [192] Maltose labelledwith 18F localized specifically bacterial infection in mice[205] Potential to label polysaccharides directly with 68Gamight be utilized extensively
As mentioned above the chemical properties of Ga(III)provide the potential for direct labelling of polysaccharidesDextran was labelled directly and resulting complex demon-strated sufficient stability in human serum however thefeasibility of the bacterial imaging was not demonstrated[206]
Trapping of nucleosides that are substrates of thymidinekinase occurring within bacteria was explored using 18Fand 125I labelled analogues of uracil [207] Promising resultswere obtained in seven bacterial species in mice Anotherstudy in the context of therapeutic bacteria developmentdemonstrated possibility of detecting Salmonella vectorswithin tumours using 18F-labelled uracil [208] However
Contrast Media amp Molecular Imaging 11
N
O
N
ON
HN
O
O
O
OO O
NH
O
O
O
O
NH
O
OGa
（3
（3
（3
（3
（3
（3
（2
(a) (b) (c)
Figure 5 Molecular structure of [68Ga]Ga-triacetylfusarinine C (a) used for the in vivo imaging of a rat with Aspergillus fumigatus infection(b) and negative control of noninfected rat (c) White arrows point at the infected (b) and normal (c) lungs Adapted from [76]
the development of 68Ga-labelled nucleosides that wouldmaintain their biological activity is challenging and fewexamples known from the literature confirm that [4 6]
7 68Ga-Citrate
As mentioned above 68GaPET provides a number of advan-tages over 67GaSPECT and following publications demon-strate it in clinical and preclinical studies [68Ga]Ga-citratedemonstrated high diagnostic accuracy of 90of osteomyeli-tis and diskitis in clinical studies (Figure 6) [18 19] Thisstudy demonstrates that [68Ga]Ga-citrate can be employedfor monitoring the response to treatment [68Ga]Ga-citratewas used clinically to follow-up surgical intervention inpatients with acute osteomyelitis and intra-abdominal infec-tion [77] The agent was also used to successfully visualizelungmalignancy and tuberculosis in patients however in caseof high prevalence of granulomatous diseases the distinctionbetween malignant and benign lung lesions was unclear [7879] Another clinical study conducted head-to-head compar-ison of [68Ga]Ga-citrate (Figure 7) and [18F]FDG in patientswith Staphylococcus aureus bacteremia [80] The detectionrate of osteomyelitis was similar and further investigationof [68Ga]Ga-citrate applicability in cases of osteomyelitisinduced by other pathogens as well as for monitoring healingprocess is warranted
Comparative study of [68Ga]Ga-citrate and [67Ga]Ga-citrate was performed in healthy and infection model rats[77] The performance of [68Ga]Ga-citrate was found supe-rior in terms of image contrast in the lower abdomen and
extremities Potential of [68Ga]Ga-citrate for the differentia-tion of acute interstitial nephritis from acute tubular necrosiswas studied in rat model of the disease and it was demon-strated that the kidney uptake correlated with the extentof mononuclear cell infiltration accompanying inflammation[209] 68Ga-labelled Apo-transferrin demonstrated bacterialinfection detection capacity in rat model with Staphylococcusaureus wherein the infection site was visualized 1 h afteradministration of the agent [14]
71 Radiolabelled Antibodies and Antibody FragmentsHuman immunoglobulin (HIG) binds to bacteria but alsoaccumulates at the sites of fungal and viral infection aswell as sterile inflammation due to binding to leukocytesThe improved specificity for bacteria was achieved for thefragments of HIG It is feasible to develop specific antibodiesto various antigens present on the bacterial cell surface [102]Monoclonal antibodies labelled with 99mTc were used forinfection imaging via granulocytes targeting NCA-95 [210]Various cytokines of interleukin family (IL-1 IL-8) labelledwith 123I or 99mTc demonstrated accumulation in the sitesof infection in various animal models [111 112 211ndash214]Registered antigranulocyte radiopharmaceuticals suchas LeuTech Scintimun and Leukoscan are based on99mTc-labelled antibodies This experience can be translatedto 68Ga however either the size of the antibodies mustbe reduced or pretargeting techniques must be appliedin order to overcome the discrepancy between the shortphysical half-life of 68Ga and slow pharmacokinetics ofantibodies
12 Contrast Media amp Molecular Imaging
(a) (b) (c) (d)
Figure 6 [68Ga]Ga-citrate PETCT examination of a patient affected by acute osteomyelitis before (left panel) and after (right panel) surgicalcurettage showing uptake in the transaxial (a c) and 3D reconstruction images (b d red area) Absence of the uptake after the therapyconfirms complete response to the treatment Adapted from [19]
Figure 7 Vertebral osteomyelitis (spondylodiscitis red arrow-heads) and abscesses in the iliopsoas and paravertebral area (redarrows) were detected by [68Ga]Ga-citrate in a patient admittedto the hospital with back pain and general symptoms The PETacquisition was performed 88min after administration of 245MBqof [68Ga]Ga-citrate Adapted from [80]
72 Radiolabelled Biotin Biotin is a growth factor utilizedin many bacteria An 111In-labelled analogue of biotin wassuccessfully utilized for diagnosis of vertebral infections ina clinical study [215] It would be rational to explore therelevance of 68Ga-labelled analogues given the advantagesof 68Ga over 111In and promising [68Ga]Ga-DOTA-Biotinanalogues [216 217] developed for monitoring survival oftransplanted avidin-coated islets
8 Miscellaneous
Stable Ga(III) complex with thiosemicarbazones demon-strated antimicrobial effect against P aeruginosa and Calbicans due to most probably both displacement of essentialFe(III) with Ga(III) and thiosemicarbazones [101] Substitu-tion of the stable Ga(III) by radioactive 68Ga might result ina specific infection imaging agent
Selective imaging of Enterobacteriaceae using 2-[18F]-fluorodeoxysorbitol (18F-FDS)was demonstrated in amurine
myositis model [218] The uptake of 18F-FDS was correlatedwith bacterial burden moreover the agent differentiatedinfection from sterile inflammation Given the potential of68Ga for the labelling of small biologically active molecules[4] it might be plausible to develop a respective analoguewith added value of the advantages that 68Ga offers includingsimpler production chemistry lowered radiation dose repet-itive examination and accessibility at clinical centers withoutcyclotrons and remote from [18F]-FDG distribution sites Asmentioned above the poor access to bacteria aggregated ina biofilm might make the imaging task challenging Severalpeptide candidates with affinity for S aureus biofilm weredesigned and labelled with 68Ga [219] The resulting agentsdemonstrated binding in vitro however it was not possible toblock the binding with excess of the cold peptide
Ionic 68Ga was found superior to [18F]-FDG in infectiondetection in the rat model with diffuse osteomyelitis [220] Inanother study the uptake of ionic 68Ga was observed in theaortic plaques of atherosclerotic mice specifically at the sitesrich inmacrophages [221] However the slow blood clearanceof ionic 68Ga presents a limitation
Chronic inflammation is the major reason of fibro-sis [222] 68Ga-labelled SST analogue ([68Ga]Ga-DOTA-NOC) demonstrated uptake in pathogenic areas in patientsaffected by idiopathic pulmonary fibrosis with potentialfor monitoring response to treatment and drug develop-ment [62] Another clinical study using [68Ga]Ga-pentixaforalso showed potential of the agent for monitoring dis-ease activity and response to treatment in idiopathic pul-monary fibrosis [223] Peptide based agents CNO2A-PEG2-c[CPGRVMHGLHLGDDEGPC] and [68Ga]Ga-NODAGA-PEG2-c[CPGRVMHGLHLGDDEGPC] for the imaging andquantification of fibrosis by PET were developed and char-acterized preclinically showing fast clearance from normal
Contrast Media amp Molecular Imaging 13
tissue and blood and binding specificity [89] Dosimetrycalculations demonstrated possibility of six examinations peryear in humans assuring disease monitoring in longitudinalstudies and routine clinical setup [224]
Several hyaluronan conjugates of oligonucleotides target-ing CD44 positive cells were developed and tested in healthyrats sham-operated rats and rats with myocardial infarction[225]The uptake of the agents was higher for the latter groupand varied dependent on the difference in the oligonucleotidestructure
TLR2 and TLR4 expression levels in neutrophils werefound higher in individuals with bacterial and viral infectionsthan those in control samples There is a possibility that IL-4IL-8 IL-10 IL-12 and TNF-a might serve as biomarkers forinfections and that IL-2 IL-8 or IL-10 is potentially able todistinguish between bacterial and viral infections [22]
Mannosylated human serum albumin labelled with 68Gavia NOTA chelator moiety ([68Ga]Ga-NOTA-MSA) wastested in a rat model of myocarditis targetingmannose recep-tors expressed onmacrophages infiltratingmyocardium [66]The uptake in the diseased myocardium was considerablyhigher than that of the normal one and it was precludedby administration of excess of nonlabelled MSA indicatingbinding specificity The tracer build-up was also observed inthe organs of macrophage accumulation
[68Ga]Ga-DOTA was investigated for the quantificationof increased blood flow which is one of the key events ininflammation [226] The uptake kinetics of [68Ga]Ga-DOTAin the site of inflammation in rats with induced inflamma-tion correlated well with that of 15O-water suggesting highrelevance [68Ga]Ga-DOTA
9 Pretargeted Imaging
The half-life of 68Ga is shorter than that of 64Cu 67Ga 99mTc89Zr 111In and 123124125I and thus in contrast to the latterit is not compatible with slow pharmacokinetics of largemolecules such as antibodies and glycoproteins The rangeof antigen-specific antibodies relevant to inflammation andinfection is broad and a number of 99mTc-labelled antibodieswere used clinically [20 21 227] The respective range of68Ga-based agents could be similarThe solution to overcomethe incompatibility of half-life time frames could be eitherthe reduction of the antibody size or the application of thepretargeting concept
The history of the pretargeting concept spans threedecades predominantly in the field of oncology [228ndash230]It was developed to improve image contrast and dosimetryin immunoimaging and radioimmunotherapy when usingradiolabelled antibody ligands with slow pharmacokinetics[231] The arsenal of antibodies is vast and diverse encourag-ing extensive investment into development of techniques thatwould allow their exploration to the fullest Pretargeting con-siders at least two major steps wherein a functionalized anti-body is first administered for target localization and clearancefrom blood and normal tissue and thereafter a radiolabelledsmall molecule capable of binding to the functionalized
antibody due to high affinity or covalent interaction is admin-istered The key properties of the radiolabelled molecules arefast pharmacokinetic and clearance Several techniques havebeen developed for the realization of pretargeting conceptincluding avidinstreptavidin-biotin systems [216 217 232233] bispecific antibodies (bsmAb) with haptens [232 234ndash254] antibody-oligonucleotide conjugates with complemen-tary oligonucleotides [255] biorthogonal systems allowingcovalent chemical reactions in vivo (Figure 8)
The high affinity of biotin to avidin and streptavidinproteins was utilized clinically and preclinically in pretar-geting approach for the imaging and therapy of pancreaticadenocarcinoma [232] glioblastoma [256] and lymphoma[257] However this pretargeting technique may requirethree steps in order to eliminate the excess of antibody-(strept)avidin conjugate circulating in the blood and notbound to the target by adding clearing agent Anotherapplication of the technique was monitoring transplantationof islets of Langerhans in the treatment for type 1 diabetesmellitus wherein the cells or cellmimetics were conjugated to(strept)avidin prior to the transplantation [216 217] Severalanalogues of biotin comprising DOTA chelate moiety forlabelling with 68Ga and ethylene glycol linker of variouslength demonstrated the influence of the latter on the affinitytowards avidin
Particular example of hapten molecules is the ones com-prising histamine-succinyl-glycine (HSG) motif and chelatemoiety [251ndash253 258] for the complexationwith 68Ga Severalanalogues were developed for the imaging of carcinoem-bryonic antigen (CEA) pretargeted with anti-CEA bsmAb[254 259 260] and two clinical studies of medullary thyroidcarcinoma and breast carcinoma positive for CEA using68Ga-labelled hapten molecules and bsmAb were initiated[261]
Bioorthogonal reactions are fast regioselective requiringsmall reagent concentration and occurring under mild con-ditions often in aqueous solution and temperature below 37∘C[262 263] Amongst various biorthogonal reaction types thecycloaddition of tetrazines and various dienophiles referredto as inverse-electron-demandDiels-Alder (IEDDA) reactionis themost successful in the context of pretargeting Antibod-ies functionalized with trans-cyclooctene (TCO) and a radi-olabelled tetrazine that can interact in vivo based on IEDDAreaction were studied [264ndash267] In particular 68Ga-labelledtetrazine dextran demonstrated favorable pharmacokineticsin a healthy mouse [264] However the proof of concept is tobe performed in a xenografted animal Accumulation of anti-TAG72 [265] and anti-A33 [266] antibodies functionalizedwith TCO in mouse xenografts was visualized respectivelyby an 111In and 64Cu-labelled tetrazine analogues Anti-CA199 antibody-TCO in combination with 177Lu-labelledtetrazine demonstrated radiotherapeutic effect in pancreaticcancer murine model [267]
Thepretargeted imaging techniquesmay contribute to theexpansion of immuno-PET with 68Ga providing the intrinsicadvantages of 68Ga and PET As mentioned above mostof the developed radiolabelled counterparts of pretargetingtechniques have demonstrated promising results There are
14 Contrast Media amp Molecular Imaging
H
ON
NN
O
OO
OO
NH
NS
NH
ONH
O
HO
ONH
O
Ga
HN
NH
NH
O
OO
HNN
HN
NH
NH
O
OO
HNN
（2
(a)
NH
O
O
NH
N
NNGa
O O
O O
O
O
O
N N
NN
OO
（2
(b)
N
N
O
O
N
N
O
O
O
NH
O
O
ONH
NHS
O
H
HO
NH
+
minus
(c)
Figure 8 Schematic presentation of pretargeting techniques (a) bispecific antibodies engineered to specifically bind with radiolabelledhapten molecules (b) bioorthogonal click chemistry for fast and specific covalent binding between for example a trans-cyclooctenefunctionalized antibody and a radiolabelled tetrazine (c) interaction between antibody-(strept)avidin conjugate and radiolabelled biotinutilizing extremely high affinity of (strept)avidin and biotin
Contrast Media amp Molecular Imaging 15
a considerable number of potential antibody biomarkersthat could be considered for the imaging of infection andinflammation
10 Theranostics Potential
Theranostics [268] embraces realization of personalizedmedicine by conducting diagnosis on individual basis andproviding possibility of predicting the efficacy of a specifictreatment and following up the response to the treatmentenabling adjustment of the latter very early in the processIn the context of nuclear medicine wherein the radiophar-maceuticals targeted at biomarkers specific to a disease cancarry either diagnostic radionuclides or therapeutic ones theconcept can be denoted as radiotheranostics [28] The tar-geted molecular imaging such as PET can offer noninvasivediagnosis specific to the disease for example tumour-typespecific and provide accurate localization of the lesions Thestrongest advantage of PET is the potential for quantificationof the target for example receptor expression investigationof the uptake kinetics and estimation of the dosimetryThesecharacteristics of PET allow for individualized treatmentselection and planning monitoring of treatment responseand detection of recurrent diseaseThe individualized patientmanagement provides such advantages as optimization ofthe treatment regimen for the improved response and exclu-sion of futile treatments minimization of risks and toxicitywith overall outcome of reduced cost and patient distressThe importance of individualized patient management wasdemonstrated by clinical studies wherein the influence ofdose of the administered radiopharmaceutical targeted atreceptors overexpressed in cancer lesions on the diagnosticoutcome was investigated in the same patient [85 269270] 68Ga-labelled SST analogues [26ndash28 271] and Affibodymolecules [5 272ndash274] used respectively in NENs andbreast cancer patients are the most prominent examplesof (radio)theranostics involving 68GaPET wherein 68Ga-labelled analogues were used not only for localization of thelesions but also for staging patient stratification prognosistherapy selection and monitoring of the response to thetreatment of NETs and other cancer types [2ndash4 6 85 176275ndash277]
The methodology can be translated to inflammationand infection allowing for accurate and specific selection oftreatment regimen and for follow-up and evaluation of theresponse to therapy resulting in improved treatment efficacyand decreased cost and side effects The accommodation ofboth imaging function and antibiotic function in the samemolecule is a novel example of a theranostic agent [278]A series of siderophores conjugated with DOTA moiety forthe radiolabelling and with antibiotics for the treatmentof bacterial infection were investigated preclinically Theaccumulation of the intravenously administered ampicillinconjugate in the site of subcutaneously injected P aeruginosain mice was clearly and focally visualized within 06 h withretention for at least 24 h These results obtained usinganalogues carrying dye for optical imaging can be translatedto 68Ga-labelled counterparts for PET
11 Conclusions
The medical need for specific agents for noninvasive quan-titative and whole-body imaging of inflammation and infec-tion has not been met yet despite decades of research How-ever the prerequisites in terms of identification of potentialtargets design and synthesis of the respective ligands andimaging technologies are evolving very fast The potentialof accurate and quantitative lesion localization as well asmonitoring of the treatment response promises personalizedpatient management
The use of 68Ga in oncology is established proving thestrong potential of 68Ga for the promotion of PET technol-ogy for effective and efficient diagnostics and personalizedmedicineThe experience of oncological 68Ga-based agents isgetting translated to inflammation and infection Pretargetedimaging technology opens wide possibilities based on anti-body biomarkers
Conflicts of Interest
The author declares that there are no conflicts of interestregarding the publication of this article
References
[1] I Velikyan ldquoContinued rapid growth inGa applications update2013 to June 2014rdquo Journal of Labelled CompoundsampRadiophar-maceuticals pp 99ndash121 2015
[2] I Velikyan ldquo 68Ga-based radiopharmaceuticals Production andapplication relationshiprdquo Molecules vol 20 no 7 pp 12913ndash12943 2015
[3] M Fani P Peitl and I Velikyan ldquoCurrent status of radiophar-maceuticals for the theranostics of neuroendocrine neoplasmsrdquoPharmaceuticals vol 10 no 1 article no 30 2017
[4] I Velikyan ldquoPositron emitting [68Ga]Ga-based imaging agentsChemistry and diversityrdquoMedicinal Chemistry vol 7 no 5 pp345ndash379 2011
[5] J Sorensen I Velikyan D Sandberg et al ldquoMeasuringHER2-receptor expression in metastatic breast cancer using[68Ga]ABY-025 Affibody PETCTrdquo Theranostics vol 6 no 2pp 262ndash271 2016
[6] I Velikyan ldquoProspective of 68Ga-Radiopharmaceutical devel-opmentrdquoTheranostics vol 4 no 1 pp 47ndash80 2014
[7] P Lankinen T J Makinen T A Poyhonen et al ldquo68Ga-DOTAVAP-P1 PET imaging capable of demonstrating the phaseof inflammation in healing bones and the progress of infectionin osteomyelitic bonesrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 35 no 2 pp 352ndash364 2008
[8] T UjulaMHuttunen P Luoto et al ldquoMatrixmetalloproteinase9 targeting peptides Syntheses 68Ga-labeling and preliminaryevaluation in a rat melanoma xenograft modelrdquo BioconjugateChemistry vol 21 no 9 pp 1612ndash1621 2010
[9] A Autio T Ujula P Luoto S Salomaki S Jalkanen and ARoivainen ldquoPET imaging of inflammation and adenocarcinomaxenografts using vascular adhesion protein 1 targeting peptide68Ga-DOTAVAP-P1 Comparison with 18F-FDGrdquo EuropeanJournal of Nuclear Medicine and Molecular Imaging vol 37 no10 pp 1918ndash1925 2010
16 Contrast Media amp Molecular Imaging
[10] J Silvola A Autio P Luoto S Jalkanen andA Roivainen ldquoPre-liminary evaluation of novel 68Ga-DOTAVAP-PEG-P2 peptidetargeting vascular adhesion protein-1rdquo Clinical Physiology andFunctional Imaging vol 30 no 1 pp 75ndash78 2010
[11] T Ujula S Salomaki P Virsu et al ldquoSynthesis 68Ga labelingand preliminary evaluation of DOTA peptide binding vascularadhesion protein-1 a potential PET imaging agent for diagnos-ing osteomyelitisrdquo Nuclear Medicine and Biology vol 36 no 6pp 631ndash641 2009
[12] A Autio T Henttinen H J Sipila S Jalkanen and ARoivainen ldquoMini-PEG spacering of VAP-1-targeting 68Ga-DOTAVAP-P1 peptide improves PET imaging of inflamma-tionrdquo EJNMMI Research vol 1 no 1 pp 1ndash7 2011
[13] K Aalto A Autio E A Kiss et al ldquoSiglec-9 is a novel leukocyteligand for vascular adhesion protein-1 and can be used in PETimaging of inflammation and cancerrdquo Blood vol 118 no 13 pp3725ndash3733 2011
[14] V Kumar D K Boddeti S G Evans F Roesch and RHowman-Giles ldquoPotential use of 68Ga-apo-transferrin as a PETimaging agent for detecting Staphylococcus aureus infectionrdquoNuclear Medicine and Biology vol 38 no 3 pp 393ndash398 2011
[15] M Petrik H Haas G Dobrozemsky et al ldquo68Ga-siderophoresfor PET imaging of invasive pulmonary aspergillosis Proof ofprinciplerdquo Journal of Nuclear Medicine vol 51 no 4 pp 639ndash645 2010
[16] M Petrik H Haas M Schrettl A Helbok M Blatzer and CDecristoforo ldquoIn vitro and in vivo evaluation of selected 68Ga-siderophores for infection imagingrdquo Nuclear Medicine andBiology vol 39 no 3 pp 361ndash369 2012
[17] M Petrik GM Franssen H Haas et al ldquoPreclinical evaluationof two 68Ga-siderophores as potential radiopharmaceuticals forAspergillus fumigatus infection imagingrdquo European Journal ofNuclearMedicine andMolecular Imaging vol 39 no 7 pp 1175ndash1183 2012
[18] A Rizzello D Di Pierro F Lodi et al ldquoSynthesis and qualitycontrol of 68Ga citrate for routine clinical PETrdquo NuclearMedicine Communications vol 30 no 7 pp 542ndash545 2009
[19] C Nanni C Errani and L Boriani ldquo 68Ga-citrate PETCT forevaluating patients with infections of the bone preliminaryresultsrdquo Journal of Nuclear Medicine vol 51 no 12 pp 1932ndash1936 2010
[20] S S Das A V Hall D W Wareham and K E Britton ldquoInfec-tion imaging with radiopharmaceuticals in the 21st centuryrdquoBrazilian Archives of Biology and Technology vol 45 no spepp 25ndash37 2002
[21] A Signore and A W J M Glaudemans ldquoThe molecularimaging approach to image infections and inflammation bynuclear medicine techniquesrdquo Annals of Nuclear Medicine vol25 no 10 pp 681ndash700 2011
[22] T Yusa K Tateda A Ohara and S Miyazaki ldquoNew possiblebiomarkers for diagnosis of infections and diagnostic distinc-tion between bacterial and viral infections in childrenrdquo Journalof Infection and Chemotherapy vol 23 no 2 pp 96ndash100 2017
[23] A Signore A W J M Glaudemans O Gheysens C Lauriand O A Catalano ldquoNuclear Medicine Imaging in PediatricInfection or Chronic Inflammatory Diseasesrdquo Seminars inNuclear Medicine vol 47 no 3 pp 286ndash303 2017
[24] I Velikyan ldquoMolecular imaging and radiotherapyTheranosticsfor personalized patient managementrdquo Theranostics vol 2 no5 pp 424ndash426 2012
[25] F Rosch and R P Baum ldquoGenerator-based PET radiophar-maceuticals for molecular imaging of tumours On the way
to THERANOSTICSrdquo Dalton Transactions vol 40 no 23 pp6104ndash6111 2011
[26] R P Baum H R Kulkarni and C Carreras ldquoPeptides andreceptors in image-guided therapy Theranostics for neuroen-docrine neoplasmsrdquo Seminars in Nuclear Medicine vol 42 no3 pp 190ndash207 2012
[27] R P Baum and H R Kulkarni ldquoTheranostics From molecularimaging using Ga-68 labeled tracers and PETCT to per-sonalized radionuclide therapy - the bad berka experiencerdquoTheranostics vol 2 no 5 pp 437ndash447 2012
[28] I Velikyan ldquoRadionuclides for Imaging andTherapy in Oncol-ogyrdquo Cancer Theranostics pp 285ndash325 2014
[29] J Czernin andWAWeber ldquoIssues and controversies in nuclearmedicine Introductionrdquo Journal of Nuclear Medicine vol 52no Supplement 2 pp 1Sndash2S 2011
[30] S J Goldsmith and S Vallabhajosula ldquoClinically proven radio-pharmaceuticals for infection imaging mechanisms and appli-cationsrdquo Seminars in Nuclear Medicine vol 39 no 1 pp 2ndash102009
[31] M F Tsan ldquoMechanism of gallium-67 accumulation in inflam-matory lesionsrdquo Journal of Nuclear Medicine vol 26 no 1 pp88ndash92 1985
[32] S L Kipper ldquoRadiolabelled leukocyte imaging of the abdomenrdquoin Nuclear Medicine Annual J Freeman Ed pp 81ndash126 RavenPress New York NY USA 1995
[33] F Jamar J Buscombe A Chiti et al ldquoEANMSNMMI guidelinefor 18F-FDG use in inflammation and infectionrdquo Journal ofNuclear Medicine vol 54 no 4 pp 647ndash658 2013
[34] C J Palestro ldquoThe current role of gallium imaging in infectionrdquoSeminars in Nuclear Medicine vol 24 no 2 pp 128ndash141 1994
[35] M S Akhtar M B Imran M A Nadeem and A ShahidldquoAntimicrobial peptides as infection imaging agents better thanradiolabeled antibioticsrdquo International Journal of Peptides vol2012 Article ID 965238 19 pages 2012
[36] D Delbeke and G M Segall ldquoStatus of and trends in nuclearmedicine in the United Statesrdquo Journal of Nuclear Medicine vol52 no 2 2011
[37] S S Gambhir J Czernin J Schwimmer D H Silverman R EColeman and M E Phelps ldquoA tabulated summary of the FDGPET literaturerdquo Journal of Nuclear Medicine vol 42 pp 1Sndash93S2001
[38] M J Lindsay B A Siegel S R Tunis et al ldquoThe NationalOncologic PET Registry ExpandedMedicare coverage for PETunder coverage with evidence developmentrdquo American Journalof Roentgenology vol 188 no 4 pp 1109ndash1113 2007
[39] F Gemmel H Van Den Wyngaert C Love M M Welling PGemmel and C J Palestro ldquoProsthetic joint infectionsradionuclide state-of-the-art imagingrdquo European Journal ofNuclearMedicine andMolecular Imaging vol 39 no 5 pp 892ndash909 2012
[40] J Sorensen ldquoHow does the patient benefit from clinical PETrdquoTheranostics vol 2 no 5 pp 427ndash436 2012
[41] S L Rice C A Roney P Daumar and J S Lewis ldquoThe nextgeneration of positron emission tomography radiopharmaceu-ticals in oncologyrdquo Seminars in Nuclear Medicine vol 41 no 4pp 265ndash282 2011
[42] R LWahl JMHerman and E Ford ldquoThePromise and Pitfallsof Positron Emission Tomography and Single-Photon EmissionComputed Tomography Molecular Imaging-Guided RadiationTherapyrdquo Seminars in Radiation Oncology vol 21 no 2 pp 88ndash100 2011
Contrast Media amp Molecular Imaging 17
[43] A W J M Glaudemans R H J A Slart J M Van Dijl MVan Oosten and G M Van Dam ldquoMolecular imaging of infec-tious and inflammatory diseases A terra incognitardquo Journal ofNuclear Medicine vol 56 no 5 pp 659ndash661 2015
[44] X Li W Bauer I Israel et al ldquoTargeting p-selectin by gallium-68-labeled fucoidan positron emission tomography for nonin-vasive characterization of vulnerable plaques Correlation within vivo 176t mrirdquo Arteriosclerosis Thrombosis and VascularBiology vol 34 no 8 pp 1661ndash1667 2014
[45] S Eichendorff P Svendsen D Bender et al ldquoBiodistributionand PET Imaging of a Novel [68Ga]-Anti-CD163-AntibodyConjugate in Rats with Collagen-Induced Arthritis and inControlsrdquoMolecular Imaging and Biology vol 17 no 1 pp 87ndash93 2014
[46] Z Zhu Y Yin K Zheng et al ldquoEvaluation of synovial angiogen-esis in patients with rheumatoid arthritis using 68Ga-PRGD2PETCT A prospective proof-of-concept cohort studyrdquo Annalsof the Rheumatic Diseases vol 73 no 6 pp 1269ndash1272 2014
[47] J S Eo J C Paeng S Lee et al ldquoAngiogenesis imaging inmyocardial infarction using 68Ga-NOTA- RGD PET Charac-terization and application to therapeutic efficacy monitoring inratsrdquo Coronary Artery Disease vol 24 no 4 pp 303ndash311 2013
[48] J H Kim Y-H Kim Y J Kim et al ldquoQuantitative positronemission tomography imaging of angiogenesis in rats with fore-limb ischemia using 68Ga-NOTA-c(RGDyK)rdquo Angiogenesisvol 16 no 4 pp 837ndash846 2013
[49] I Laitinen J Notni K Pohle et al ldquoComparison of cyclicRGD peptides for 120572v1205733 integrin detection in a rat model ofmyocardial infarctionrdquo EJNMMI Research vol 3 no 1 pp 1ndash9 2013
[50] M Kiugel I Dijkgraaf V Kyto et al ldquoDimeric [68Ga]DOTA-RGD Peptide Targeting 120572 ltinfgtvltinfgt 120573 ltinfgt3ltinfgt Inte-grin Reveals Extracellular Matrix Alterations after MyocardialInfarctionrdquo Molecular Imaging and Biology vol 16 no 6 pp793ndash801 2014
[51] M Gronman M Tarkia T Kiviniemi et al ldquoImaging of 120572v1205733integrin expression in experimental myocardial ischemia with[68Ga]NODAGA-RGD positron emission tomographyrdquo Jour-nal of Translational Medicine vol 15 no 1 p 144 2017
[52] J Haukkala I Laitinen P Luoto et al ldquo68Ga-DOTA-RGDpep-tide Biodistribution and binding into atherosclerotic plaquesin micerdquo European Journal of Nuclear Medicine and MolecularImaging vol 36 no 12 pp 2058ndash2067 2009
[53] H Virtanen A Autio R Siitonen et al ldquo68Ga-DOTA-Siglec-9- a new imaging tool to detect synovitisrdquo Arthritis Research ampTherapy vol 17 no 1 article no 308 2015
[54] J Retamal J Sorensen M Lubberink et al ldquoFeasibility of(68) Ga-labeled Siglec-9 peptide for the imaging of acutelung inflammation a pilot study in a porcine model of acuterespiratory distress syndromerdquoAm JNuclMedMol Imaging vol6 no 1 pp 18ndash31 2016
[55] J M U Silvola H Virtanen R Siitonen et al ldquoLeukocytetrafficking-associated vascular adhesion protein 1 is expressedand functionally active in atherosclerotic plaquesrdquo ScientificReports vol 6 Article ID 35089 2016
[56] H Ahtinen J Kulkova L Lindholm et al ldquo68Ga-DOTA-Siglec-9 PETCT imaging of peri-implant tissue responses andstaphylococcal infectionsrdquo EJNMMI Research vol 4 no 1article no 45 pp 1ndash11 2014
[57] A Autio S Jalkanen and A Roivainen ldquoNuclear imaging ofinflammation Homing-associated molecules as targetsrdquo EJN-MMI Research vol 3 no 1 pp 1ndash7 2013
[58] J TThackeray T Derlin AHaghikia et al ldquoMolecular Imagingof the Chemokine Receptor CXCR4 after Acute MyocardialInfarctionrdquo JACC Cardiovascular Imaging vol 8 no 12 pp1417ndash1426 2015
[59] J S Schmid A Schirbel A K Buck S Kropf H-J Westerand C Lapa ldquoPentixafor-Positron Emission TomographyComputed Tomography Detects Chemokine Receptor CXCR4Expression after Ischemic Strokerdquo Circulation CardiovascularImaging vol 9 no 9 Article ID e005217 2016
[60] J Zhou G Hao H Weng et al ldquoIn vivo evaluation ofmedical device-associated inflammation using a macrophage-specific positron emission tomography (PET) imaging proberdquoBioorganic amp Medicinal Chemistry Letters vol 23 no 7 pp2044ndash2047 2013
[61] S A Kularatne M-J Belanger X Meng et al ldquoComparativeanalysis of folate derived PET imaging agents with [ 18F]-2-fluoro-2-deoxy-d-glucose using a rodent inflammatory pawmodelrdquo Molecular Pharmaceutics vol 10 no 8 pp 3103ndash31112013
[62] V Ambrosini M Zompatori F De Luca et al ldquo68Ga-DOTANOCPETCTAllows Somatostatin Receptor Imaging inIdiopathic Pulmonary Fibrosis Preliminary Resultsrdquo Journal ofNuclear Medicine vol 51 no 12 pp 1950ndash1955 2010
[63] T Lincke J Singer R Kluge O Sabri and R Paschke ldquoRela-tive quantification of indium-111 pentetreotide and gallium-68DOTATOC uptake in the thyroid gland and association withthyroid pathologiesrdquoThyroid vol 19 no 4 pp 381ndash389 2009
[64] A Rominger T Saam E Vogl et al ldquoIn vivo imaging ofmacrophage activity in the coronary arteries using 68Ga-DOTATATE PETCT correlation with coronary calcium bur-den and risk factorsrdquo Journal of Nuclear Medicine vol 51 no 2pp 193ndash197 2010
[65] J M Tarkin F R Joshi N R Evans et al ldquoDetection ofAtherosclerotic Inflammation by 68Ga-DOTATATE PET Com-pared to [18F]FDG PET Imagingrdquo Journal of the AmericanCollege of Cardiology vol 69 no 14 pp 1774ndash1791 2017
[66] S-P Lee H-J Im S Kang et al ldquoNoninvasive imaging ofmyocardial inflammation in myocarditis using 68Ga-taggedmannosylated human serum albumin positron emissiontomographyrdquoTheranostics vol 7 no 2 pp 413ndash424 2017
[67] Z Zha J Song S R Choi et al ldquo68Ga-Bivalent PolypegylatedStyrylpyridine Conjugates for Imaging A120573 Plaques in CerebralAmyloid Angiopathyrdquo Bioconjugate Chemistry vol 27 no 5 pp1314ndash1323 2016
[68] H Watanabe M Ono S Iikuni et al ldquoA 68Ga complex basedon benzofuran scaffold for the detection of 120573-amyloid plaquesrdquoBioorganic amp Medicinal Chemistry Letters vol 24 no 20 pp4834ndash4837 2014
[69] D Cressier M Dhilly T T Cao Pham et al ldquoGallium-68 Com-plexes Conjugated to Pittsburgh Compound B Radiolabelingand Biological EvaluationrdquoMolecular Imaging and Biology vol18 no 3 pp 334ndash343 2016
[70] D Satpati CArjun R KrishnamohanG Samuel and S Baner-jee ldquo68Ga-labeledCiprofloxacinConjugates as Radiotracers forTargeting Bacterial InfectionrdquoChemical Biology ampDrug Designvol 87 no 5 pp 680ndash686 2016
[71] T Ebenhan N Chadwick and M M Sathekge ldquoPeptidesynthesis characterization and 68Ga-radiolabeling of NOTA-conjugated ubiquicidin fragments for prospective infectionimaging with PETCTrdquo Nuclear Medicine and Biology vol 41no 5 pp 390ndash400 2014
18 Contrast Media amp Molecular Imaging
[72] T Ebenhan J R Zeevaart and J D Venter ldquoPreclinicalevaluation of 68Ga-labeled 1 4 7-triazacyclononane-1 4 7-triacetic acid-ubiquicidin as a radioligand for PET infectionimagingrdquo Journal of Nuclear Medicine vol 55 no 2 pp 308ndash314 2014
[73] B B Mokaleng T Ebenhan S Ramesh et al ldquoSynthesis 68Ga-radiolabeling and preliminary in vivo assessment of adepsipeptide-derived compound as a potential PETCTinfection imaging agentrdquo BioMed Research International vol2015 Article ID 284354 2015
[74] T Ebenhan B Mokaleng J Venter H Kruger J Zeevaart andM Sathekge ldquoPreclinical Assessment of a 68Ga-DOTA-Functionalized Depsipeptide as a Radiodiagnostic InfectionImaging AgentrdquoMolecules vol 22 no 9 p 1403 2017
[75] S Chopra B Singh A Koul A Mishra and H Wester ldquoSyn-thesis of DOTA conjugated GF-17 and RAWVAWR-NH2 andradiolabeling with 68Ga as a potential PET tracer for infectionimagingrdquo J Nucl Med vol 57 Supplement 2 p 1115 2016
[76] M Petrik HHaas P Laverman et al ldquo 68Ga-triacetylfusarinineC and 68Ga-ferrioxamine e for aspergillus infection imaginguptake specificity in various microorganismsrdquoMolecular Imag-ing and Biology vol 16 no 1 pp 102ndash108 2014
[77] V Kumar and D K Boddeti ldquo 68Ga-radiopharmaceuticals forPET imaging of infection and inflammationrdquo Recent Results inCancer Research vol 194 pp 189ndash219 2013
[78] M Vorster A Maes A Jacobs et al ldquoEvaluating the possiblerole of 68Ga-citrate PETCT in the characterization of indeter-minate lung lesionsrdquo Annals of Nuclear Medicine vol 28 no 6pp 523ndash530 2014
[79] M Vorster B Mokaleng M M Sathekge and T Ebenhan ldquoAmodified technique for efficient radiolabeling of 68Ga-citratefrom a SnO2-based 68Ge68Ga generator for better infectionimagingrdquoHellenic Journal of Nuclear Medicine vol 16 no 3 pp193ndash198 2013
[80] S Salomaeki J Kemppainen U Hohenthal et al ldquoHead-to-head comparison of 68Ga-Citrate and 18F-FDG PETCT fordetection of infectious foci in patients with staphylococcusaureus bacteraemiardquo Contrast Media amp Molecular Imaging vol2017 p 8 2017
[81] L Fass ldquoImaging and cancer a reviewrdquoMolecular Oncology vol2 no 2 pp 115ndash152 2008
[82] A Chopra L Shan W C Eckelman et al ldquoMolecular imagingand contrast agent database (MICAD) Evolution and progressrdquoMolecular Imaging and Biology vol 14 no 1 pp 4ndash13 2012
[83] A Sanchez-Crespo P Andreo and S A Larsson ldquoPositronflight in human tissues and its influence on PET image spatialresolutionrdquo European Journal of Nuclear Medicine and Molecu-lar Imaging vol 31 no 1 pp 44ndash51 2004
[84] H W A M De Jong L Perk G W M Visser R Boellaard GAM S Van Dongen and A A Lammertsma ldquoHigh resolutionPET imaging characteristics of68Ga 124i and89Zr comparedto18Frdquo in Proceedings of the Nuclear Science Symposium Con-ference Record 2005 IEEE pp 1624ndash1627 Puerto Rico October2005
[85] I Velikyan A Sundin B Eriksson et al ldquoIn vivo bindingof [68Ga]-DOTATOC to somatostatin receptors in neuroen-docrine tumours - impact of peptide massrdquo Nuclear Medicineand Biology vol 37 no 3 pp 265ndash275 2010
[86] U Eberlein and M Lassmann ldquoDosimetry of [68Ga]-labeledcompoundsrdquo Applied Radiation and Isotopes vol 76 pp 70ndash742013
[87] C PettinatoA SarnelliMDiDonna et al ldquo68Ga-DOTANOCBiodistribution and dosimetry in patients affected by neuroen-docrine tumorsrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 35 no 1 pp 72ndash79 2008
[88] B P Burke G S Clemente and S J Archibald ldquoRecentadvances in chelator design and labelling methodology for68Ga radiopharmaceuticalsrdquo Journal of Labelled Compoundsand Radiopharmaceuticals vol 57 no 4 pp 239ndash243 2014
[89] I Velikyan U Rosenstrom S Estrada et al ldquoSynthesis andpreclinical evaluation of 68Ga-labeled collagelin analogs forimaging and quantification of fibrosisrdquo Nuclear Medicine andBiology vol 41 no 9 pp 728ndash736 2014
[90] M F Ferreira G Pereira J P Andre and etal C ldquoGa[NO2A-N-(120572-amino)propionate] chelates Synthesis and evaluation aspotential tracers for 68Ga PETrdquoDalton Transactions vol 43 no21 pp 8037ndash8047 2014
[91] J Notni J Simecek and H-J Wester ldquoPhosphinic acid func-tionalized polyazacycloalkane chelators for radiodiagnosticsand radiotherapeutics Unique characteristics and applicationsrdquoChemMedChem vol 9 no 6 pp 1107ndash1115 2014
[92] J Simecek O Zemek P Hermann J Notni and H J WesterldquoTailored gallium( III) chelator NOPO synthesis characteriza-tion bioconjugation and application in preclinical Ga-68-PETimagingrdquoMolecular Pharmaceutics 2013
[93] D Parker B P Waldron and D S Yufit ldquoCrystallographicand solution NMR structural analyses of four hexacoordinatedgallium(iii) complexes based on ligands derived from 6-amino-perhydro-14-diazepinerdquo Dalton Transactions vol 42 no 22pp 8001ndash8008 2013
[94] B P Waldron D Parker C Burchardt D S Yufit M ZimnyandF Roesch ldquoStructure and stability of hexadentate complexesof ligands based on AAZTA for efficient PET labelling withgallium-68rdquo Chemical Communications vol 49 no 6 pp 579ndash581 2013
[95] D Parker and B PWaldron ldquoConformational analysis and syn-thetic approaches to polydentate perhydro-diazepine ligandsfor the complexation of gallium(iii)rdquo Organic amp BiomolecularChemistry vol 11 no 17 pp 2827ndash2838 2013
[96] I Velikyan H Maecke and B Langstrom ldquoConvenient prepa-ration of 68Ga-based PET-radiopharmaceuticals at room tem-peraturerdquo Bioconjugate Chemistry vol 19 no 2 pp 569ndash5732008
[97] J Erchegyi R Cescato B Waser J E Rivier and J C ReubildquoN-Imidazolebenzyl-histidine substitution in somatostatin andin its octapeptide analogue modulates receptor selectivity andfunctionrdquo Journal of Medicinal Chemistry vol 54 no 17 pp5981ndash5987 2011
[98] R Saha N Saha R S Donofrio and L L Bestervelt ldquoMicrobialsiderophores Amini reviewrdquo Journal of Basic Microbiology vol53 no 4 pp 303ndash317 2013
[99] V Nikolova S Angelova N Markova and T Dudev ldquoGalliumas a Therapeutic Agent A Thermodynamic Evaluation of theCompetition between Ga3+ and Fe3+ Ions in MetalloproteinsrdquoThe Journal of Physical Chemistry B vol 120 no 9 pp 2241ndash2248 2016
[100] C R Chitambar ldquoGallium and its competing roles with ironin biological systemsrdquo Biochimica et Biophysica Acta (BBA) -Molecular Cell Research vol 1863 no 8 pp 2044ndash2053 2016
[101] J A Lessa M A Soares and R G dos Santos ldquoGallium(III)complexes with 2-acetylpyridine-derived thiosemicarbazonesantimicrobial and cytotoxic effects and investigation on theinteractions with tubulinrdquo BioMetals vol 26 pp 151ndash165 2013
Contrast Media amp Molecular Imaging 19
[102] M van Oosten M Hahn L M A Crane et al ldquoTargetedimaging of bacterial infections Advances hurdles and hopesrdquoFEMS Microbiology Reviews vol 39 no 6 pp 892ndash916 2015
[103] M Vorster AMaes C V DWiele andM Sathekge ldquoGallium-68 PET A Powerful Generator-based Alternative to Infectionand Inflammation Imagingrdquo Seminars in Nuclear Medicine vol46 no 5 pp 436ndash447 2016
[104] M Kircher and C Lapa ldquoNovel Noninvasive Nuclear MedicineImaging Techniques for Cardiac Inflammationrdquo Current Car-diovascular Imaging Reports vol 10 no 2 article no 6 2017
[105] D AHammoud ldquoMolecular imaging of inflammation Currentstatusrdquo Journal of Nuclear Medicine vol 57 no 8 pp 1161ndash11652016
[106] D R Brenner D Scherer K Muir et al ldquoA review of the appli-cation of inflammatory biomarkers in epidemiologic cancerresearchrdquo Cancer Epidemiology Biomarkers amp Prevention vol23 no 9 pp 1729ndash1751 2014
[107] M D Turner B Nedjai T Hurst and D J PenningtonldquoCytokines and chemokines at the crossroads of cell signallingand inflammatory diseaserdquo Biochimica et Biophysica Acta (BBA)- Molecular Cell Research vol 1843 no 11 pp 2563ndash2582 2014
[108] L Werner H Guzner-Gur and I Dotan ldquoInvolvement ofCXCR4CXCR7CXCL12 interactions in inflammatory boweldiseaserdquoTheranostics vol 3 no 1 pp 40ndash46 2013
[109] S Jalkanen and M Salmi ldquoVAP-1 and CD73 endothelial cellsurface enzymes in leukocyte extravasationrdquo ArteriosclerosisThrombosis and Vascular Biology vol 28 no 1 pp 18ndash26 2008
[110] G Malviya F Galli I Sonni and A Signore ldquoImaging T-lymphocytes in inflammatory diseases A nuclear medicineapproachrdquo The Quarterly Journal of Nuclear Medicine andMolecular Imaging vol 58 no 3 pp 237ndash257 2014
[111] S Gratz H J RennenO C BoermanW J Oyen and P Burmaldquo(99m)Tc-interleukin-8 for imaging acute osteomyelitisrdquo Jour-nal of Nuclear Medicine vol 42 no 8 pp 1257ndash1264 2001
[112] S Gratz H J Rennen O C Boerman W J Oyen andF H Corstens ldquoRapid imaging of experimental colitis with(99m)Tc-interleukin-8 in rabbitsrdquo Journal of Nuclear Medicnevol 42 no 6 pp 917ndash923 2001
[113] C Alkim H Alkim A R Koksal S Boga and I SenldquoAngiogenesis in inflammatory bowel diseaserdquo InternationalJournal of Inflammation vol 2015 Article ID 970890 2015
[114] I S Alam T H Witney G Tomasi et al ldquoRadiolabeled RGDtracer kinetics annotates differential 120572v1205733 integrin expressionlinked to cell intrinsic and vessel expressionrdquoMolecular Imagingand Biology vol 16 no 4 pp 558ndash566 2014
[115] J Notni K Pohle and H-J Wester ldquoBe spoilt for choice withradiolabelled RGD peptides Preclinical evaluation of 68Ga-TRAP(RGD)3rdquoNuclear Medicine and Biology vol 40 no 1 pp33ndash41 2013
[116] J Oxboel M Brandt-Larsen C Schjoeth-Eskesen et al ldquoCom-parison of two new angiogenesis PET tracers 68Ga-NODAGA-E[c(RGDyK)]2 and 64Cu-NODAGA-E[c(RGDyK)]2 in vivoimaging studies in human xenograft tumorsrdquo Nuclear Medicineand Biology vol 41 no 3 pp 259ndash267 2014
[117] J Simecek J Notni T G Kapp H Kessler and H-J WesterldquoBenefits of NOPO as chelator in gallium-68 peptides exempli-fied by preclinical characterization of 68Ga-NOPO-c(RGDfK)rdquoMolecular Pharmaceutics vol 11 no 5 pp 1687ndash1695 2014
[118] M Trajkovic-Arsic P Mohajerani A Sarantopoulos et alldquoMultimodal molecular imaging of integrin avb3 for in vivodetection of pancreatic cancerrdquo Journal of NuclearMedicine vol55 no 3 pp 446ndash451 2014
[119] H Cai and P S Conti ldquoRGD-based PET tracers for imagingreceptor integrin 120572 v1205733 expressionrdquo Journal of Labelled Com-pounds and Radiopharmaceuticals vol 56 no 5 pp 264ndash2792013
[120] I Dijkgraaf S Y A Terry W J Mcbride et al ldquoImagingintegrin alpha-v-beta-3 expression in tumors with an 18F-labeled dimeric RGD peptiderdquo Contrast Media amp MolecularImaging vol 8 no 3 pp 238ndash245 2013
[121] P A Knetsch M Petrik C Rangger et al ldquo[68Ga]NS3-RGD and [68Ga] Oxo-DO3A-RGD for imaging 120572v1205733 integrinexpression Synthesis evaluation and comparisonrdquo NuclearMedicine and Biology vol 40 no 1 pp 65ndash72 2013
[122] Z Liu and F Wang ldquoDevelopment of RGD-based radiotracersfor tumor imaging and therapy Translating from bench tobedsiderdquo Current Molecular Medicine vol 13 no 10 pp 1487ndash1505 2013
[123] H Choi J H Phi J C Paeng et al ldquoImaging of integrin 120572v1205733expression using 68Ga-RGD positron emission tomography inpediatric cerebral infarctrdquoMolecular Imaging vol 12 no 4 pp213ndash217 2013
[124] H-J Yoon K W Kang I K Chun et al ldquoCorrelation of breastcancer subtypes based on estrogen receptor progesteronereceptor and HER2 with functional imaging parameters from68Ga-RGD PETCT and 18F-FDG PETCTrdquo European Journalof Nuclear Medicine and Molecular Imaging vol 41 no 8 pp1534ndash1543 2014
[125] R P Baum H R Kulkarni D Muller et al ldquoFirst-in-human study demonstrating tumor-angiogenesis by PETCTimaging with 68Ga-NODAGA-THERANOST a high-affinitypeptidomimetic for 120572v1205733 integrin receptor targetingrdquo CancerBiotherapy andRadiopharmaceuticals vol 30 no 4 pp 152ndash1592015
[126] R Haubner A Finkenstedt A Stegmayr et alldquo[68Ga]NODAGA-RGD ndash Metabolic stability biodistributionand dosimetry data from patients with hepatocellularcarcinoma and liver cirrhosisrdquo European Journal of NuclearMedicine and Molecular Imaging vol 43 no 11 pp 2005ndash20132016
[127] V Lopez-Rodrıguez C Galindo-Sarco F O Garcıa-Perez GFerro-Flores O Arrieta and M A Avila-Rodrıguez ldquoPET-based human dosimetry of the dimeric 120572v1205733 integrin ligand68Ga-DOTA-E-[c(RGDfK)]2 a potential tracer for imagingtumor angiogenesisrdquo Journal of Nuclear Medicine vol 57 no 3pp 404ndash409 2016
[128] M V Backer Z Levashova V Patel et al ldquoMolecular imagingof VEGF receptors in angiogenic vasculature with single-chainVEGF-based probesrdquo Nature Medicine vol 13 no 4 pp 504ndash509 2007
[129] MV Backer Z Levashova R Levenson F G Blankenberg andJ M Backer ldquoCysteine-containing fusion tag for site-specificconjugation of therapeutic and imaging agents to targetingproteinsrdquoMethods in Molecular Biology (Clifton NJ) vol 494pp 275ndash294 2008
[130] M Eder A V Krivoshein M Backer J M Backer UHaberkorn and M Eisenhut ldquoScVEGF-PEG-HBED-CC andscVEGF-PEG-NOTA conjugates comparison of easy-to-labelrecombinant proteins for [68Ga]PET imaging of VEGF recep-tors in angiogenic vasculaturerdquo Nuclear Medicine and Biologyvol 37 no 4 pp 405ndash412 2010
[131] E Blom I Velikyan A Monazzam P Razifar et al ldquoSynthe-sis and characterization of scVEGF-PEG-[ 68Ga]NOTA andscVEGF-PEG-[ 68Ga]DOTA PET tracersrdquo Journal of Labelled
20 Contrast Media amp Molecular Imaging
Compounds and Radiopharmaceuticals vol 54 no 11 pp 685ndash692 2011
[132] S Gratz M Behe and O C Boerman ldquo 99119898Tc-E-selectinbinding peptide for imaging acute osteomyelitis in a novel ratmodelrdquo Nuclear Medicine Communications vol 22 no 9 pp1003ndash1013 2001
[133] S B Jensen M Kakela L Joslashdal et al ldquoExploring the radiosyn-thesis and in vitro characteristics of [68Ga]Ga-DOTA-Siglec-9rdquoJournal of Labelled Compounds and Radiopharmaceuticals vol60 no 9 pp 439ndash449 2017
[134] B A Teicher and S P Fricker ldquoCXCL12 (SDF-1)CXCR4pathway in cancerrdquo Clinical Cancer Research vol 16 no 11 pp2927ndash2931 2010
[135] O Jacobson I D Weiss D O Kiesewetter J M Farber andX Chen ldquoPET of tumor CXCR4 expression with 4-18F-T140rdquoJournal of Nuclear Medicine vol 51 no 11 pp 1796ndash1804 2010
[136] A Aghanejad A R Jalilian Y Fazaeli et al ldquoSynthesis andevaluation of [67Ga]-AMD3100 A novel imaging agent fortargeting the chemokine receptorCXCR4rdquo Scientia Pharmaceu-tica vol 82 no 1 pp 29ndash42 2014
[137] O Jacobson I D Weiss L P Szajek et al ldquoPET imaging ofCXCR4 using copper-64 labeled peptide antagonistrdquoTheranos-tics vol 1 pp 251ndash262 2011
[138] O Jacobson I D Weiss L P Szajek et al ldquoImprovement ofCXCR4 tracer specificity for PET imagingrdquo Journal of Con-trolled Release vol 157 no 2 pp 216ndash223 2012
[139] H J Wester U Keller M Schottelius et al ldquoDisclosing theCXCR4 expression in lymphoproliferative diseases by targetedmolecular imagingrdquo Theranostics vol 5 no 6 pp 618ndash6302015
[140] E Gourni O Demmer M Schottelius et al ldquoPET of CXCR4expression by a 68Ga-labeled highly specific targeted contrastagentrdquo Journal of NuclearMedicine vol 52 no 11 pp 1803ndash18102011
[141] O Demmer I Dijkgraaf U Schumacher et al ldquoDesignsynthesis and functionalization of dimeric peptides targetingchemokine receptor CXCR4rdquo Journal of Medicinal Chemistryvol 54 no 21 pp 7648ndash7662 2011
[142] O Demmer E Gourni U Schumacher H Kessler and H-JWester ldquoPET Imaging of CXCR4 Receptors in Cancer by a NewOptimized Ligandrdquo ChemMedChem vol 6 no 10 pp 1789ndash1791 2011
[143] U Hennrich L Seyler M Schafer et al ldquoSynthesis and invitro evaluation of 68Ga-DOTA-4-FBn-TN14003 a novel tracerfor the imaging of CXCR4 expressionrdquo Bioorganic amp MedicinalChemistry vol 20 no 4 pp 1502ndash1510 2012
[144] G P C George E Stevens O Aberg et al ldquoPreclinical evalua-tion of a CXCR4-specific 68Ga-labelled TN14003 derivative forcancer PET imagingrdquo Bioorganic amp Medicinal Chemistry vol22 no 2 pp 796ndash803 2014
[145] S Poty E Gourni P Desogere et al ldquoAMD3100 A VersatilePlatform for CXCR4 Targeting 68Ga-Based Radiopharmaceu-ticalsrdquo Bioconjugate Chemistry vol 27 no 3 pp 752ndash761 2016
[146] K Philipp-Abbrederis K Herrmann S Knop et al ldquoIn vivomolecular imaging of chemokine receptor CXCR4 expressionin patients with advancedmultiple myelomardquo EMBOMolecularMedicine vol 7 no 4 pp 477ndash487 2015
[147] Z Wang M Zhang L Wang et al ldquoProspective study of 68Ga-NOTA-NFB Radiation dosimetry in healthy volunteers andfirst application in glioma patientsrdquo Theranostics vol 5 no 8pp 882ndash889 2015
[148] I M Jackson P J Scott and S Thompson ldquoClinical Applica-tions of Radiolabeled Peptides for PETrdquo Seminars in NuclearMedicine vol 47 no 5 pp 493ndash523 2017
[149] C Lapa T Reiter R A Werner et al ldquo[68Ga]Pentixafor-PETCT for Imaging of Chemokine Receptor 4 Expression afterMyocardial Infarctionrdquo JACC Cardiovascular Imaging vol 8no 12 pp 1466ndash1468 2015
[150] C Rischpler S G Nekolla H Kossmann et al ldquoUpregu-lated myocardial CXCR4-expression after myocardial infarc-tion assessed by simultaneous GA-68 pentixafor PETMRIrdquoJournal of Nuclear Cardiology vol 23 no 1 pp 131ndash133 2016
[151] F Hyafil J Pelisek I Laitinen et al ldquoImaging the CytokineReceptorCXCR4 in atherosclerotic plaqueswith the radiotracer68Ga-Pentixafor for PETrdquo Journal of Nuclear Medicine vol 58no 3 pp 499ndash506 2017
[152] Y Yi ldquoFolate receptor-targeted diagnostics and therapeutics forinflammatory diseasesrdquo ImmuneNetwork vol 16 no 6 pp 337ndash343 2016
[153] C M Paulos M J Turk G J Breur and P S Low ldquoFolatereceptor-mediated targeting of therapeutic and imaging agentsto activated macrophages in rheumatoid arthritisrdquo AdvancedDrug Delivery Reviews vol 56 no 8 pp 1205ndash1217 2004
[154] W Han R Zaynagetdinov F E Yull et al ldquoMolecular imagingof folate receptor 120573-positive macrophages during acute lunginflammationrdquo American Journal of Respiratory Cell and Molec-ular Biology vol 53 no 1 pp 50ndash59 2015
[155] B Kuhle C Muller and T L Ross ldquoA Novel 68Ga-Labeledpteroic acid-based PET tracer for tumor imaging via the folatereceptorrdquo Recent Results in Cancer Research vol 194 pp 257ndash267 2013
[156] C Brand V A Longo M Groaning W A Weber and TReiner ldquoDevelopment of a New Folate-Derived Ga-68-BasedPET Imaging AgentrdquoMolecular Imaging and Biology vol 19 no5 pp 754ndash761 2017
[157] M Fani XWang G Nicolas et al ldquoDevelopment of new folate-based PET radiotracers Preclinical evaluation of 68Ga-DOTA-folate conjugatesrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 38 no 1 pp 108ndash119 2011
[158] C J Mathias M R Lewis D E Reichert et al ldquoPreparationof 66Ga- and 68Ga-labeled Ga(III)-deferoxamine-folate aspotential folate-receptor-targeted PET radiopharmaceuticalsrdquoNuclear Medicine and Biology vol 30 no 7 pp 725ndash731 2003
[159] S-M Kim N Choi S Hwang et al ldquoFolate receptor-specific positron emission tomography imaging with folic acid-conjugated tissue inhibitor of metalloproteinase-2rdquo Bulletin ofthe Korean Chemical Society vol 34 no 11 pp 3243ndash3248 2013
[160] M Fani M-L Tamma G P Nicolas et al ldquoIn vivo imagingof folate receptor positive tumor xenografts using novel 68Ga-NODAGA-folate conjugatesrdquo Molecular Pharmaceutics vol 9no 5 pp 1136ndash1145 2012
[161] C Muller and R Schibli ldquoProspects in folate receptor-targetedradionuclide therapyrdquo Frontiers in Oncology vol 3 Article IDArticle 249 2013
[162] A Jain A Mathur U Pandey et al ldquoSynthesis and evaluationof a 68Ga labeled folic acid derivative for targeting folatereceptorsrdquo Applied Radiation and Isotopes vol 116 pp 77ndash842016
[163] W Xia A R Hilgenbrink E L Matteson M B Lockwood J-X Cheng and P S Low ldquoA functional folate receptor is inducedduring macrophage activation and can be used to target drugsto activated macrophagesrdquo Blood vol 113 no 2 pp 438ndash4462009
Contrast Media amp Molecular Imaging 21
[164] E P Krenning W A P Breeman P P M Kooij et alldquoLocalisation of endocrine-related tumours with radioiodi-nated analogue of somatostatinrdquoThe Lancet vol 1 no 8632 pp242ndash244 1989
[165] E P Krenning D J KwekkeboomWH Bakker et al ldquoSomato-statin receptor scintigraphy with [111In-DTPA-d-Phe1]- and[123I-Tyr3]-octreotide the Rotterdam experience with morethan 1000 patientsrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 20 no 8 pp 716ndash731 1993
[166] A Stahl G Meisetschlager M Schottelius et al ldquo[123I]Mtr-TOCA a radioiodinated and carbohydrated analogue ofoctreotide Scintigraphic comparison with [111In]octreotiderdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 33 no 1 pp 45ndash52 2006
[167] R Lebtahi J le Cloirec C Houzard et al ldquoDetection of neu-roendocrine tumors 99mTc-P829 scintigraphy compared with111In-pentetreotide scintigraphyrdquo Journal of Nuclear Medicinevol 43 no 7 pp 889ndash895 2002
[168] C Decristoforo T Maina B Nock M Gabriel P Cordopatisand R Moncayo ldquo99mTc-demotate 1 First data in tumourpatients - Results of a pilotphase I studyrdquo European Journal ofNuclearMedicine andMolecular Imaging vol 30 no 9 pp 1211ndash1219 2003
[169] C Decristoforo S J Mather W Cholewinski E DonnemillerG Riccabona and R Moncayo ldquo(99m)Tc-EDDAHYNIC-TOC A new (99m)Tc-labelled radiopharmaceutical forimaging somatostatin receptor-positive tumours First clinicalresults and intra-patient comparison with 111In-labelledoctreotide derivativesrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 27 no 9 pp 1318ndash1325 2000
[170] A Hubalewska-Dydejczyk K Fross-Baron R Mikołajczak etal ldquo99mTc-EDDAHYNIC-octreotate scintigraphy an efficientmethod for the detection and staging of carcinoid tumoursResults of 3 yearsrsquo experiencerdquo European Journal of NuclearMedicine and Molecular Imaging vol 33 no 10 pp 1123ndash11332006
[171] M Bangard M Behe S Guhlke et al ldquoDetection of somato-statin receptor-positive tumours using the new 99mC-tricine-HYNIC-D-Phe1-Tyr3-octreotide First results in patients andcomparison with 111In-DTPA-D-Phe1-octreotiderdquo EuropeanJournal of Nuclear Medicine and Molecular Imaging vol 27 no6 pp 628ndash637 2000
[172] A Helisch G J Forster H Reber et al ldquoPre-therapeuticdosimetry and biodistribution of 86Y-DOTA- Phe1-Tyr3-octreotide versus 111In-pentetreotide in patients with advancedneuroendocrine tumoursrdquo European Journal of NuclearMedicine and Molecular Imaging vol 31 no 10 pp 1386ndash13922004
[173] M Henze J Schuhmacher P Hipp et al ldquoPET imaging ofsomatostatin receptors using [68GA]DOTA-D-Phe1-Tyr3-Octreotide First results in patients with meningiomasrdquo Journalof Nuclear Medicine vol 42 no 7 pp 1053ndash1056 2001
[174] I Kayani J B Bomanji A Groves et al ldquoFunctional imaging ofneuroendocrine tumors with combined PETCT using 68Ga-DOTATATE (Dota-DPhe1 Tyr3-octreotate) and 18F-FDGrdquoCancer vol 112 no 11 pp 2447ndash2455 2008
[175] A Al-Nahhas ldquoNuclear medicine imaging of neuroendocrinetumoursrdquo Clinical Medicine vol 12 no 4 pp 377ndash380 2012
[176] V Ambrosini S Nicolini P Caroli et al ldquoPETCT imaging indifferent types of lung cancer an overviewrdquo European Journal ofRadiology vol 81 no 5 pp 988ndash1001 2012
[177] V Ambrosini D Campana P Tomassetti and S Fanti ldquo68Ga-labelled peptides for diagnosis of gastroenteropancreatic NETrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 39 no 1 pp S52ndashS60 2012
[178] K E Oberg J-C Reubi D J Kwekkeboom and E P KrenningldquoRole of somatostatins in gastroenteropancreatic neuroen-docrine tumor development and therapyrdquoGastroenterology vol139 no 3 pp 753-753 2010
[179] K Oberg ldquoGallium-68 somatostatin receptor PETCT Is ittime to replace 111Indium DTPA octreotide for patients withneuroendocrine tumorsrdquo Endocrine Journal vol 42 no 1 pp3-4 2012
[180] R Srirajaskanthan I Kayani A M Quigley J Soh M ECaplin and J Bomanji ldquoThe role of 68Ga-DOTATATE PET inpatients with neuroendocrine tumors and negative or equivocalfindings on 111In-DTPA-octreotide scintigraphyrdquo Journal ofNuclear Medicine vol 51 no 6 pp 875ndash882 2010
[181] A Kroiss D Putzer and C Uprimny ldquoFunctional imag-ing in phaeochromocytoma and neuroblastoma with 68Ga-DOTA-Tyr3-octreotide positron emission tomography and123I-metaiodobenzylguanidinerdquo European Journal of NuclearMedicine and Molecular Imaging vol 38 no 5 pp 865ndash8732011
[182] M Naji C Zhao S J Welsh et al ldquo68Ga-DOTA-TATE PETvs 123I-MIBG in identifying malignant neural crest tumoursrdquoMolecular Imaging and Biology vol 13 no 4 pp 769ndash775 2011
[183] V Ambrosini P Tomassetti P Castellucci et al ldquoComparisonbetween 68Ga-DOTA-NOC and 18F-DOPA PET for the detec-tion of gastro-entero-pancreatic and lung neuro-endocrinetumoursrdquo European Journal of Nuclear Medicine and MolecularImaging vol 35 no 8 pp 1431ndash1438 2008
[184] D Putzer M Gabriel B Henninger et al ldquoBone metastasesin patients with neuroendocrine tumor 68Ga- DOTA-Tyr3-octreotide PET in comparison to CT and bone scintigraphyrdquoJournal of Nuclear Medicine vol 50 no 8 pp 1214ndash1221 2009
[185] L K Anzola-Fuentes M Chianelli F Galli et al ldquoSomatostatinreceptor scintigraphy in patients with rheumatoid arthritis andsecondary Sjogrenrsquos syndrome treated with Infliximab a pilotstudyrdquo EJNMMI Research vol 6 no 1 article no 49 2016
[186] T Nobashi Y Nakamoto T Kubo et al ldquoThe utility of PETCTwith 68Ga-DOTATOC in sarcoidosis comparison with 67Ga-scintigraphyrdquoAnnals ofNuclearMedicine vol 30 no 8 pp 544ndash552 2016
[187] C Boy T A Heusner T D Poeppel et al ldquo68Ga-DOTATOCPETCT and somatostatin receptor (sst1-sst5) expression innormal human tissue Correlation of sst2mRNAand SUVmaxrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 38 no 7 pp 1224ndash1236 2011
[188] P Rinne S Hellberg M Kiugel et al ldquoComparison of Somato-statin Receptor 2-Targeting PET Tracers in the Detection ofMouse Atherosclerotic Plaquesrdquo Molecular Imaging and Biol-ogy vol 18 no 1 pp 99ndash108 2016
[189] M Asti E Ferrari S Croci et al ldquoSynthesis and characteri-zation of 68Ga-labeled curcumin and curcuminoid complexesas potential radiotracers for imaging of cancer and alzheimersdiseaserdquo Inorganic Chemistry vol 53 no 10 pp 4922ndash49332014
[190] A Signore I Santino and A W J M Glaudemans ldquoIn vivoimaging of microorganismsrdquo Clinical and Translational Imag-ing vol 4 no 3 pp 161-162 2016
[191] S Auletta F Galli C Lauri D Martinelli I Santino andA Signore ldquoImaging bacteria with radiolabelled quinolones
22 Contrast Media amp Molecular Imaging
cephalosporins and siderophores for imaging infection a sys-tematic reviewrdquo Clinical and Translational Imaging vol 4 no 4pp 229ndash252 2016
[192] X Ning S Lee Z Wang et al ldquoMaltodextrin-based imagingprobes detect bacteria in vivo with high sensitivity and speci-ficityrdquo Nature Materials vol 10 no 8 pp 602ndash607 2011
[193] J Ady andY Fong ldquoImaging for infection Fromvisualization ofinflammation to visualization of microbesrdquo Surgical Infectionsvol 15 no 6 pp 700ndash707 2014
[194] J M Sierra D Rodriguez-Puig A Soriano J Mensa C Pieraand J Vila ldquoAccumulation of 99mTc-ciprofloxacin in Staphy-lococcus aureus and Pseudomonas aeruginosardquo AntimicrobialAgents and Chemotherapy vol 52 no 7 pp 2691-2692 2008
[195] D I Andersson and D Hughes ldquoMicrobiological effects ofsublethal levels of antibioticsrdquoNature ReviewsMicrobiology vol12 no 7 pp 465ndash478 2014
[196] N Dumarey D Blocklet T Appelboom L Tant and ASchoutens ldquoInfecton is not specific for bacterial osteo-articularinfective pathologyrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 29 no 4 pp 530ndash535 2002
[197] K E Britton D W Wareham S S Das et al ldquoImaging bacte-rial infection with 99mTc-ciprofloxacin (Infecton)rdquo Journal ofClinical Pathology vol 55 no 11 pp 817ndash823 2002
[198] G Ferro-Flores M A Avila-Rodrıguez and F O Garcıa-PerezldquoImaging of bacteria with radiolabeled ubiquicidin by SPECTand PET techniquesrdquo Clinical and Translational Imaging vol 4no 3 pp 175ndash182 2016
[199] P S Hiemstra M T van den Barselaar M Roest P H Nibber-ing and R van Furth ldquoUbiquicidin a novel murine microbi-cidal protein present in the cytosolic fraction of macrophagesrdquoJournal of Leukocyte Biology vol 66 no 3 pp 423ndash428 1999
[200] M S Akhtar A Qaisar J Irfanullah et al ldquoAntimicrobialpeptide 99mTc-ubiquicidin 29ndash41 as human infection-imagingagent clinical trialrdquo Journal of Nuclear Medicne vol 46 no 4pp 567ndash573 2005
[201] M Assadi K Vahdat I Nabipour et al ldquoDiagnostic value of99mTc-ubiquicidin scintigraphy for osteomyelitis and compar-isons with 99mTc-methylene diphosphonate scintigraphy andmagnetic resonance imagingrdquo Nuclear Medicine Communica-tions vol 32 no 8 pp 716ndash723 2011
[202] T Emery ldquoExchange of Iron by Gallium in SiderophoresrdquoBiochemistry vol 25 no 16 pp 4629ndash4633 1986
[203] M Petrik C Zhai H Haas and C Decristoforo ldquoSiderophoresfor molecular imaging applicationsrdquo Clinical and TranslationalImaging vol 5 no 1 pp 15ndash27 2017
[204] H J Flint E A BayerM T Rincon R Lamed and B AWhiteldquoPolysaccharide utilization by gut bacteria potential for newinsights from genomic analysisrdquo Nature Reviews Microbiologyvol 6 no 2 pp 121ndash131 2008
[205] GGowrishankarMNamavari E B Jouannot et al ldquoInvestiga-tion of 6-[18F]-fluoromaltose as a novel PET tracer for imagingbacterial infectionrdquo PLoS ONE vol 9 no 9 Article ID e1079512014
[206] N Gholipour M Akhlaghi A M Kheirabadi et al ldquoChelator-free radiolabeling of dextran with 68Ga for PET studiesrdquoJournal of Radioanalytical and Nuclear Chemistry vol 311 no3 pp 1811ndash1817 2017
[207] C Bettegowda C A Foss I Cheong et al ldquoImaging bac-terial infections with radiolabeled 1-(21015840-deoxy-21015840- fluoro-120573-D-arabinofuranosyl)-5-iodouracilrdquo Proceedings of the NationalAcadamy of Sciences of the United States of America vol 102 no4 pp 1145ndash1150 2005
[208] S A Soghomonyan M Doubrovin J Pike et al ldquoPositronemission tomography (PET) imaging of tumor-localizedSalmonella expressing HSV1-TKrdquo Cancer GeneTherapy vol 12no 1 pp 101ndash108 2005
[209] C Palestro K Nichols S Sheikh-Fayyaz S Dewey P Singhaland K Bhargava ldquoCan Gallium-68 PET differentiate acuteinterstitial nephritis from acute tubular necrosisrdquo Journal ofNuclear Medicne vol 57 Supplement 2 p 551 2016
[210] A J Morguet D L Munz V Ivancevic et al ldquoImmunoscintig-raphy using technetium-99m-labeled anti-NCA-95 antigranu-locyte antibodies as an adjunct to echocardiography in subacuteinfective endocarditisrdquo Journal of the American College ofCardiology vol 23 no 5 pp 1171ndash1178 1994
[211] C van der Laken O Boerman W Oyen et al ldquoIn Vivo Expres-sion of Interleukin-1 Receptors during Various ExperimentallyInduced Inflammatory Conditionsrdquo The Journal of InfectiousDiseases vol 177 no 5 pp 1398ndash1401 1998
[212] C J Van Der Laken O C Boerman W J G Oyen M T PVan De Ven J W M Van Der Meer and F H M CorstensldquoScintigraphic detection of infection and inflammation Newdevelopments with special emphasis on receptor interactionrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 25 no 5 pp 535ndash546 1998
[213] C J van der LakenOC BoermanW J GOyenM T P van deVen J W M van der Meer and F H M Corstens ldquoImaging ofinfection in rabbits with radioiodinated interleukin-1 (120572 and 120573)its receptor antagonist and a chemotactic peptide a comparativestudyrdquo European Journal of Nuclear Medicine and MolecularImaging vol 25 no 4 pp 347ndash352 1998
[214] C J Van Der Laken O C BoermanW J G Oyen M T P VanDe Ven F H M Corstens and J W M Ven Der Meer ldquoThekinetics of radiolabelled interleukin-8 in infection and sterileinflammationrdquo Nuclear Medicine Communications vol 19 no3 pp 271ndash282 1998
[215] E Lazzeri P Erba M Perri et al ldquoScintigraphic imaging ofvertebral osteomyelitis with 111in-biotinrdquoThe Spine Journal vol33 no 7 pp E198ndashE204 2008
[216] E Blom B Langstrom and I Velikyan ldquo68Ga-labeling of biotinanalogues and their characterizationrdquo Bioconjugate Chemistryvol 20 no 6 pp 1146ndash1151 2009
[217] O Eriksson F Carlsson E Blom et al ldquoPreclinical evaluationof a 68Ga-labeled biotin analogue for applications in islettransplantationrdquo Nuclear Medicine and Biology vol 39 no 3pp 415ndash421 2012
[218] E A Weinstein A A Ordonez V P DeMarco et alldquoImaging Enterobacteriaceae infection in vivo with 18F-fluoro-deoxysorbitol positron emission tomographyrdquo Science Transla-tional Medicine vol 6 no 259 p 259ra146 2014
[219] K M Nielsen M H Kyneb A K O Alstrup et alldquo68Ga-labeled phage-display selected peptides as tracers forpositron emission tomography imaging of Staphylococcusaureus biofilm-associated infections Selection radiolabellingand preliminary biological evaluationrdquo Nuclear Medicine andBiology vol 43 no 10 pp 593ndash605 2016
[220] T J Makinen P Lankinen T Poyhonen J Jalava H T Aroand A Roivainen ldquoComparison of 18F-FDG and 68Ga PETimaging in the assessment of experimental osteomyelitis due toStaphylococcus aureusrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 32 no 11 pp 1259ndash1268 2005
[221] JMU Silvola I LaitinenH J Sipila et al ldquoUptake of 68galliumin atherosclerotic plaques in LDLRminusminusApoB100100micerdquo EJN-MMI Research vol 1 no 1 pp 1ndash8 2011
Contrast Media amp Molecular Imaging 23
[222] T A Wynn ldquoCellular and molecular mechanisms of fibrosisrdquoThe Journal of Pathology vol 214 no 2 pp 199ndash210 2008
[223] T Derlin D Jonigk J Bauersachs and FM Bengel ldquoMolecularImaging of Chemokine Receptor CXCR4 in NonndashSmall CellLung Cancer Using 68Ga-Pentixafor PETCT ComparisonWith 18F-FDGrdquo Clinical Nuclear Medicine 2016
[224] I Velikyan U Rosenstrom T N Bulenga O Eriksson andG Antoni ldquoFeasibility of multiple examinations using68ga-labelled collagelin analogues Organ distribution in rat forextrapolation to human organ and whole-body radiationdosimetryrdquo Pharmaceuticals vol 9 no 2 article no 31 2016
[225] S Jadhav M Kakela J Makila et al ldquoSynthesis and in VivoPET Imaging of Hyaluronan Conjugates of OligonucleotidesrdquoBioconjugate Chemistry vol 27 no 2 pp 391ndash403 2016
[226] A Autio A Saraste N Kudomi et al ldquoAssessment of bloodflow with (68) Ga-DOTA PET in experimental inflammation avalidation study using (15) O-waterrdquo American Journal ofNuclear Medicine and Molecular Imaging vol 4 no 6 pp 571ndash579 2014
[227] G Davies A Rolle A Maurer et al ldquoTowards translationalimmunoPETMR imaging of invasive pulmonary aspergillosisthe Humanised Monoclonal Antibody JF5 detects in vivordquoTheranostics vol 7 no 14 pp 3398ndash3414 2017
[228] DGoodwin CMeares GDavid et al ldquoMonoclonal antibodiesas reversible equilibrium carriers of radiopharmaceuticalsrdquoInternational Journal of Radiation Applications and Instrumen-tation Part B Nuclear Medicine and Biology vol 13 no 4 pp383ndash391 1986
[229] D A Goodwin C F Mears M McTigue and G S DavidldquoMonoclonal antibody hapten radiopharmaceutical deliveryrdquoNuclear Medicine Communications vol 7 no 8 pp 569ndash5801986
[230] S E Halpern and R O Dillman ldquoProblems associated withradioimmunodetection and possibilities for future solutionsrdquo JBiol Response Mod vol 6 no 3 pp 235ndash262 1987
[231] H Hong J Sun and W Cai ldquoRadionuclide-based cancerimaging targeting the carcinoembryonic antigenrdquo BiomarkerInsights vol 3 pp 435ndash451 2008
[232] G J Forster E B Santos P M Smith-Jones P Zanzonico andS M Larson ldquoPretargeted radioimmunotherapy with a single-chain antibodystreptavidin construct and radiolabeledDOTA-biotin Strategies for reduction of the renal doserdquo Journal ofNuclear Medicine vol 47 no 1 pp 140ndash149 2006
[233] Z Yao M Zhang H Kobayashi et al ldquoImproved targeting ofradiolabeled streptavidin in tumors pretargeted with biotiny-lated monoclonal antibodies through an avidin chaserdquo Journalof Nuclear Medicine vol 36 no 5 pp 837ndash841 1995
[234] C-H Chang R M Sharkey E A Rossi et al ldquoMolecularAdvances in Pretargeting Radioimunotherapy with BispecificAntibodies 1 Supported in part by USPHS Grant R01-CA-84379from the NIH and Department of Energy Grant DE-FG01-00NE22941 (both to R M S)1rdquo Mol Cancer Ther vol 1 no 7pp 553ndash563 2002
[235] R M Sharkey E A Rossi W J McBride C-H Chang andD M Goldenberg ldquoRecombinant Bispecific Monoclonal Anti-bodies Prepared by theDock-and-Lock Strategy for PretargetedRadioimmunotherapyrdquo Seminars in Nuclear Medicine vol 40no 3 pp 190ndash203 2010
[236] R M Sharkey E A Rossi C-H Chang and D M Golden-berg ldquoImproved cancer therapy and molecular imaging withmultivalent multispecific antibodiesrdquo Cancer Biotherapy andRadiopharmaceuticals vol 25 no 1 pp 1ndash12 2010
[237] D M Goldenberg R M Sharkey G Paganelli J Barbet andJ Chatal ldquoAntibody pretargeting advances cancer radioim-munodetection and radioimmunotherapyrdquo Journal of ClinicalOncology vol 24 no 5 pp 823ndash834 2006
[238] O C Boerman F G van Schaijk W J G Oyen and FH M Corstens ldquoPretargeted radioimmunotherapy of cancerprogress step by steprdquo Journal of Nuclear Medicine vol 44 no3 pp 400ndash411 2003
[239] J Schuhmacher S Kaul G Klivenyi et al ldquoImmunoscintigra-phy with positron emission tomography Gallium-68 chelateimaging of breast cancer pretargeted with bispecific anti-MUC1anti-Ga chelate antibodiesrdquo Cancer Research vol 61 no9 pp 3712ndash3717 2001
[240] J Schuhmacher G Klivenyi S Kaul et al ldquoPretargeting ofhuman mammary carcinoma xenografts with bispecific anti-MUC1anti-Ga chelate antibodies and immunoscintigraphywith PETrdquo Nuclear Medicine and Biology vol 28 no 7 pp 821ndash828 2001
[241] C Somasundaram S Matzku J Schuhmacher and M ZollerldquoDevelopment of a bispecific monoclonal antibody against agallium-67 chelate and the human melanoma-associated anti-gen p97 for potential use in pretargeted immunoscintigraphyrdquoCancer Immunology Immunotherapy vol 36 no 5 pp 337ndash3451993
[242] E A Rossi D L Rossi R Stein D M Goldenberg and C-H Chang ldquoA bispecific antibody-IFN1205722b immunocytokine tar-geting CD20 and HLA-DR is highly toxic to human lymphomaandmultiplemyeloma cellsrdquoCancer Research vol 70 no 19 pp7600ndash7609 2010
[243] R M Sharkey H Karacay S Litwin et al ldquoImproved ther-apeutic results by pretargeted radioimmunotherapy of non-Hodgkinrsquos lymphoma with a new recombinant trivalent anti-CD20 bispecific antibodyrdquo Cancer Research vol 68 no 13 pp5282ndash5290 2008
[244] G L Griffiths C-H Chang W J McBride et al ldquoReagentsandmethods for PETusing bispecific antibody pretargeting and68Ga-radiolabeled bivalent hapten-peptide-chelate conjugatesrdquoJournal of Nuclear Medicine vol 45 no 1 pp 30ndash39 2004
[245] J Watine M Miedouge and B Friedberg ldquoCarcinoembryonicantigen as an independent prognostic factor of recurrence andsurvival in patients resected for colorectal liver metastases Asystematic reviewrdquo Diseases of the Colon amp Rectum vol 44 no12 pp 1791ndash1799 2001
[246] M J Goldstein and E P Mitchell ldquoCarcinoembryonic antigenin the staging and follow-up of patients with colorectal cancerrdquoCancer Investigation vol 23 no 4 pp 338ndash351 2005
[247] D V Gold D M Goldenberg H Karacay et al ldquoA novelbispecific trivalent antibody construct for targeting pancreaticcarcinomardquo Cancer Research vol 68 no 12 pp 4819ndash48262008
[248] J Schuhmacher G Klivenyi R Matys et al ldquoMultistep tumortargeting in nudemice using bispecific antibodies and a galliumchelate suitable for immunoscintigraphy with positron emis-sion tomographyrdquo Cancer Research vol 55 no 1 pp 115ndash1231995
[249] G Klivenyi J Schuhmacher E Patzelt et al ldquoGallium-68chelate imaging of human colon carcinoma xenografts pre-targeted with bispecific anti-CD44(V6)anti-gallium chelateantibodiesrdquo Journal ofNuclearMedicine vol 39 no 10 pp 1769ndash1776 1998
[250] M Zoller J Schuhmacher J Reed W Maier-Borst and SMatzku ldquoEstablishment and characterization of monoclonal
24 Contrast Media amp Molecular Imaging
antibodies against an octahedral gallium chelate suitable forimmunoscintigraphy with PETrdquo Journal of Nuclear Medicinevol 33 no 7 pp 1366ndash1372 1992
[251] R M Sharkey T M Cardillo E A Rossi et al ldquoSignal ampli-fication in molecular imaging by pretargeting a multivalentbispecific antibodyrdquo Nature Medicine vol 11 no 11 pp 1250ndash1255 2005
[252] D M Goldenberg and R M Sharkey ldquoNovel radiolabeledantibody conjugatesrdquo Oncogene vol 26 no 25 pp 3734ndash37442007
[253] D M Goldenberg E A Rossi R M Sharkey W J McBrideand C-H Chang ldquoMultifunctional antibodies by the dock-and-lock method for improved cancer imaging and therapy bypretargetingrdquo Journal of NuclearMedicine vol 49 no 1 pp 158ndash163 2008
[254] R Schoffelen R M Sharkey D M Goldenberg et al ldquoPre-targeted immuno-positron emission tomography imaging ofcarcinoembryonic antigen-expressing tumors with a bispecificantibody and a68Ga- And18F-labeled hapten peptide in micewith human tumor xenograftsrdquoMolecular Cancer Therapeuticsvol 9 no 4 pp 1019ndash1027 2010
[255] E S Bos W H Kuijpers M Meesters-Winters et al ldquoIn vitroevaluation of DNA-DNA hybridization as a two-step approachin radioimmunotherapy of cancerrdquoCancer Research vol 54 no13 pp 3479ndash3486 1994
[256] G Paganelli M Bartolomei M Ferrari et al ldquoPre-TargetedLocoregional Radioimmunotherapy withrdquo Cancer biotherapyand radiopharmaceuticals vol 16 no 3 pp 227ndash235 2001
[257] A Forero P L Weiden J M Vose et al ldquoPhase 1 trial of a novelanti-CD20 fusion protein in pretargeted radioimmunotherapyfor B-cell non-Hodgkin lymphomardquo Blood vol 104 no 1 pp227ndash236 2004
[258] DM Goldenberg C-H Chang E A RossiW J McBride andR M Sharkey ldquoPretargeted molecular imaging and radioim-munotherapyrdquoTheranostics vol 2 no 5 pp 523ndash540 2012
[259] H Karacay R M Sharkey W J McBride E A Rossi C-HChang and D M Goldenberg ldquoOptimization of hapten-peptide labeling for pretargeted immunoPET of bispecificantibody using generator-produced 68Gardquo Journal of NuclearMedicine vol 52 no 4 pp 555ndash559 2011
[260] J R Oh and B C Ahn ldquoFalse-positive uptake on radioiodinewhole-body scintigraphy physiologic and pathologic variantsunrelated to thyroid cancerrdquo American Journal of NuclearMedicine and Molecular Imaging vol 2 no 2 pp 141ndash150 2012
[261] E Frampas C Rousseau C Bodet-Milin J Barbet J-F Chataland F Kraeber-Bodere ldquoImprovement of radioimmunotherapyusing pretargetingrdquo Frontiers in Oncology vol 3 Article ID00159 2013
[262] C S McKay and M G Finn ldquoClick chemistry in complexmixtures Bioorthogonal bioconjugationrdquo Chemistry amp Biologyvol 21 no 9 pp 1075ndash1101 2014
[263] B L Oliveira Z Guo and G J Bernardes ldquoInverse electrondemand DielsndashAlder reactions in chemical biologyrdquo ChemicalSociety Reviews vol 46 no 16 pp 4895ndash4950 2017
[264] B Nichols Z Qin J Yang D R Vera and N K Devaraj ldquo68Gachelating bioorthogonal tetrazine polymers for the multisteplabeling of cancer biomarkersrdquo Chemical Communications vol50 no 40 pp 5215ndash5217 2014
[265] R Rossin P R Verkerk S M van den Bosch et al ldquoInvivo chemistry for pretargeted tumor imaging in live micerdquoAngewandte Chemie International Edition vol 49 no 19 pp3375ndash3378 2010
[266] B M Zeglis K K Sevak T Reiner et al ldquoA pretargetedPET imaging strategy based on bioorthogonal diels-alder clickchemistryrdquo Journal of Nuclear Medicine vol 54 no 8 pp 1389ndash1396 2013
[267] J L Houghton R Membreno D Abdel-Atti et al ldquoEstablish-ment of the invivo efficacy of pretargeted radioimmunotherapyutilizing inverse electron demand diels-alder click chemistryrdquoMolecular Cancer Therapeutics vol 16 no 1 pp 124ndash133 2017
[268] J Funkhouser ldquoReinventing pharma the theranostic revolu-tionrdquo Current Drug Discovery pp 17ndash19 2002
[269] J Sorensen I Velikyan A Wennborg et al ldquoMeasuring HER2-expression in metastatic breast cancer using 68Ga-ABY025PETCTrdquo European Journal of Nuclear Medicine and MolecularImaging vol 41 pp S226ndashS226 2014
[270] I Velikyan A Wennborg J Feldwisch et al ldquoGMP compliantpreparation of a 68Gallium-labeled Affibody analogue forbreast cancer patient examination first-in-manrdquoEur JNuclMedMol Imaging vol 41 pp S228ndashS229 2014
[271] K Oberg ldquoMolecular imaging radiotherapy Theranostics forpersonalized patient management of neuroendocrine tumors(NETs)rdquoTheranostics vol 2 no 5 pp 448ndash458 2012
[272] I Velikyan AWennborg J FeldwischH Lindman J Carlssonand J Sorensen ldquoGood manufacturing practice production of [(68) Ga]Ga-ABY-025 for HER2 specific breast cancer imagingrdquoAmerican Journal of Nuclear Medicine and Molecular Imagingvol 6 no 2 pp 135ndash153 2016
[273] M Sandstrom K Lindskog I Velikyan et al ldquoBiodistributionand radiation dosimetry of the anti-HER2 Affibody molecule68Ga-ABY-025 in breast cancer patientsrdquo Journal of NuclearMedicine vol 57 no 6 pp 867ndash871 2016
[274] D Sandberg V Tolmachev I Velikyan et al ldquoIntra-imagereferencing for simplified assessment of HER2-expression inbreast cancer metastases using the Affibody molecule ABY-025with PET and SPECTrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 44 no 8 pp 1337ndash1346 2017
[275] H ZhangM AMoroz I Serganova et al ldquoImaging expressionof the human somatostatin receptor subtype-2 reporter genewith 68Ga-DOTATOCrdquo Journal ofNuclearMedicine vol 52 no1 pp 123ndash131 2011
[276] M Naji and A Al-Nahhas ldquo68Ga-labelled peptides in themanagement of neuroectodermal tumoursrdquo European Journalof Nuclear Medicine and Molecular Imaging vol 39 no 1 ppS61ndashS67 2012
[277] I Velikyan ldquoThe diversity of 68Ga-Based imaging agentsrdquoRecent Results in Cancer Research vol 194 pp 101ndash131 2013
[278] K Ferreira H-Y Hu V Fetz et al ldquoMultivalent siderophore-dotam conjugates as theranostics for imaging and treatment ofbacterial infectionsrdquo Angewandte Chemie International Editionvol 56 no 28 pp 8272ndash8276 2017
Computational and Mathematical Methods in Medicine
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Evidence-Based Complementary andAlternative Medicine
Volume 2018Hindawiwwwhindawicom
Submit your manuscripts atwwwhindawicom
Contrast Media amp Molecular Imaging 5
5 Imaging Inflammation
Inflammatory response is a complex process involvingimmune system cells (T- and B-lymphocytes NK cellsmacrophages monocytes neutrophils eosinophils andmastcells) and products of their (patho)physiological activity forexample cytokines involved in the cell signaling Variousfunctions of the cells and their products as well as theirreceptors provide a broad range of potential imaging targets[103ndash107] Targeting the white blood cells of the immunesystem such as macrophages monocytes lymphocytes andneutrophils for the detection of their upregulation and traf-ficking secretion of cytokines and chemokines and phago-cytosis has been investigated both clinically and preclinicallyReceptors such as SSTRNCA-90 integrins folate bombesinvascular cell adhesion protein-1 and interleukins expressedby activated T-cells CXCR2 expressed on neutrophils andCXCR4 overexpressed by leukocytes have demonstratedpotential for in vivo targeted imaging [108] Respectiveligands and substrates can be considered for radiolabellingCytokines including interferons lymphokines interleukinsand chemokines bind to various receptors for example IL1and IL2 receptor types IFN CD40 CD37 CD30 CD4CCR5 and IL1-17R receptor family Folate CD64 NCA90and CD15 receptors expressed on macrophages leukocytesand granulocytes can serve as targets Not only do moleculesof such super families as chemokine integrin selectin andimmunoglobulin participate in the cell emigration cascadebut also enzymes on the surface of endothelia cells andleukocytes contribute to the leukocyte extravasation [109]Receptors on the endothelial wall for example for bindingof IL1 and TNF120572 are another category of the targets Theseare only few examples of targets for potential imaging agentdevelopment (Table 3) Many targets were utilized in oncol-ogy [28] and their translation to inflammation is feasible
51 Targeting Cell Receptors with Antibodies Radiolabelled(99mTc 111In and 123I) anti-CD2 anti-CD5 anti-CD25 anti-CD45 antibodies and their fragments were used for the imag-ing of T-lymphocyte infiltration in various inflammatorydiseases [110] Typically for antibody slow pharmacokineticsthe time delay between the administration and examina-tion stretches up to 24 hours Interleukin-8 labelled with99mTc was studied in rabbits with induced acute pyogenicosteomyelitis [111] and induced acute colitis [112] The agentwas found suitable for the scintigraphic evaluation of therespective diseases CD163 receptor expressed in monocytesand activated macrophages was targeted with an anti-CD163antibody labelled with 68Ga in rats with acute collagen-induced arthritis [45]The agent demonstrated specific bind-ing and thus potential for studies of inflammatory diseases
52 Targeting Angiogenesis Angiogenesis plays an importantrole in wound healing chronic inflammation and tumourgrowth [113] The family of vascular endothelial growthfactors (VEGF) and integrins play crucial role in the angio-genesis cascade Integrin receptors are overexpressed on thesurface of vascular endothelial cells during angiogenesis inmalignances tissue healing and inflammation The largest
group is radiolabelled peptide ligands comprising arginine-glycine-aspartic acid (RGD) sequence and peptidomimeticstargeting 120572v1205733 integrin receptors Various analogues weredeveloped introducing cyclization andmultimerization vari-ety of chelatecoligand moieties PKM such as carbohy-drate and polyethylene glycol chains [114ndash121] Various RGDanalogues labelled with 18F 68Ga and 99mTc were usedin oncological clinical trials [122] The majority of themcomprised 18F however advantages of 68Ga such as accessi-bility of the radionuclide more straightforward and efficientlabelling chemistry lower radiation dose and better imagecontrast renderedmore extensive development of 68Ga-basedanalogues [123ndash127]
The imaging agents tested in cancer systems can berelevant for the imaging of inflammation related diseasesTheimaging and evaluation of synovial angiogenesis in patientswith rheumatoid arthritis was accomplished using [68Ga]Ga-PRGD2 [46] The elevated agent uptake was detected inthe sites of active inflammation rich neovasculature andphysiological integrin receptor expression while no traceraccumulationwas detected in axillary lymphnodeswith reac-tive hyperplasia and strenuous skeletal muscles [68Ga]Ga-PRGD2PET-CT was found useful for the evaluation of syn-ovial angiogenesis and follow-up of the treatment response
[68Ga]Ga-NOTA-c(RGDyK)was developed for the imag-ing of myocardial infarction (MI) and follow-up of theresponse to the therapeutic intervention and demonstratedpromising results preclinically [47] The uptake in the MIlesions was enhanced and correlated with the vascularendothelial growth factor expression Dynamic [68Ga]Ga-NOTA-c(RGDyK)PET scanning with subsequent kineticmodeling studies in rats with forelimb ischemia showedhigher uptake and distribution volume in the ischemicarea as compared to that of sham operation and controlregions [48] Monitoring myocardial repair and angiogenesisafter ischemic injury was found plausible using [68Ga]Ga-NODAGA-RGD and [68Ga]Ga-TRAP-(RGD)3 in rat model[49] Elevated uptake of [68Ga]Ga-DOTA-E-[c(RGDfK)]2was observed in the infarcted area while no accumulationwas detected in the noninfarcted myocardium of the samerats [50]The uptake of [68Ga]Ga-DOTA-RGD in atheroscle-rotic plaques was studied in vivo in atherosclerotic micewith promising results [52] Elevated uptake of [68Ga]Ga-NODAGA-RGD in injured myocardium as compared toviable ischemic areas in pig model presumably indicatedincreased expression of 120572V1205733 receptors associated with injuryrepair in the presence of coronary stenosis [51]
Although targeting VEGF receptors were studied in thecontext of cancerous diseases chronic inflammation can alsobe considered A ligand consisting of a single chain (scVEGF3ndash112 amino acids of human VEGF121) [128 129] was labelledwith 68Ga and the resulting agent showed distinct uptake inthe tumour xenografts in mice however high kidney uptakeneeded to be addressed [130 131]
53 Targeting Selectins P-selectin is expressed on the activeendothelium surface and platelets and operates the migra-tion of leukocytes in response to inflammatory cytokines
6 Contrast Media amp Molecular Imaging
Table 3 68Ga-based imaging agents for inflammation and infection investigated preclinically and clinically
E-selectin binding peptide labelled with 99mTc accumu-lated in acute osteomyelitic lesions in rats presumably byinteraction with activated vascular endothelium [132] Ananalogue of P-selectin natural ligand fucoidan labelled with68Ga could discriminate active and inactive atheroschleroticplaques in mice [44]
54 Targeting Vascular Adhesion Protein-1 Vascular adhe-sion protein-1 (VAP-1) and CD73 are endothelial surfaceenzymes involved in the recruitment of leukocytes and theirmovement from the blood into the tissue [109] Endothelialactivation that takes place during inflammation can be uti-lized for specific targeting imaging Several peptide analogues
Contrast Media amp Molecular Imaging 7
300
250
200
150
100
50
0
(kBq
ml)
Inflammation
Kidneys
Muscle
Inflammation
Kidneys
Muscle
Figure 1 PET images of the distribution of [68Ga]Ga-DOTAVAP-P1 [68Ga]Ga-DOTAVAP-PEG-P1 and [68Ga]Ga-DOTA-Siglec-9 inturpentine-induced rat model of sterile inflammation All three peptide analogues showed target-to-nontarget ratio above 6 with rapidaccumulation in the inflammation site and renal clearance Adapted from [57]
labelledwith 68Gawere designed for the visualization ofVAP-1 and showed promising results in animals with inducedinfection and sterile inflammation [7ndash13 133] The bindingwas proven specific and it was possible to differentiate inflam-mation from infection [68Ga]Ga-Siglec targeting VAP-1demonstrated preclinical potential for imaging of synovialinflammation in patients with rheumatic diseases [53] Thesame agent was utilized for respiratory distress syndrome(ARDS an inflammatory lung injury) imaging in a porcinemodel [54] Imaging VAP-1 with [68Ga]Ga-Siglec was foundpromising also for the detection of inflamed atheroscle-rotic lesions [55] and inflammatory response induced bycatheter implantation and staphylococcal infection [56]68Ga-Siglec and two more peptide analogues with affinityto VAP-1 ([68Ga]Ga-DOTAVAP-P1 [68Ga]Ga-DOTAVAP-PEG-P1 and [68Ga]Ga-DOTA-Siglec-9) were investigated inrat model of sterile skinmuscle inflammation (Figure 1) [57]They showed distinct uptake in the affected sites
55 Targeting Chemokines Cytokines are produced bymacrophages B-lymphocytes T-lymphocytes and mast cellsand act through receptors modulating for example immuneresponse to infection and inflammation Cytokines includechemokines interleukins interferons and lymphokines thatcan be classified in broad families exhibiting diverse func-tions for example IL-1 and IL-6 superfamilies and TNFTNFreceptor superfamily Therapeutics targeting cytokines are inclinical use for example inhibiting TNF or IL-6 in rheumaticdiseases
Chemokine receptors are physiologically expressed onB-lymphocytes T-lymphocytes macrophages neutrophilseosinophils monocytes and hematopoietic stem cells [134]Imaging agents targeting CXCR4 are based on inhibitors(AMD3100) or small peptides (NFB T140 pentixafor andTN14003) and comprise 18F 67Ga 68Ga or 64Cu [135ndash148] They were developed and studied for the imaging of
various cancerous diseases lung breast prostate cancersacute myeloid leukemia and glioblastoma
The application of CXCR4 targeting agents was extendedbeyond oncology Clinical caseimage reports [149 150]were published on the utilization of [68Ga]Ga-pentixafor fordetection and quantification of CXCR4 receptor density inischemic heart diseases reflecting the role of the receptorin inflammatory and progenitor cell recruitment [58 59]The same agent was successfully used in the assessment ofmacrophage infiltration in atherosclerotic plaques in rabbitdisease model [151]
56 Targeting Folate Receptors Folate receptors (FRs) areoverexpressed on a variety of cancer cells and activatedmacrophages but not on normal cells [152 153] Theenhanced expression of FR was found in lung macrophagesduring acute inflammation [154] The majority of the nuclearimaging agents based on folic acid or pteroic acid [155] weredeveloped for diagnosis of cancers overexpressing FR recep-tors such as breast cervical ovarian colorectal nasopharyn-geal renal and endometrial cancers Various 68Ga-labelledagents demonstrated accumulation in cell cultures and micebearing folate-receptor positive human nasopharyngeal car-cinoma cell line (KB) xenografts [6 156ndash162] [68Ga]Ga-DOTA-PEG-FA comprising folic acid was investigated forthe detection and quantification of inflammatory response tomedical implants using mice with subcutaneously implantedpolylactic acid and poly(N-isopropylacrylamide) particles asa model [60] The agent was accumulated in the area of theimplant most probably reflecting interaction of [68Ga]Ga-DOTA-PEG-FA with folate receptor expressed on activatedmacrophages Another folic acid based agent [68Ga]Ga-DOTA-folate was successfully tested in an inflammatory pawrat model (Figure 2) [61] Distinct accumulation in inflamedhand and foot joints of rheumatoid arthritis of a 99mTc-labelled folate analogue was observed in a patient while no
8 Contrast Media amp Molecular Imaging
NH ONHONH
OOO
HOHN O
HN
NN
N N
HO
O
N
N
O
O
N
N
O
O
O
Ga+
minus
（3
(a)
2
15
1
05
0
(b)
Figure 2 Accumulation of [68Ga]Ga-DOTA-folate (a) in the site of inflammation of rat inflammatory pawmodel induced by subcutaneouslyinjected Complete Freundrsquos Adjuvant (b) Adapted from [61]
4
2
0
Figure 3 Intense atherosclerotic inflammation (white arrows) was detected by [68Ga]Ga-DOTA-TATE in a patient with acute coronarysyndrome Adapted from [65]
uptake was detected in a nonarthritis patientrsquos hands and feet[163]
57 Targeting Somatostatin Receptors Somatostatin receptor(SSTR) ligand analogues have found an extensive appli-cation in diagnosis and radiotherapy of neuroendocrinetumours The elevated expression of SSTRs is known also insmall cell lung cancer breast cancer renal cell carcinomaprostate cancer and malignant lymphoma A number ofsomatostatin ligand analogues labelled with gamma- andpositron-emitting radionuclides were used clinically foroncological cases [85 164ndash174] 68Ga-labelled somatostatinanalogues demonstrated superior performance in terms ofhigher specificity and sensitivity detection rate shorterexamination time and quantification possibility and havebecome a golden standard for the detection of neuroen-docrine tumours (NETs) taking over that title from [111In]-pentetreotide (OctreoScan) and demonstrating specificityand sensitivity of over 90 [27 175ndash180] 68Ga-labelledagents for the imaging of NETs demonstrated advantages
also over other radionuclides and tracers such as [18F]FDG[174] 123I-metaiodobenzylguanidine ([123I]MIBG) [181 182][18F]DOPA [183] [99mTc]-dicarboxy propane diphosphonate[184] and [18F]NaF
SSTR are also overexpressed on activated macrophagesand T-lymphocytes 68Ga-labelled analogues were used ininflammation related diseases such as idiopathic pulmonaryfibrosis [62] Gravesrsquo and Hashimotorsquos diseases [63] coro-nary artery plaque imaging and characterization [64] andatherosclerotic inflammation with excellent macrophagespecificity (Figure 3) [65] Promising diagnostic potential ofa 99mTc-labelled analogue was demonstrated in patients withrheumatoid arthritis and secondary Sjogrenrsquos syndrome andthe method was suggested for the assistance in anti-TNFalpha antibody treatment planning [185] [68Ga]Ga-DOTA-TOCPET-CT was found superior to 67Ga-CitrateSPECT indetection of sarcoidosis lesions [186] A clinical study demon-strated correlation between uptake of [68Ga]Ga-DOTA-TOCand SST2 mRNA expression and recorded the information ina database [187] providing tools for accurate quantification
Contrast Media amp Molecular Imaging 9
and evaluation of disease progression and treatment responsein cancerous and inflammatory diseases involving SSTRsPreclinical study using atherosclerotic mice demonstratedsuperior targeting properties of [68Ga]Ga-DOTA-NOC ascompared to [18F]FDR-NOC [188] overall confirming thepotential of SSTR targeting for atherosclerotic plaque imag-ing
58 Imaging Neuroinflammation Despite difficulty ofdesigning 68Ga-labelled molecules capable of blood-brainbarrier penetration several agents were suggested for theimaging of neuroinflammation in particular A120573 plaquesdeposited on blood vessels [67ndash69] Bivalent styrylpyridineslabelled with 68Ga demonstrated high specificity and affinityfor A120573 plaques using postmortem Alzheimerrsquos disease (AD)brain sections [67] Benzofuran derivative comprising 68Gashowed promising results in terms of binding specificityand affinity investigated in vitro in sections of Tg2576mice [68] Although the synthesis of a 68Ga-labelledPittsburgh compound analogue was successful the in vitrobinding to amyloid deposits was limited [69] The commondisadvantage of these agents is poor blood-brain barrierpenetration nevertheless the exploration of more successfulanalogues continues Curcumin functions as an antioxidantantimicrobial anti-inflammatory and anticancer agentDiacetyl-curcumin and bis(dehydroxy)curcumin labelledwith 68Ga demonstrated in vitro binding to 120573-amyloid fibrilsand lung cancer cells [189] Potential application of the agentscould include diagnostic imaging of Alzheimerrsquos disease andvarious cancers
6 Imaging Infection
Infection imaging can be indirect utilizing targets involvedin the immune response namely inflammation as presentedin the inflammation targets section above or direct utilizingpathogen related targets The direct imaging is especiallycrucial in cases where inflammatory response is absent Thedifference in biochemistry and structure between bacterialand human cells might exclude physiological uptake byhuman tissuemaking it easier tomeet the favorable character-istics of an imaging agent However discrimination betweenthe various infectious microorganisms pathogenic bacteriaand microbiota targeting specific bacteria type as well asdifficulty of accessing bacteria aggregated in a biofilm makesthe task very challenging [190 191] The specific targetingof infection would require accumulation of the radioactivesignal in the pathogen The radiolabelled targeting agentsfor infection can be roughly divided into several groupsantibiotics based antimicrobial protein and peptide basedsiderophore and other metabolisable compound based andantigen-specific antibodies and antibody fragments (Table 3)
61 Radiolabelled Antibiotics Antimicrobials act on the pro-cesses that are specific to microbes for example bacteria andfungi and thus corresponding imaging agents might distin-guish infection from inflammation [191] They might requireinternalization or may bind to the cell surface dependent on
their biological action mechanism [191ndash193] The possibilityof antibiotic resistance development exists also in the case ofimaging agents even though the amount of such agents wouldbe subnanomolar [194 195] Another complication is possiblenonspecific uptake of antibiotics based agents by leucocytes[196] Considerable number of various antibiotic analogueshave been labelled with 99mTc 111In 131I 11C and 18F[102] and evaluated preclinically and clinically with 99mTc-ciprofloxacin becoming a commercial product (Infecton) [21197 198] However the further improvement of specificityis desirable [191] Antibiotics are accessible and cheap andthey demonstrate high sensitivity [102 191] making thedevelopment of 68Ga-labelled analogues very attractive giventhe earlier mentioned advantages that 68Ga as a radionu-clide in combination with PET provides Two 68Ga-labelledanalogues based on ciprofloxacin demonstrated potential fordiscrimination between bacterial infection and inflammationin rats infected with Staphylococcus aureus [70]
62 Radiolabelled Antimicrobial Proteins and Peptides Anti-microbial proteins and peptides for example serprocidinscathelicidins and defensins produced by the cells of immunesystem target microbial membrane lipids and impose micro-bicidal effect [35 43] They present a large group of poten-tial candidates for microbial imaging including bacteriafungi parasites and viruses Antimicrobial peptides havedemonstrated higher specificity for infection than antibioticanalogues They accumulate at infection but not sterileinflammation sites The most thoroughly studied antimicro-bial peptide ubiquicidin UBI [29ndash41] labelled with 99mTc[199] demonstrated promising results in human clinical trials[200 201] It has the potential for quantification of viableinfecting microorganisms and consequently for monitoringthe efficacy of antimicrobial therapy in patients
Fragments of an antimicrobial peptide ubiquicidin con-jugated to NOTA and labelled with 68Ga [68Ga]Ga-NOTA-UBI29-41 and [68Ga]Ga-NOTA-UBI30-41 demonstratedpossibility for the distinction between infection and inflam-mation in a rabbit model [71 72] Antimicrobial peptidefragments GF-17 and RAWVAWR-NH2 of respectivelyhuman cathelicidin LL-37 andhuman lysozyme active againstE coli and S aureus were labelled with 68Ga and theirbiodistribution in normal rats demonstrated fast clearancefrom liver [75] Antimicrobial depsipeptide based agent[68Ga]Ga-DOTA-TBIA101 targeting bacterial lipopolysac-charides detected muscular E coli-infection in mice (Fig-ure 4) [73] The agent was also studied in healthy rabbitsand various disease model rabbits such as sterile inflam-mation Staphylococcus aureus infection andMycobacteriumtuberculosis [74] The clearance of [68Ga]Ga-DOTA-TBIA101from blood and normal tissue was fast and enhanced uptakein sterile inflammation and Mycobacterium tuberculosis siteswas observed The improvement of the bacterial selectivitywill require modification of the agent structure
63 Radiolabelled Siderophores Bacteria and fungi producevarious siderophores for harvesting iron which is essentialfor their survival and growth [34 98 191] Siderophores
10 Contrast Media amp Molecular Imaging
(a)
(b)
(c) (d)
(e)
Figure 4 Left panel presents maximum intensity projection images of [68Ga]Ga-DOTA-TBIA101 distribution in a healthy mouse (a) and amouse with muscular infection site (MIS) in the right hind muscle tissue (white arrows) Right panel presents coronal (c) sagittal (d) andaxial (e) images with uptake in theMIS (white arrow) and absence of the uptake in the contralateralmuscle tissue Ki and Bl stand respectivelyfor kidney and bladder Reproduced from [73]
can also play a critical role in the development of biofilmsby microbes They are low molecular weight compoundsspecifically chelating Fe(III) and Ga(III) can form stablecomplexes with them mimicking Fe(III) [202 203]
Desferri-triacetylfusarinine C (TAFC) and desferri-ferricrocin (FC) labelled with 68Ga were used for theimaging of invasive pulmonary aspergillosis (IPA) caused byAspergillus fumigatus [15] [68Ga]Ga-TAFC demonstratedsuperior characteristics in terms of specific target bindingmetabolic stability and fast blood clearance in a rat modelof A fumigatus infection Seven analogues were developedin another study with TAFC and ferrioxamine E (FOXE)showing favorable binding clearance elimination andstability characteristics [16] as well as lung uptake inrat of invasive aspergillosis model wherein the uptakeextent was correlated with disease severity [17] [68Ga]Ga-triacetylfusarinine C and [68Ga]Ga-ferrioxamine E wereinvestigated in rat model of A fumigatus and demonstratedrapid uptake in the lungs (Figure 5) [76]
64 Radiolabelled Metabolisable Agents Mammalian micro-biota consumes (poly)saccharides in particular maltose andmaltodextrins [204] The transport mechanism is specific
to bacteria and is absent in mammalian cells making itpossible to utilize these (poly)saccharides for imaging agentdevelopment Maltodextrin functionalized with a fluorescentdye was internalized through the bacteria-specific maltodex-trin transport pathway and discriminated between activebacteria and inflammation in vivo [192] Maltose labelledwith 18F localized specifically bacterial infection in mice[205] Potential to label polysaccharides directly with 68Gamight be utilized extensively
As mentioned above the chemical properties of Ga(III)provide the potential for direct labelling of polysaccharidesDextran was labelled directly and resulting complex demon-strated sufficient stability in human serum however thefeasibility of the bacterial imaging was not demonstrated[206]
Trapping of nucleosides that are substrates of thymidinekinase occurring within bacteria was explored using 18Fand 125I labelled analogues of uracil [207] Promising resultswere obtained in seven bacterial species in mice Anotherstudy in the context of therapeutic bacteria developmentdemonstrated possibility of detecting Salmonella vectorswithin tumours using 18F-labelled uracil [208] However
Contrast Media amp Molecular Imaging 11
N
O
N
ON
HN
O
O
O
OO O
NH
O
O
O
O
NH
O
OGa
（3
（3
（3
（3
（3
（3
（2
(a) (b) (c)
Figure 5 Molecular structure of [68Ga]Ga-triacetylfusarinine C (a) used for the in vivo imaging of a rat with Aspergillus fumigatus infection(b) and negative control of noninfected rat (c) White arrows point at the infected (b) and normal (c) lungs Adapted from [76]
the development of 68Ga-labelled nucleosides that wouldmaintain their biological activity is challenging and fewexamples known from the literature confirm that [4 6]
7 68Ga-Citrate
As mentioned above 68GaPET provides a number of advan-tages over 67GaSPECT and following publications demon-strate it in clinical and preclinical studies [68Ga]Ga-citratedemonstrated high diagnostic accuracy of 90of osteomyeli-tis and diskitis in clinical studies (Figure 6) [18 19] Thisstudy demonstrates that [68Ga]Ga-citrate can be employedfor monitoring the response to treatment [68Ga]Ga-citratewas used clinically to follow-up surgical intervention inpatients with acute osteomyelitis and intra-abdominal infec-tion [77] The agent was also used to successfully visualizelungmalignancy and tuberculosis in patients however in caseof high prevalence of granulomatous diseases the distinctionbetween malignant and benign lung lesions was unclear [7879] Another clinical study conducted head-to-head compar-ison of [68Ga]Ga-citrate (Figure 7) and [18F]FDG in patientswith Staphylococcus aureus bacteremia [80] The detectionrate of osteomyelitis was similar and further investigationof [68Ga]Ga-citrate applicability in cases of osteomyelitisinduced by other pathogens as well as for monitoring healingprocess is warranted
Comparative study of [68Ga]Ga-citrate and [67Ga]Ga-citrate was performed in healthy and infection model rats[77] The performance of [68Ga]Ga-citrate was found supe-rior in terms of image contrast in the lower abdomen and
extremities Potential of [68Ga]Ga-citrate for the differentia-tion of acute interstitial nephritis from acute tubular necrosiswas studied in rat model of the disease and it was demon-strated that the kidney uptake correlated with the extentof mononuclear cell infiltration accompanying inflammation[209] 68Ga-labelled Apo-transferrin demonstrated bacterialinfection detection capacity in rat model with Staphylococcusaureus wherein the infection site was visualized 1 h afteradministration of the agent [14]
71 Radiolabelled Antibodies and Antibody FragmentsHuman immunoglobulin (HIG) binds to bacteria but alsoaccumulates at the sites of fungal and viral infection aswell as sterile inflammation due to binding to leukocytesThe improved specificity for bacteria was achieved for thefragments of HIG It is feasible to develop specific antibodiesto various antigens present on the bacterial cell surface [102]Monoclonal antibodies labelled with 99mTc were used forinfection imaging via granulocytes targeting NCA-95 [210]Various cytokines of interleukin family (IL-1 IL-8) labelledwith 123I or 99mTc demonstrated accumulation in the sitesof infection in various animal models [111 112 211ndash214]Registered antigranulocyte radiopharmaceuticals suchas LeuTech Scintimun and Leukoscan are based on99mTc-labelled antibodies This experience can be translatedto 68Ga however either the size of the antibodies mustbe reduced or pretargeting techniques must be appliedin order to overcome the discrepancy between the shortphysical half-life of 68Ga and slow pharmacokinetics ofantibodies
12 Contrast Media amp Molecular Imaging
(a) (b) (c) (d)
Figure 6 [68Ga]Ga-citrate PETCT examination of a patient affected by acute osteomyelitis before (left panel) and after (right panel) surgicalcurettage showing uptake in the transaxial (a c) and 3D reconstruction images (b d red area) Absence of the uptake after the therapyconfirms complete response to the treatment Adapted from [19]
Figure 7 Vertebral osteomyelitis (spondylodiscitis red arrow-heads) and abscesses in the iliopsoas and paravertebral area (redarrows) were detected by [68Ga]Ga-citrate in a patient admittedto the hospital with back pain and general symptoms The PETacquisition was performed 88min after administration of 245MBqof [68Ga]Ga-citrate Adapted from [80]
72 Radiolabelled Biotin Biotin is a growth factor utilizedin many bacteria An 111In-labelled analogue of biotin wassuccessfully utilized for diagnosis of vertebral infections ina clinical study [215] It would be rational to explore therelevance of 68Ga-labelled analogues given the advantagesof 68Ga over 111In and promising [68Ga]Ga-DOTA-Biotinanalogues [216 217] developed for monitoring survival oftransplanted avidin-coated islets
8 Miscellaneous
Stable Ga(III) complex with thiosemicarbazones demon-strated antimicrobial effect against P aeruginosa and Calbicans due to most probably both displacement of essentialFe(III) with Ga(III) and thiosemicarbazones [101] Substitu-tion of the stable Ga(III) by radioactive 68Ga might result ina specific infection imaging agent
Selective imaging of Enterobacteriaceae using 2-[18F]-fluorodeoxysorbitol (18F-FDS)was demonstrated in amurine
myositis model [218] The uptake of 18F-FDS was correlatedwith bacterial burden moreover the agent differentiatedinfection from sterile inflammation Given the potential of68Ga for the labelling of small biologically active molecules[4] it might be plausible to develop a respective analoguewith added value of the advantages that 68Ga offers includingsimpler production chemistry lowered radiation dose repet-itive examination and accessibility at clinical centers withoutcyclotrons and remote from [18F]-FDG distribution sites Asmentioned above the poor access to bacteria aggregated ina biofilm might make the imaging task challenging Severalpeptide candidates with affinity for S aureus biofilm weredesigned and labelled with 68Ga [219] The resulting agentsdemonstrated binding in vitro however it was not possible toblock the binding with excess of the cold peptide
Ionic 68Ga was found superior to [18F]-FDG in infectiondetection in the rat model with diffuse osteomyelitis [220] Inanother study the uptake of ionic 68Ga was observed in theaortic plaques of atherosclerotic mice specifically at the sitesrich inmacrophages [221] However the slow blood clearanceof ionic 68Ga presents a limitation
Chronic inflammation is the major reason of fibro-sis [222] 68Ga-labelled SST analogue ([68Ga]Ga-DOTA-NOC) demonstrated uptake in pathogenic areas in patientsaffected by idiopathic pulmonary fibrosis with potentialfor monitoring response to treatment and drug develop-ment [62] Another clinical study using [68Ga]Ga-pentixaforalso showed potential of the agent for monitoring dis-ease activity and response to treatment in idiopathic pul-monary fibrosis [223] Peptide based agents CNO2A-PEG2-c[CPGRVMHGLHLGDDEGPC] and [68Ga]Ga-NODAGA-PEG2-c[CPGRVMHGLHLGDDEGPC] for the imaging andquantification of fibrosis by PET were developed and char-acterized preclinically showing fast clearance from normal
Contrast Media amp Molecular Imaging 13
tissue and blood and binding specificity [89] Dosimetrycalculations demonstrated possibility of six examinations peryear in humans assuring disease monitoring in longitudinalstudies and routine clinical setup [224]
Several hyaluronan conjugates of oligonucleotides target-ing CD44 positive cells were developed and tested in healthyrats sham-operated rats and rats with myocardial infarction[225]The uptake of the agents was higher for the latter groupand varied dependent on the difference in the oligonucleotidestructure
TLR2 and TLR4 expression levels in neutrophils werefound higher in individuals with bacterial and viral infectionsthan those in control samples There is a possibility that IL-4IL-8 IL-10 IL-12 and TNF-a might serve as biomarkers forinfections and that IL-2 IL-8 or IL-10 is potentially able todistinguish between bacterial and viral infections [22]
Mannosylated human serum albumin labelled with 68Gavia NOTA chelator moiety ([68Ga]Ga-NOTA-MSA) wastested in a rat model of myocarditis targetingmannose recep-tors expressed onmacrophages infiltratingmyocardium [66]The uptake in the diseased myocardium was considerablyhigher than that of the normal one and it was precludedby administration of excess of nonlabelled MSA indicatingbinding specificity The tracer build-up was also observed inthe organs of macrophage accumulation
[68Ga]Ga-DOTA was investigated for the quantificationof increased blood flow which is one of the key events ininflammation [226] The uptake kinetics of [68Ga]Ga-DOTAin the site of inflammation in rats with induced inflamma-tion correlated well with that of 15O-water suggesting highrelevance [68Ga]Ga-DOTA
9 Pretargeted Imaging
The half-life of 68Ga is shorter than that of 64Cu 67Ga 99mTc89Zr 111In and 123124125I and thus in contrast to the latterit is not compatible with slow pharmacokinetics of largemolecules such as antibodies and glycoproteins The rangeof antigen-specific antibodies relevant to inflammation andinfection is broad and a number of 99mTc-labelled antibodieswere used clinically [20 21 227] The respective range of68Ga-based agents could be similarThe solution to overcomethe incompatibility of half-life time frames could be eitherthe reduction of the antibody size or the application of thepretargeting concept
The history of the pretargeting concept spans threedecades predominantly in the field of oncology [228ndash230]It was developed to improve image contrast and dosimetryin immunoimaging and radioimmunotherapy when usingradiolabelled antibody ligands with slow pharmacokinetics[231] The arsenal of antibodies is vast and diverse encourag-ing extensive investment into development of techniques thatwould allow their exploration to the fullest Pretargeting con-siders at least two major steps wherein a functionalized anti-body is first administered for target localization and clearancefrom blood and normal tissue and thereafter a radiolabelledsmall molecule capable of binding to the functionalized
antibody due to high affinity or covalent interaction is admin-istered The key properties of the radiolabelled molecules arefast pharmacokinetic and clearance Several techniques havebeen developed for the realization of pretargeting conceptincluding avidinstreptavidin-biotin systems [216 217 232233] bispecific antibodies (bsmAb) with haptens [232 234ndash254] antibody-oligonucleotide conjugates with complemen-tary oligonucleotides [255] biorthogonal systems allowingcovalent chemical reactions in vivo (Figure 8)
The high affinity of biotin to avidin and streptavidinproteins was utilized clinically and preclinically in pretar-geting approach for the imaging and therapy of pancreaticadenocarcinoma [232] glioblastoma [256] and lymphoma[257] However this pretargeting technique may requirethree steps in order to eliminate the excess of antibody-(strept)avidin conjugate circulating in the blood and notbound to the target by adding clearing agent Anotherapplication of the technique was monitoring transplantationof islets of Langerhans in the treatment for type 1 diabetesmellitus wherein the cells or cellmimetics were conjugated to(strept)avidin prior to the transplantation [216 217] Severalanalogues of biotin comprising DOTA chelate moiety forlabelling with 68Ga and ethylene glycol linker of variouslength demonstrated the influence of the latter on the affinitytowards avidin
Particular example of hapten molecules is the ones com-prising histamine-succinyl-glycine (HSG) motif and chelatemoiety [251ndash253 258] for the complexationwith 68Ga Severalanalogues were developed for the imaging of carcinoem-bryonic antigen (CEA) pretargeted with anti-CEA bsmAb[254 259 260] and two clinical studies of medullary thyroidcarcinoma and breast carcinoma positive for CEA using68Ga-labelled hapten molecules and bsmAb were initiated[261]
Bioorthogonal reactions are fast regioselective requiringsmall reagent concentration and occurring under mild con-ditions often in aqueous solution and temperature below 37∘C[262 263] Amongst various biorthogonal reaction types thecycloaddition of tetrazines and various dienophiles referredto as inverse-electron-demandDiels-Alder (IEDDA) reactionis themost successful in the context of pretargeting Antibod-ies functionalized with trans-cyclooctene (TCO) and a radi-olabelled tetrazine that can interact in vivo based on IEDDAreaction were studied [264ndash267] In particular 68Ga-labelledtetrazine dextran demonstrated favorable pharmacokineticsin a healthy mouse [264] However the proof of concept is tobe performed in a xenografted animal Accumulation of anti-TAG72 [265] and anti-A33 [266] antibodies functionalizedwith TCO in mouse xenografts was visualized respectivelyby an 111In and 64Cu-labelled tetrazine analogues Anti-CA199 antibody-TCO in combination with 177Lu-labelledtetrazine demonstrated radiotherapeutic effect in pancreaticcancer murine model [267]
Thepretargeted imaging techniquesmay contribute to theexpansion of immuno-PET with 68Ga providing the intrinsicadvantages of 68Ga and PET As mentioned above mostof the developed radiolabelled counterparts of pretargetingtechniques have demonstrated promising results There are
14 Contrast Media amp Molecular Imaging
H
ON
NN
O
OO
OO
NH
NS
NH
ONH
O
HO
ONH
O
Ga
HN
NH
NH
O
OO
HNN
HN
NH
NH
O
OO
HNN
（2
(a)
NH
O
O
NH
N
NNGa
O O
O O
O
O
O
N N
NN
OO
（2
(b)
N
N
O
O
N
N
O
O
O
NH
O
O
ONH
NHS
O
H
HO
NH
+
minus
(c)
Figure 8 Schematic presentation of pretargeting techniques (a) bispecific antibodies engineered to specifically bind with radiolabelledhapten molecules (b) bioorthogonal click chemistry for fast and specific covalent binding between for example a trans-cyclooctenefunctionalized antibody and a radiolabelled tetrazine (c) interaction between antibody-(strept)avidin conjugate and radiolabelled biotinutilizing extremely high affinity of (strept)avidin and biotin
Contrast Media amp Molecular Imaging 15
a considerable number of potential antibody biomarkersthat could be considered for the imaging of infection andinflammation
10 Theranostics Potential
Theranostics [268] embraces realization of personalizedmedicine by conducting diagnosis on individual basis andproviding possibility of predicting the efficacy of a specifictreatment and following up the response to the treatmentenabling adjustment of the latter very early in the processIn the context of nuclear medicine wherein the radiophar-maceuticals targeted at biomarkers specific to a disease cancarry either diagnostic radionuclides or therapeutic ones theconcept can be denoted as radiotheranostics [28] The tar-geted molecular imaging such as PET can offer noninvasivediagnosis specific to the disease for example tumour-typespecific and provide accurate localization of the lesions Thestrongest advantage of PET is the potential for quantificationof the target for example receptor expression investigationof the uptake kinetics and estimation of the dosimetryThesecharacteristics of PET allow for individualized treatmentselection and planning monitoring of treatment responseand detection of recurrent diseaseThe individualized patientmanagement provides such advantages as optimization ofthe treatment regimen for the improved response and exclu-sion of futile treatments minimization of risks and toxicitywith overall outcome of reduced cost and patient distressThe importance of individualized patient management wasdemonstrated by clinical studies wherein the influence ofdose of the administered radiopharmaceutical targeted atreceptors overexpressed in cancer lesions on the diagnosticoutcome was investigated in the same patient [85 269270] 68Ga-labelled SST analogues [26ndash28 271] and Affibodymolecules [5 272ndash274] used respectively in NENs andbreast cancer patients are the most prominent examplesof (radio)theranostics involving 68GaPET wherein 68Ga-labelled analogues were used not only for localization of thelesions but also for staging patient stratification prognosistherapy selection and monitoring of the response to thetreatment of NETs and other cancer types [2ndash4 6 85 176275ndash277]
The methodology can be translated to inflammationand infection allowing for accurate and specific selection oftreatment regimen and for follow-up and evaluation of theresponse to therapy resulting in improved treatment efficacyand decreased cost and side effects The accommodation ofboth imaging function and antibiotic function in the samemolecule is a novel example of a theranostic agent [278]A series of siderophores conjugated with DOTA moiety forthe radiolabelling and with antibiotics for the treatmentof bacterial infection were investigated preclinically Theaccumulation of the intravenously administered ampicillinconjugate in the site of subcutaneously injected P aeruginosain mice was clearly and focally visualized within 06 h withretention for at least 24 h These results obtained usinganalogues carrying dye for optical imaging can be translatedto 68Ga-labelled counterparts for PET
11 Conclusions
The medical need for specific agents for noninvasive quan-titative and whole-body imaging of inflammation and infec-tion has not been met yet despite decades of research How-ever the prerequisites in terms of identification of potentialtargets design and synthesis of the respective ligands andimaging technologies are evolving very fast The potentialof accurate and quantitative lesion localization as well asmonitoring of the treatment response promises personalizedpatient management
The use of 68Ga in oncology is established proving thestrong potential of 68Ga for the promotion of PET technol-ogy for effective and efficient diagnostics and personalizedmedicineThe experience of oncological 68Ga-based agents isgetting translated to inflammation and infection Pretargetedimaging technology opens wide possibilities based on anti-body biomarkers
Conflicts of Interest
The author declares that there are no conflicts of interestregarding the publication of this article
References
[1] I Velikyan ldquoContinued rapid growth inGa applications update2013 to June 2014rdquo Journal of Labelled CompoundsampRadiophar-maceuticals pp 99ndash121 2015
[2] I Velikyan ldquo 68Ga-based radiopharmaceuticals Production andapplication relationshiprdquo Molecules vol 20 no 7 pp 12913ndash12943 2015
[3] M Fani P Peitl and I Velikyan ldquoCurrent status of radiophar-maceuticals for the theranostics of neuroendocrine neoplasmsrdquoPharmaceuticals vol 10 no 1 article no 30 2017
[4] I Velikyan ldquoPositron emitting [68Ga]Ga-based imaging agentsChemistry and diversityrdquoMedicinal Chemistry vol 7 no 5 pp345ndash379 2011
[5] J Sorensen I Velikyan D Sandberg et al ldquoMeasuringHER2-receptor expression in metastatic breast cancer using[68Ga]ABY-025 Affibody PETCTrdquo Theranostics vol 6 no 2pp 262ndash271 2016
[6] I Velikyan ldquoProspective of 68Ga-Radiopharmaceutical devel-opmentrdquoTheranostics vol 4 no 1 pp 47ndash80 2014
[7] P Lankinen T J Makinen T A Poyhonen et al ldquo68Ga-DOTAVAP-P1 PET imaging capable of demonstrating the phaseof inflammation in healing bones and the progress of infectionin osteomyelitic bonesrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 35 no 2 pp 352ndash364 2008
[8] T UjulaMHuttunen P Luoto et al ldquoMatrixmetalloproteinase9 targeting peptides Syntheses 68Ga-labeling and preliminaryevaluation in a rat melanoma xenograft modelrdquo BioconjugateChemistry vol 21 no 9 pp 1612ndash1621 2010
[9] A Autio T Ujula P Luoto S Salomaki S Jalkanen and ARoivainen ldquoPET imaging of inflammation and adenocarcinomaxenografts using vascular adhesion protein 1 targeting peptide68Ga-DOTAVAP-P1 Comparison with 18F-FDGrdquo EuropeanJournal of Nuclear Medicine and Molecular Imaging vol 37 no10 pp 1918ndash1925 2010
16 Contrast Media amp Molecular Imaging
[10] J Silvola A Autio P Luoto S Jalkanen andA Roivainen ldquoPre-liminary evaluation of novel 68Ga-DOTAVAP-PEG-P2 peptidetargeting vascular adhesion protein-1rdquo Clinical Physiology andFunctional Imaging vol 30 no 1 pp 75ndash78 2010
[11] T Ujula S Salomaki P Virsu et al ldquoSynthesis 68Ga labelingand preliminary evaluation of DOTA peptide binding vascularadhesion protein-1 a potential PET imaging agent for diagnos-ing osteomyelitisrdquo Nuclear Medicine and Biology vol 36 no 6pp 631ndash641 2009
[12] A Autio T Henttinen H J Sipila S Jalkanen and ARoivainen ldquoMini-PEG spacering of VAP-1-targeting 68Ga-DOTAVAP-P1 peptide improves PET imaging of inflamma-tionrdquo EJNMMI Research vol 1 no 1 pp 1ndash7 2011
[13] K Aalto A Autio E A Kiss et al ldquoSiglec-9 is a novel leukocyteligand for vascular adhesion protein-1 and can be used in PETimaging of inflammation and cancerrdquo Blood vol 118 no 13 pp3725ndash3733 2011
[14] V Kumar D K Boddeti S G Evans F Roesch and RHowman-Giles ldquoPotential use of 68Ga-apo-transferrin as a PETimaging agent for detecting Staphylococcus aureus infectionrdquoNuclear Medicine and Biology vol 38 no 3 pp 393ndash398 2011
[15] M Petrik H Haas G Dobrozemsky et al ldquo68Ga-siderophoresfor PET imaging of invasive pulmonary aspergillosis Proof ofprinciplerdquo Journal of Nuclear Medicine vol 51 no 4 pp 639ndash645 2010
[16] M Petrik H Haas M Schrettl A Helbok M Blatzer and CDecristoforo ldquoIn vitro and in vivo evaluation of selected 68Ga-siderophores for infection imagingrdquo Nuclear Medicine andBiology vol 39 no 3 pp 361ndash369 2012
[17] M Petrik GM Franssen H Haas et al ldquoPreclinical evaluationof two 68Ga-siderophores as potential radiopharmaceuticals forAspergillus fumigatus infection imagingrdquo European Journal ofNuclearMedicine andMolecular Imaging vol 39 no 7 pp 1175ndash1183 2012
[18] A Rizzello D Di Pierro F Lodi et al ldquoSynthesis and qualitycontrol of 68Ga citrate for routine clinical PETrdquo NuclearMedicine Communications vol 30 no 7 pp 542ndash545 2009
[19] C Nanni C Errani and L Boriani ldquo 68Ga-citrate PETCT forevaluating patients with infections of the bone preliminaryresultsrdquo Journal of Nuclear Medicine vol 51 no 12 pp 1932ndash1936 2010
[20] S S Das A V Hall D W Wareham and K E Britton ldquoInfec-tion imaging with radiopharmaceuticals in the 21st centuryrdquoBrazilian Archives of Biology and Technology vol 45 no spepp 25ndash37 2002
[21] A Signore and A W J M Glaudemans ldquoThe molecularimaging approach to image infections and inflammation bynuclear medicine techniquesrdquo Annals of Nuclear Medicine vol25 no 10 pp 681ndash700 2011
[22] T Yusa K Tateda A Ohara and S Miyazaki ldquoNew possiblebiomarkers for diagnosis of infections and diagnostic distinc-tion between bacterial and viral infections in childrenrdquo Journalof Infection and Chemotherapy vol 23 no 2 pp 96ndash100 2017
[23] A Signore A W J M Glaudemans O Gheysens C Lauriand O A Catalano ldquoNuclear Medicine Imaging in PediatricInfection or Chronic Inflammatory Diseasesrdquo Seminars inNuclear Medicine vol 47 no 3 pp 286ndash303 2017
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to THERANOSTICSrdquo Dalton Transactions vol 40 no 23 pp6104ndash6111 2011
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[30] S J Goldsmith and S Vallabhajosula ldquoClinically proven radio-pharmaceuticals for infection imaging mechanisms and appli-cationsrdquo Seminars in Nuclear Medicine vol 39 no 1 pp 2ndash102009
[31] M F Tsan ldquoMechanism of gallium-67 accumulation in inflam-matory lesionsrdquo Journal of Nuclear Medicine vol 26 no 1 pp88ndash92 1985
[32] S L Kipper ldquoRadiolabelled leukocyte imaging of the abdomenrdquoin Nuclear Medicine Annual J Freeman Ed pp 81ndash126 RavenPress New York NY USA 1995
[33] F Jamar J Buscombe A Chiti et al ldquoEANMSNMMI guidelinefor 18F-FDG use in inflammation and infectionrdquo Journal ofNuclear Medicine vol 54 no 4 pp 647ndash658 2013
[34] C J Palestro ldquoThe current role of gallium imaging in infectionrdquoSeminars in Nuclear Medicine vol 24 no 2 pp 128ndash141 1994
[35] M S Akhtar M B Imran M A Nadeem and A ShahidldquoAntimicrobial peptides as infection imaging agents better thanradiolabeled antibioticsrdquo International Journal of Peptides vol2012 Article ID 965238 19 pages 2012
[36] D Delbeke and G M Segall ldquoStatus of and trends in nuclearmedicine in the United Statesrdquo Journal of Nuclear Medicine vol52 no 2 2011
[37] S S Gambhir J Czernin J Schwimmer D H Silverman R EColeman and M E Phelps ldquoA tabulated summary of the FDGPET literaturerdquo Journal of Nuclear Medicine vol 42 pp 1Sndash93S2001
[38] M J Lindsay B A Siegel S R Tunis et al ldquoThe NationalOncologic PET Registry ExpandedMedicare coverage for PETunder coverage with evidence developmentrdquo American Journalof Roentgenology vol 188 no 4 pp 1109ndash1113 2007
[39] F Gemmel H Van Den Wyngaert C Love M M Welling PGemmel and C J Palestro ldquoProsthetic joint infectionsradionuclide state-of-the-art imagingrdquo European Journal ofNuclearMedicine andMolecular Imaging vol 39 no 5 pp 892ndash909 2012
[40] J Sorensen ldquoHow does the patient benefit from clinical PETrdquoTheranostics vol 2 no 5 pp 427ndash436 2012
[41] S L Rice C A Roney P Daumar and J S Lewis ldquoThe nextgeneration of positron emission tomography radiopharmaceu-ticals in oncologyrdquo Seminars in Nuclear Medicine vol 41 no 4pp 265ndash282 2011
[42] R LWahl JMHerman and E Ford ldquoThePromise and Pitfallsof Positron Emission Tomography and Single-Photon EmissionComputed Tomography Molecular Imaging-Guided RadiationTherapyrdquo Seminars in Radiation Oncology vol 21 no 2 pp 88ndash100 2011
Contrast Media amp Molecular Imaging 17
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[44] X Li W Bauer I Israel et al ldquoTargeting p-selectin by gallium-68-labeled fucoidan positron emission tomography for nonin-vasive characterization of vulnerable plaques Correlation within vivo 176t mrirdquo Arteriosclerosis Thrombosis and VascularBiology vol 34 no 8 pp 1661ndash1667 2014
[45] S Eichendorff P Svendsen D Bender et al ldquoBiodistributionand PET Imaging of a Novel [68Ga]-Anti-CD163-AntibodyConjugate in Rats with Collagen-Induced Arthritis and inControlsrdquoMolecular Imaging and Biology vol 17 no 1 pp 87ndash93 2014
[46] Z Zhu Y Yin K Zheng et al ldquoEvaluation of synovial angiogen-esis in patients with rheumatoid arthritis using 68Ga-PRGD2PETCT A prospective proof-of-concept cohort studyrdquo Annalsof the Rheumatic Diseases vol 73 no 6 pp 1269ndash1272 2014
[47] J S Eo J C Paeng S Lee et al ldquoAngiogenesis imaging inmyocardial infarction using 68Ga-NOTA- RGD PET Charac-terization and application to therapeutic efficacy monitoring inratsrdquo Coronary Artery Disease vol 24 no 4 pp 303ndash311 2013
[48] J H Kim Y-H Kim Y J Kim et al ldquoQuantitative positronemission tomography imaging of angiogenesis in rats with fore-limb ischemia using 68Ga-NOTA-c(RGDyK)rdquo Angiogenesisvol 16 no 4 pp 837ndash846 2013
[49] I Laitinen J Notni K Pohle et al ldquoComparison of cyclicRGD peptides for 120572v1205733 integrin detection in a rat model ofmyocardial infarctionrdquo EJNMMI Research vol 3 no 1 pp 1ndash9 2013
[50] M Kiugel I Dijkgraaf V Kyto et al ldquoDimeric [68Ga]DOTA-RGD Peptide Targeting 120572 ltinfgtvltinfgt 120573 ltinfgt3ltinfgt Inte-grin Reveals Extracellular Matrix Alterations after MyocardialInfarctionrdquo Molecular Imaging and Biology vol 16 no 6 pp793ndash801 2014
[51] M Gronman M Tarkia T Kiviniemi et al ldquoImaging of 120572v1205733integrin expression in experimental myocardial ischemia with[68Ga]NODAGA-RGD positron emission tomographyrdquo Jour-nal of Translational Medicine vol 15 no 1 p 144 2017
[52] J Haukkala I Laitinen P Luoto et al ldquo68Ga-DOTA-RGDpep-tide Biodistribution and binding into atherosclerotic plaquesin micerdquo European Journal of Nuclear Medicine and MolecularImaging vol 36 no 12 pp 2058ndash2067 2009
[53] H Virtanen A Autio R Siitonen et al ldquo68Ga-DOTA-Siglec-9- a new imaging tool to detect synovitisrdquo Arthritis Research ampTherapy vol 17 no 1 article no 308 2015
[54] J Retamal J Sorensen M Lubberink et al ldquoFeasibility of(68) Ga-labeled Siglec-9 peptide for the imaging of acutelung inflammation a pilot study in a porcine model of acuterespiratory distress syndromerdquoAm JNuclMedMol Imaging vol6 no 1 pp 18ndash31 2016
[55] J M U Silvola H Virtanen R Siitonen et al ldquoLeukocytetrafficking-associated vascular adhesion protein 1 is expressedand functionally active in atherosclerotic plaquesrdquo ScientificReports vol 6 Article ID 35089 2016
[56] H Ahtinen J Kulkova L Lindholm et al ldquo68Ga-DOTA-Siglec-9 PETCT imaging of peri-implant tissue responses andstaphylococcal infectionsrdquo EJNMMI Research vol 4 no 1article no 45 pp 1ndash11 2014
[57] A Autio S Jalkanen and A Roivainen ldquoNuclear imaging ofinflammation Homing-associated molecules as targetsrdquo EJN-MMI Research vol 3 no 1 pp 1ndash7 2013
[58] J TThackeray T Derlin AHaghikia et al ldquoMolecular Imagingof the Chemokine Receptor CXCR4 after Acute MyocardialInfarctionrdquo JACC Cardiovascular Imaging vol 8 no 12 pp1417ndash1426 2015
[59] J S Schmid A Schirbel A K Buck S Kropf H-J Westerand C Lapa ldquoPentixafor-Positron Emission TomographyComputed Tomography Detects Chemokine Receptor CXCR4Expression after Ischemic Strokerdquo Circulation CardiovascularImaging vol 9 no 9 Article ID e005217 2016
[60] J Zhou G Hao H Weng et al ldquoIn vivo evaluation ofmedical device-associated inflammation using a macrophage-specific positron emission tomography (PET) imaging proberdquoBioorganic amp Medicinal Chemistry Letters vol 23 no 7 pp2044ndash2047 2013
[61] S A Kularatne M-J Belanger X Meng et al ldquoComparativeanalysis of folate derived PET imaging agents with [ 18F]-2-fluoro-2-deoxy-d-glucose using a rodent inflammatory pawmodelrdquo Molecular Pharmaceutics vol 10 no 8 pp 3103ndash31112013
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[63] T Lincke J Singer R Kluge O Sabri and R Paschke ldquoRela-tive quantification of indium-111 pentetreotide and gallium-68DOTATOC uptake in the thyroid gland and association withthyroid pathologiesrdquoThyroid vol 19 no 4 pp 381ndash389 2009
[64] A Rominger T Saam E Vogl et al ldquoIn vivo imaging ofmacrophage activity in the coronary arteries using 68Ga-DOTATATE PETCT correlation with coronary calcium bur-den and risk factorsrdquo Journal of Nuclear Medicine vol 51 no 2pp 193ndash197 2010
[65] J M Tarkin F R Joshi N R Evans et al ldquoDetection ofAtherosclerotic Inflammation by 68Ga-DOTATATE PET Com-pared to [18F]FDG PET Imagingrdquo Journal of the AmericanCollege of Cardiology vol 69 no 14 pp 1774ndash1791 2017
[66] S-P Lee H-J Im S Kang et al ldquoNoninvasive imaging ofmyocardial inflammation in myocarditis using 68Ga-taggedmannosylated human serum albumin positron emissiontomographyrdquoTheranostics vol 7 no 2 pp 413ndash424 2017
[67] Z Zha J Song S R Choi et al ldquo68Ga-Bivalent PolypegylatedStyrylpyridine Conjugates for Imaging A120573 Plaques in CerebralAmyloid Angiopathyrdquo Bioconjugate Chemistry vol 27 no 5 pp1314ndash1323 2016
[68] H Watanabe M Ono S Iikuni et al ldquoA 68Ga complex basedon benzofuran scaffold for the detection of 120573-amyloid plaquesrdquoBioorganic amp Medicinal Chemistry Letters vol 24 no 20 pp4834ndash4837 2014
[69] D Cressier M Dhilly T T Cao Pham et al ldquoGallium-68 Com-plexes Conjugated to Pittsburgh Compound B Radiolabelingand Biological EvaluationrdquoMolecular Imaging and Biology vol18 no 3 pp 334ndash343 2016
[70] D Satpati CArjun R KrishnamohanG Samuel and S Baner-jee ldquo68Ga-labeledCiprofloxacinConjugates as Radiotracers forTargeting Bacterial InfectionrdquoChemical Biology ampDrug Designvol 87 no 5 pp 680ndash686 2016
[71] T Ebenhan N Chadwick and M M Sathekge ldquoPeptidesynthesis characterization and 68Ga-radiolabeling of NOTA-conjugated ubiquicidin fragments for prospective infectionimaging with PETCTrdquo Nuclear Medicine and Biology vol 41no 5 pp 390ndash400 2014
18 Contrast Media amp Molecular Imaging
[72] T Ebenhan J R Zeevaart and J D Venter ldquoPreclinicalevaluation of 68Ga-labeled 1 4 7-triazacyclononane-1 4 7-triacetic acid-ubiquicidin as a radioligand for PET infectionimagingrdquo Journal of Nuclear Medicine vol 55 no 2 pp 308ndash314 2014
[73] B B Mokaleng T Ebenhan S Ramesh et al ldquoSynthesis 68Ga-radiolabeling and preliminary in vivo assessment of adepsipeptide-derived compound as a potential PETCTinfection imaging agentrdquo BioMed Research International vol2015 Article ID 284354 2015
[74] T Ebenhan B Mokaleng J Venter H Kruger J Zeevaart andM Sathekge ldquoPreclinical Assessment of a 68Ga-DOTA-Functionalized Depsipeptide as a Radiodiagnostic InfectionImaging AgentrdquoMolecules vol 22 no 9 p 1403 2017
[75] S Chopra B Singh A Koul A Mishra and H Wester ldquoSyn-thesis of DOTA conjugated GF-17 and RAWVAWR-NH2 andradiolabeling with 68Ga as a potential PET tracer for infectionimagingrdquo J Nucl Med vol 57 Supplement 2 p 1115 2016
[76] M Petrik HHaas P Laverman et al ldquo 68Ga-triacetylfusarinineC and 68Ga-ferrioxamine e for aspergillus infection imaginguptake specificity in various microorganismsrdquoMolecular Imag-ing and Biology vol 16 no 1 pp 102ndash108 2014
[77] V Kumar and D K Boddeti ldquo 68Ga-radiopharmaceuticals forPET imaging of infection and inflammationrdquo Recent Results inCancer Research vol 194 pp 189ndash219 2013
[78] M Vorster A Maes A Jacobs et al ldquoEvaluating the possiblerole of 68Ga-citrate PETCT in the characterization of indeter-minate lung lesionsrdquo Annals of Nuclear Medicine vol 28 no 6pp 523ndash530 2014
[79] M Vorster B Mokaleng M M Sathekge and T Ebenhan ldquoAmodified technique for efficient radiolabeling of 68Ga-citratefrom a SnO2-based 68Ge68Ga generator for better infectionimagingrdquoHellenic Journal of Nuclear Medicine vol 16 no 3 pp193ndash198 2013
[80] S Salomaeki J Kemppainen U Hohenthal et al ldquoHead-to-head comparison of 68Ga-Citrate and 18F-FDG PETCT fordetection of infectious foci in patients with staphylococcusaureus bacteraemiardquo Contrast Media amp Molecular Imaging vol2017 p 8 2017
[81] L Fass ldquoImaging and cancer a reviewrdquoMolecular Oncology vol2 no 2 pp 115ndash152 2008
[82] A Chopra L Shan W C Eckelman et al ldquoMolecular imagingand contrast agent database (MICAD) Evolution and progressrdquoMolecular Imaging and Biology vol 14 no 1 pp 4ndash13 2012
[83] A Sanchez-Crespo P Andreo and S A Larsson ldquoPositronflight in human tissues and its influence on PET image spatialresolutionrdquo European Journal of Nuclear Medicine and Molecu-lar Imaging vol 31 no 1 pp 44ndash51 2004
[84] H W A M De Jong L Perk G W M Visser R Boellaard GAM S Van Dongen and A A Lammertsma ldquoHigh resolutionPET imaging characteristics of68Ga 124i and89Zr comparedto18Frdquo in Proceedings of the Nuclear Science Symposium Con-ference Record 2005 IEEE pp 1624ndash1627 Puerto Rico October2005
[85] I Velikyan A Sundin B Eriksson et al ldquoIn vivo bindingof [68Ga]-DOTATOC to somatostatin receptors in neuroen-docrine tumours - impact of peptide massrdquo Nuclear Medicineand Biology vol 37 no 3 pp 265ndash275 2010
[86] U Eberlein and M Lassmann ldquoDosimetry of [68Ga]-labeledcompoundsrdquo Applied Radiation and Isotopes vol 76 pp 70ndash742013
[87] C PettinatoA SarnelliMDiDonna et al ldquo68Ga-DOTANOCBiodistribution and dosimetry in patients affected by neuroen-docrine tumorsrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 35 no 1 pp 72ndash79 2008
[88] B P Burke G S Clemente and S J Archibald ldquoRecentadvances in chelator design and labelling methodology for68Ga radiopharmaceuticalsrdquo Journal of Labelled Compoundsand Radiopharmaceuticals vol 57 no 4 pp 239ndash243 2014
[89] I Velikyan U Rosenstrom S Estrada et al ldquoSynthesis andpreclinical evaluation of 68Ga-labeled collagelin analogs forimaging and quantification of fibrosisrdquo Nuclear Medicine andBiology vol 41 no 9 pp 728ndash736 2014
[90] M F Ferreira G Pereira J P Andre and etal C ldquoGa[NO2A-N-(120572-amino)propionate] chelates Synthesis and evaluation aspotential tracers for 68Ga PETrdquoDalton Transactions vol 43 no21 pp 8037ndash8047 2014
[91] J Notni J Simecek and H-J Wester ldquoPhosphinic acid func-tionalized polyazacycloalkane chelators for radiodiagnosticsand radiotherapeutics Unique characteristics and applicationsrdquoChemMedChem vol 9 no 6 pp 1107ndash1115 2014
[92] J Simecek O Zemek P Hermann J Notni and H J WesterldquoTailored gallium( III) chelator NOPO synthesis characteriza-tion bioconjugation and application in preclinical Ga-68-PETimagingrdquoMolecular Pharmaceutics 2013
[93] D Parker B P Waldron and D S Yufit ldquoCrystallographicand solution NMR structural analyses of four hexacoordinatedgallium(iii) complexes based on ligands derived from 6-amino-perhydro-14-diazepinerdquo Dalton Transactions vol 42 no 22pp 8001ndash8008 2013
[94] B P Waldron D Parker C Burchardt D S Yufit M ZimnyandF Roesch ldquoStructure and stability of hexadentate complexesof ligands based on AAZTA for efficient PET labelling withgallium-68rdquo Chemical Communications vol 49 no 6 pp 579ndash581 2013
[95] D Parker and B PWaldron ldquoConformational analysis and syn-thetic approaches to polydentate perhydro-diazepine ligandsfor the complexation of gallium(iii)rdquo Organic amp BiomolecularChemistry vol 11 no 17 pp 2827ndash2838 2013
[96] I Velikyan H Maecke and B Langstrom ldquoConvenient prepa-ration of 68Ga-based PET-radiopharmaceuticals at room tem-peraturerdquo Bioconjugate Chemistry vol 19 no 2 pp 569ndash5732008
[97] J Erchegyi R Cescato B Waser J E Rivier and J C ReubildquoN-Imidazolebenzyl-histidine substitution in somatostatin andin its octapeptide analogue modulates receptor selectivity andfunctionrdquo Journal of Medicinal Chemistry vol 54 no 17 pp5981ndash5987 2011
[98] R Saha N Saha R S Donofrio and L L Bestervelt ldquoMicrobialsiderophores Amini reviewrdquo Journal of Basic Microbiology vol53 no 4 pp 303ndash317 2013
[99] V Nikolova S Angelova N Markova and T Dudev ldquoGalliumas a Therapeutic Agent A Thermodynamic Evaluation of theCompetition between Ga3+ and Fe3+ Ions in MetalloproteinsrdquoThe Journal of Physical Chemistry B vol 120 no 9 pp 2241ndash2248 2016
[100] C R Chitambar ldquoGallium and its competing roles with ironin biological systemsrdquo Biochimica et Biophysica Acta (BBA) -Molecular Cell Research vol 1863 no 8 pp 2044ndash2053 2016
[101] J A Lessa M A Soares and R G dos Santos ldquoGallium(III)complexes with 2-acetylpyridine-derived thiosemicarbazonesantimicrobial and cytotoxic effects and investigation on theinteractions with tubulinrdquo BioMetals vol 26 pp 151ndash165 2013
Contrast Media amp Molecular Imaging 19
[102] M van Oosten M Hahn L M A Crane et al ldquoTargetedimaging of bacterial infections Advances hurdles and hopesrdquoFEMS Microbiology Reviews vol 39 no 6 pp 892ndash916 2015
[103] M Vorster AMaes C V DWiele andM Sathekge ldquoGallium-68 PET A Powerful Generator-based Alternative to Infectionand Inflammation Imagingrdquo Seminars in Nuclear Medicine vol46 no 5 pp 436ndash447 2016
[104] M Kircher and C Lapa ldquoNovel Noninvasive Nuclear MedicineImaging Techniques for Cardiac Inflammationrdquo Current Car-diovascular Imaging Reports vol 10 no 2 article no 6 2017
[105] D AHammoud ldquoMolecular imaging of inflammation Currentstatusrdquo Journal of Nuclear Medicine vol 57 no 8 pp 1161ndash11652016
[106] D R Brenner D Scherer K Muir et al ldquoA review of the appli-cation of inflammatory biomarkers in epidemiologic cancerresearchrdquo Cancer Epidemiology Biomarkers amp Prevention vol23 no 9 pp 1729ndash1751 2014
[107] M D Turner B Nedjai T Hurst and D J PenningtonldquoCytokines and chemokines at the crossroads of cell signallingand inflammatory diseaserdquo Biochimica et Biophysica Acta (BBA)- Molecular Cell Research vol 1843 no 11 pp 2563ndash2582 2014
[108] L Werner H Guzner-Gur and I Dotan ldquoInvolvement ofCXCR4CXCR7CXCL12 interactions in inflammatory boweldiseaserdquoTheranostics vol 3 no 1 pp 40ndash46 2013
[109] S Jalkanen and M Salmi ldquoVAP-1 and CD73 endothelial cellsurface enzymes in leukocyte extravasationrdquo ArteriosclerosisThrombosis and Vascular Biology vol 28 no 1 pp 18ndash26 2008
[110] G Malviya F Galli I Sonni and A Signore ldquoImaging T-lymphocytes in inflammatory diseases A nuclear medicineapproachrdquo The Quarterly Journal of Nuclear Medicine andMolecular Imaging vol 58 no 3 pp 237ndash257 2014
[111] S Gratz H J RennenO C BoermanW J Oyen and P Burmaldquo(99m)Tc-interleukin-8 for imaging acute osteomyelitisrdquo Jour-nal of Nuclear Medicine vol 42 no 8 pp 1257ndash1264 2001
[112] S Gratz H J Rennen O C Boerman W J Oyen andF H Corstens ldquoRapid imaging of experimental colitis with(99m)Tc-interleukin-8 in rabbitsrdquo Journal of Nuclear Medicnevol 42 no 6 pp 917ndash923 2001
[113] C Alkim H Alkim A R Koksal S Boga and I SenldquoAngiogenesis in inflammatory bowel diseaserdquo InternationalJournal of Inflammation vol 2015 Article ID 970890 2015
[114] I S Alam T H Witney G Tomasi et al ldquoRadiolabeled RGDtracer kinetics annotates differential 120572v1205733 integrin expressionlinked to cell intrinsic and vessel expressionrdquoMolecular Imagingand Biology vol 16 no 4 pp 558ndash566 2014
[115] J Notni K Pohle and H-J Wester ldquoBe spoilt for choice withradiolabelled RGD peptides Preclinical evaluation of 68Ga-TRAP(RGD)3rdquoNuclear Medicine and Biology vol 40 no 1 pp33ndash41 2013
[116] J Oxboel M Brandt-Larsen C Schjoeth-Eskesen et al ldquoCom-parison of two new angiogenesis PET tracers 68Ga-NODAGA-E[c(RGDyK)]2 and 64Cu-NODAGA-E[c(RGDyK)]2 in vivoimaging studies in human xenograft tumorsrdquo Nuclear Medicineand Biology vol 41 no 3 pp 259ndash267 2014
[117] J Simecek J Notni T G Kapp H Kessler and H-J WesterldquoBenefits of NOPO as chelator in gallium-68 peptides exempli-fied by preclinical characterization of 68Ga-NOPO-c(RGDfK)rdquoMolecular Pharmaceutics vol 11 no 5 pp 1687ndash1695 2014
[118] M Trajkovic-Arsic P Mohajerani A Sarantopoulos et alldquoMultimodal molecular imaging of integrin avb3 for in vivodetection of pancreatic cancerrdquo Journal of NuclearMedicine vol55 no 3 pp 446ndash451 2014
[119] H Cai and P S Conti ldquoRGD-based PET tracers for imagingreceptor integrin 120572 v1205733 expressionrdquo Journal of Labelled Com-pounds and Radiopharmaceuticals vol 56 no 5 pp 264ndash2792013
[120] I Dijkgraaf S Y A Terry W J Mcbride et al ldquoImagingintegrin alpha-v-beta-3 expression in tumors with an 18F-labeled dimeric RGD peptiderdquo Contrast Media amp MolecularImaging vol 8 no 3 pp 238ndash245 2013
[121] P A Knetsch M Petrik C Rangger et al ldquo[68Ga]NS3-RGD and [68Ga] Oxo-DO3A-RGD for imaging 120572v1205733 integrinexpression Synthesis evaluation and comparisonrdquo NuclearMedicine and Biology vol 40 no 1 pp 65ndash72 2013
[122] Z Liu and F Wang ldquoDevelopment of RGD-based radiotracersfor tumor imaging and therapy Translating from bench tobedsiderdquo Current Molecular Medicine vol 13 no 10 pp 1487ndash1505 2013
[123] H Choi J H Phi J C Paeng et al ldquoImaging of integrin 120572v1205733expression using 68Ga-RGD positron emission tomography inpediatric cerebral infarctrdquoMolecular Imaging vol 12 no 4 pp213ndash217 2013
[124] H-J Yoon K W Kang I K Chun et al ldquoCorrelation of breastcancer subtypes based on estrogen receptor progesteronereceptor and HER2 with functional imaging parameters from68Ga-RGD PETCT and 18F-FDG PETCTrdquo European Journalof Nuclear Medicine and Molecular Imaging vol 41 no 8 pp1534ndash1543 2014
[125] R P Baum H R Kulkarni D Muller et al ldquoFirst-in-human study demonstrating tumor-angiogenesis by PETCTimaging with 68Ga-NODAGA-THERANOST a high-affinitypeptidomimetic for 120572v1205733 integrin receptor targetingrdquo CancerBiotherapy andRadiopharmaceuticals vol 30 no 4 pp 152ndash1592015
[126] R Haubner A Finkenstedt A Stegmayr et alldquo[68Ga]NODAGA-RGD ndash Metabolic stability biodistributionand dosimetry data from patients with hepatocellularcarcinoma and liver cirrhosisrdquo European Journal of NuclearMedicine and Molecular Imaging vol 43 no 11 pp 2005ndash20132016
[127] V Lopez-Rodrıguez C Galindo-Sarco F O Garcıa-Perez GFerro-Flores O Arrieta and M A Avila-Rodrıguez ldquoPET-based human dosimetry of the dimeric 120572v1205733 integrin ligand68Ga-DOTA-E-[c(RGDfK)]2 a potential tracer for imagingtumor angiogenesisrdquo Journal of Nuclear Medicine vol 57 no 3pp 404ndash409 2016
[128] M V Backer Z Levashova V Patel et al ldquoMolecular imagingof VEGF receptors in angiogenic vasculature with single-chainVEGF-based probesrdquo Nature Medicine vol 13 no 4 pp 504ndash509 2007
[129] MV Backer Z Levashova R Levenson F G Blankenberg andJ M Backer ldquoCysteine-containing fusion tag for site-specificconjugation of therapeutic and imaging agents to targetingproteinsrdquoMethods in Molecular Biology (Clifton NJ) vol 494pp 275ndash294 2008
[130] M Eder A V Krivoshein M Backer J M Backer UHaberkorn and M Eisenhut ldquoScVEGF-PEG-HBED-CC andscVEGF-PEG-NOTA conjugates comparison of easy-to-labelrecombinant proteins for [68Ga]PET imaging of VEGF recep-tors in angiogenic vasculaturerdquo Nuclear Medicine and Biologyvol 37 no 4 pp 405ndash412 2010
[131] E Blom I Velikyan A Monazzam P Razifar et al ldquoSynthe-sis and characterization of scVEGF-PEG-[ 68Ga]NOTA andscVEGF-PEG-[ 68Ga]DOTA PET tracersrdquo Journal of Labelled
20 Contrast Media amp Molecular Imaging
Compounds and Radiopharmaceuticals vol 54 no 11 pp 685ndash692 2011
[132] S Gratz M Behe and O C Boerman ldquo 99119898Tc-E-selectinbinding peptide for imaging acute osteomyelitis in a novel ratmodelrdquo Nuclear Medicine Communications vol 22 no 9 pp1003ndash1013 2001
[133] S B Jensen M Kakela L Joslashdal et al ldquoExploring the radiosyn-thesis and in vitro characteristics of [68Ga]Ga-DOTA-Siglec-9rdquoJournal of Labelled Compounds and Radiopharmaceuticals vol60 no 9 pp 439ndash449 2017
[134] B A Teicher and S P Fricker ldquoCXCL12 (SDF-1)CXCR4pathway in cancerrdquo Clinical Cancer Research vol 16 no 11 pp2927ndash2931 2010
[135] O Jacobson I D Weiss D O Kiesewetter J M Farber andX Chen ldquoPET of tumor CXCR4 expression with 4-18F-T140rdquoJournal of Nuclear Medicine vol 51 no 11 pp 1796ndash1804 2010
[136] A Aghanejad A R Jalilian Y Fazaeli et al ldquoSynthesis andevaluation of [67Ga]-AMD3100 A novel imaging agent fortargeting the chemokine receptorCXCR4rdquo Scientia Pharmaceu-tica vol 82 no 1 pp 29ndash42 2014
[137] O Jacobson I D Weiss L P Szajek et al ldquoPET imaging ofCXCR4 using copper-64 labeled peptide antagonistrdquoTheranos-tics vol 1 pp 251ndash262 2011
[138] O Jacobson I D Weiss L P Szajek et al ldquoImprovement ofCXCR4 tracer specificity for PET imagingrdquo Journal of Con-trolled Release vol 157 no 2 pp 216ndash223 2012
[139] H J Wester U Keller M Schottelius et al ldquoDisclosing theCXCR4 expression in lymphoproliferative diseases by targetedmolecular imagingrdquo Theranostics vol 5 no 6 pp 618ndash6302015
[140] E Gourni O Demmer M Schottelius et al ldquoPET of CXCR4expression by a 68Ga-labeled highly specific targeted contrastagentrdquo Journal of NuclearMedicine vol 52 no 11 pp 1803ndash18102011
[141] O Demmer I Dijkgraaf U Schumacher et al ldquoDesignsynthesis and functionalization of dimeric peptides targetingchemokine receptor CXCR4rdquo Journal of Medicinal Chemistryvol 54 no 21 pp 7648ndash7662 2011
[142] O Demmer E Gourni U Schumacher H Kessler and H-JWester ldquoPET Imaging of CXCR4 Receptors in Cancer by a NewOptimized Ligandrdquo ChemMedChem vol 6 no 10 pp 1789ndash1791 2011
[143] U Hennrich L Seyler M Schafer et al ldquoSynthesis and invitro evaluation of 68Ga-DOTA-4-FBn-TN14003 a novel tracerfor the imaging of CXCR4 expressionrdquo Bioorganic amp MedicinalChemistry vol 20 no 4 pp 1502ndash1510 2012
[144] G P C George E Stevens O Aberg et al ldquoPreclinical evalua-tion of a CXCR4-specific 68Ga-labelled TN14003 derivative forcancer PET imagingrdquo Bioorganic amp Medicinal Chemistry vol22 no 2 pp 796ndash803 2014
[145] S Poty E Gourni P Desogere et al ldquoAMD3100 A VersatilePlatform for CXCR4 Targeting 68Ga-Based Radiopharmaceu-ticalsrdquo Bioconjugate Chemistry vol 27 no 3 pp 752ndash761 2016
[146] K Philipp-Abbrederis K Herrmann S Knop et al ldquoIn vivomolecular imaging of chemokine receptor CXCR4 expressionin patients with advancedmultiple myelomardquo EMBOMolecularMedicine vol 7 no 4 pp 477ndash487 2015
[147] Z Wang M Zhang L Wang et al ldquoProspective study of 68Ga-NOTA-NFB Radiation dosimetry in healthy volunteers andfirst application in glioma patientsrdquo Theranostics vol 5 no 8pp 882ndash889 2015
[148] I M Jackson P J Scott and S Thompson ldquoClinical Applica-tions of Radiolabeled Peptides for PETrdquo Seminars in NuclearMedicine vol 47 no 5 pp 493ndash523 2017
[149] C Lapa T Reiter R A Werner et al ldquo[68Ga]Pentixafor-PETCT for Imaging of Chemokine Receptor 4 Expression afterMyocardial Infarctionrdquo JACC Cardiovascular Imaging vol 8no 12 pp 1466ndash1468 2015
[150] C Rischpler S G Nekolla H Kossmann et al ldquoUpregu-lated myocardial CXCR4-expression after myocardial infarc-tion assessed by simultaneous GA-68 pentixafor PETMRIrdquoJournal of Nuclear Cardiology vol 23 no 1 pp 131ndash133 2016
[151] F Hyafil J Pelisek I Laitinen et al ldquoImaging the CytokineReceptorCXCR4 in atherosclerotic plaqueswith the radiotracer68Ga-Pentixafor for PETrdquo Journal of Nuclear Medicine vol 58no 3 pp 499ndash506 2017
[152] Y Yi ldquoFolate receptor-targeted diagnostics and therapeutics forinflammatory diseasesrdquo ImmuneNetwork vol 16 no 6 pp 337ndash343 2016
[153] C M Paulos M J Turk G J Breur and P S Low ldquoFolatereceptor-mediated targeting of therapeutic and imaging agentsto activated macrophages in rheumatoid arthritisrdquo AdvancedDrug Delivery Reviews vol 56 no 8 pp 1205ndash1217 2004
[154] W Han R Zaynagetdinov F E Yull et al ldquoMolecular imagingof folate receptor 120573-positive macrophages during acute lunginflammationrdquo American Journal of Respiratory Cell and Molec-ular Biology vol 53 no 1 pp 50ndash59 2015
[155] B Kuhle C Muller and T L Ross ldquoA Novel 68Ga-Labeledpteroic acid-based PET tracer for tumor imaging via the folatereceptorrdquo Recent Results in Cancer Research vol 194 pp 257ndash267 2013
[156] C Brand V A Longo M Groaning W A Weber and TReiner ldquoDevelopment of a New Folate-Derived Ga-68-BasedPET Imaging AgentrdquoMolecular Imaging and Biology vol 19 no5 pp 754ndash761 2017
[157] M Fani XWang G Nicolas et al ldquoDevelopment of new folate-based PET radiotracers Preclinical evaluation of 68Ga-DOTA-folate conjugatesrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 38 no 1 pp 108ndash119 2011
[158] C J Mathias M R Lewis D E Reichert et al ldquoPreparationof 66Ga- and 68Ga-labeled Ga(III)-deferoxamine-folate aspotential folate-receptor-targeted PET radiopharmaceuticalsrdquoNuclear Medicine and Biology vol 30 no 7 pp 725ndash731 2003
[159] S-M Kim N Choi S Hwang et al ldquoFolate receptor-specific positron emission tomography imaging with folic acid-conjugated tissue inhibitor of metalloproteinase-2rdquo Bulletin ofthe Korean Chemical Society vol 34 no 11 pp 3243ndash3248 2013
[160] M Fani M-L Tamma G P Nicolas et al ldquoIn vivo imagingof folate receptor positive tumor xenografts using novel 68Ga-NODAGA-folate conjugatesrdquo Molecular Pharmaceutics vol 9no 5 pp 1136ndash1145 2012
[161] C Muller and R Schibli ldquoProspects in folate receptor-targetedradionuclide therapyrdquo Frontiers in Oncology vol 3 Article IDArticle 249 2013
[162] A Jain A Mathur U Pandey et al ldquoSynthesis and evaluationof a 68Ga labeled folic acid derivative for targeting folatereceptorsrdquo Applied Radiation and Isotopes vol 116 pp 77ndash842016
[163] W Xia A R Hilgenbrink E L Matteson M B Lockwood J-X Cheng and P S Low ldquoA functional folate receptor is inducedduring macrophage activation and can be used to target drugsto activated macrophagesrdquo Blood vol 113 no 2 pp 438ndash4462009
Contrast Media amp Molecular Imaging 21
[164] E P Krenning W A P Breeman P P M Kooij et alldquoLocalisation of endocrine-related tumours with radioiodi-nated analogue of somatostatinrdquoThe Lancet vol 1 no 8632 pp242ndash244 1989
[165] E P Krenning D J KwekkeboomWH Bakker et al ldquoSomato-statin receptor scintigraphy with [111In-DTPA-d-Phe1]- and[123I-Tyr3]-octreotide the Rotterdam experience with morethan 1000 patientsrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 20 no 8 pp 716ndash731 1993
[166] A Stahl G Meisetschlager M Schottelius et al ldquo[123I]Mtr-TOCA a radioiodinated and carbohydrated analogue ofoctreotide Scintigraphic comparison with [111In]octreotiderdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 33 no 1 pp 45ndash52 2006
[167] R Lebtahi J le Cloirec C Houzard et al ldquoDetection of neu-roendocrine tumors 99mTc-P829 scintigraphy compared with111In-pentetreotide scintigraphyrdquo Journal of Nuclear Medicinevol 43 no 7 pp 889ndash895 2002
[168] C Decristoforo T Maina B Nock M Gabriel P Cordopatisand R Moncayo ldquo99mTc-demotate 1 First data in tumourpatients - Results of a pilotphase I studyrdquo European Journal ofNuclearMedicine andMolecular Imaging vol 30 no 9 pp 1211ndash1219 2003
[169] C Decristoforo S J Mather W Cholewinski E DonnemillerG Riccabona and R Moncayo ldquo(99m)Tc-EDDAHYNIC-TOC A new (99m)Tc-labelled radiopharmaceutical forimaging somatostatin receptor-positive tumours First clinicalresults and intra-patient comparison with 111In-labelledoctreotide derivativesrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 27 no 9 pp 1318ndash1325 2000
[170] A Hubalewska-Dydejczyk K Fross-Baron R Mikołajczak etal ldquo99mTc-EDDAHYNIC-octreotate scintigraphy an efficientmethod for the detection and staging of carcinoid tumoursResults of 3 yearsrsquo experiencerdquo European Journal of NuclearMedicine and Molecular Imaging vol 33 no 10 pp 1123ndash11332006
[171] M Bangard M Behe S Guhlke et al ldquoDetection of somato-statin receptor-positive tumours using the new 99mC-tricine-HYNIC-D-Phe1-Tyr3-octreotide First results in patients andcomparison with 111In-DTPA-D-Phe1-octreotiderdquo EuropeanJournal of Nuclear Medicine and Molecular Imaging vol 27 no6 pp 628ndash637 2000
[172] A Helisch G J Forster H Reber et al ldquoPre-therapeuticdosimetry and biodistribution of 86Y-DOTA- Phe1-Tyr3-octreotide versus 111In-pentetreotide in patients with advancedneuroendocrine tumoursrdquo European Journal of NuclearMedicine and Molecular Imaging vol 31 no 10 pp 1386ndash13922004
[173] M Henze J Schuhmacher P Hipp et al ldquoPET imaging ofsomatostatin receptors using [68GA]DOTA-D-Phe1-Tyr3-Octreotide First results in patients with meningiomasrdquo Journalof Nuclear Medicine vol 42 no 7 pp 1053ndash1056 2001
[174] I Kayani J B Bomanji A Groves et al ldquoFunctional imaging ofneuroendocrine tumors with combined PETCT using 68Ga-DOTATATE (Dota-DPhe1 Tyr3-octreotate) and 18F-FDGrdquoCancer vol 112 no 11 pp 2447ndash2455 2008
[175] A Al-Nahhas ldquoNuclear medicine imaging of neuroendocrinetumoursrdquo Clinical Medicine vol 12 no 4 pp 377ndash380 2012
[176] V Ambrosini S Nicolini P Caroli et al ldquoPETCT imaging indifferent types of lung cancer an overviewrdquo European Journal ofRadiology vol 81 no 5 pp 988ndash1001 2012
[177] V Ambrosini D Campana P Tomassetti and S Fanti ldquo68Ga-labelled peptides for diagnosis of gastroenteropancreatic NETrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 39 no 1 pp S52ndashS60 2012
[178] K E Oberg J-C Reubi D J Kwekkeboom and E P KrenningldquoRole of somatostatins in gastroenteropancreatic neuroen-docrine tumor development and therapyrdquoGastroenterology vol139 no 3 pp 753-753 2010
[179] K Oberg ldquoGallium-68 somatostatin receptor PETCT Is ittime to replace 111Indium DTPA octreotide for patients withneuroendocrine tumorsrdquo Endocrine Journal vol 42 no 1 pp3-4 2012
[180] R Srirajaskanthan I Kayani A M Quigley J Soh M ECaplin and J Bomanji ldquoThe role of 68Ga-DOTATATE PET inpatients with neuroendocrine tumors and negative or equivocalfindings on 111In-DTPA-octreotide scintigraphyrdquo Journal ofNuclear Medicine vol 51 no 6 pp 875ndash882 2010
[181] A Kroiss D Putzer and C Uprimny ldquoFunctional imag-ing in phaeochromocytoma and neuroblastoma with 68Ga-DOTA-Tyr3-octreotide positron emission tomography and123I-metaiodobenzylguanidinerdquo European Journal of NuclearMedicine and Molecular Imaging vol 38 no 5 pp 865ndash8732011
[182] M Naji C Zhao S J Welsh et al ldquo68Ga-DOTA-TATE PETvs 123I-MIBG in identifying malignant neural crest tumoursrdquoMolecular Imaging and Biology vol 13 no 4 pp 769ndash775 2011
[183] V Ambrosini P Tomassetti P Castellucci et al ldquoComparisonbetween 68Ga-DOTA-NOC and 18F-DOPA PET for the detec-tion of gastro-entero-pancreatic and lung neuro-endocrinetumoursrdquo European Journal of Nuclear Medicine and MolecularImaging vol 35 no 8 pp 1431ndash1438 2008
[184] D Putzer M Gabriel B Henninger et al ldquoBone metastasesin patients with neuroendocrine tumor 68Ga- DOTA-Tyr3-octreotide PET in comparison to CT and bone scintigraphyrdquoJournal of Nuclear Medicine vol 50 no 8 pp 1214ndash1221 2009
[185] L K Anzola-Fuentes M Chianelli F Galli et al ldquoSomatostatinreceptor scintigraphy in patients with rheumatoid arthritis andsecondary Sjogrenrsquos syndrome treated with Infliximab a pilotstudyrdquo EJNMMI Research vol 6 no 1 article no 49 2016
[186] T Nobashi Y Nakamoto T Kubo et al ldquoThe utility of PETCTwith 68Ga-DOTATOC in sarcoidosis comparison with 67Ga-scintigraphyrdquoAnnals ofNuclearMedicine vol 30 no 8 pp 544ndash552 2016
[187] C Boy T A Heusner T D Poeppel et al ldquo68Ga-DOTATOCPETCT and somatostatin receptor (sst1-sst5) expression innormal human tissue Correlation of sst2mRNAand SUVmaxrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 38 no 7 pp 1224ndash1236 2011
[188] P Rinne S Hellberg M Kiugel et al ldquoComparison of Somato-statin Receptor 2-Targeting PET Tracers in the Detection ofMouse Atherosclerotic Plaquesrdquo Molecular Imaging and Biol-ogy vol 18 no 1 pp 99ndash108 2016
[189] M Asti E Ferrari S Croci et al ldquoSynthesis and characteri-zation of 68Ga-labeled curcumin and curcuminoid complexesas potential radiotracers for imaging of cancer and alzheimersdiseaserdquo Inorganic Chemistry vol 53 no 10 pp 4922ndash49332014
[190] A Signore I Santino and A W J M Glaudemans ldquoIn vivoimaging of microorganismsrdquo Clinical and Translational Imag-ing vol 4 no 3 pp 161-162 2016
[191] S Auletta F Galli C Lauri D Martinelli I Santino andA Signore ldquoImaging bacteria with radiolabelled quinolones
22 Contrast Media amp Molecular Imaging
cephalosporins and siderophores for imaging infection a sys-tematic reviewrdquo Clinical and Translational Imaging vol 4 no 4pp 229ndash252 2016
[192] X Ning S Lee Z Wang et al ldquoMaltodextrin-based imagingprobes detect bacteria in vivo with high sensitivity and speci-ficityrdquo Nature Materials vol 10 no 8 pp 602ndash607 2011
[193] J Ady andY Fong ldquoImaging for infection Fromvisualization ofinflammation to visualization of microbesrdquo Surgical Infectionsvol 15 no 6 pp 700ndash707 2014
[194] J M Sierra D Rodriguez-Puig A Soriano J Mensa C Pieraand J Vila ldquoAccumulation of 99mTc-ciprofloxacin in Staphy-lococcus aureus and Pseudomonas aeruginosardquo AntimicrobialAgents and Chemotherapy vol 52 no 7 pp 2691-2692 2008
[195] D I Andersson and D Hughes ldquoMicrobiological effects ofsublethal levels of antibioticsrdquoNature ReviewsMicrobiology vol12 no 7 pp 465ndash478 2014
[196] N Dumarey D Blocklet T Appelboom L Tant and ASchoutens ldquoInfecton is not specific for bacterial osteo-articularinfective pathologyrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 29 no 4 pp 530ndash535 2002
[197] K E Britton D W Wareham S S Das et al ldquoImaging bacte-rial infection with 99mTc-ciprofloxacin (Infecton)rdquo Journal ofClinical Pathology vol 55 no 11 pp 817ndash823 2002
[198] G Ferro-Flores M A Avila-Rodrıguez and F O Garcıa-PerezldquoImaging of bacteria with radiolabeled ubiquicidin by SPECTand PET techniquesrdquo Clinical and Translational Imaging vol 4no 3 pp 175ndash182 2016
[199] P S Hiemstra M T van den Barselaar M Roest P H Nibber-ing and R van Furth ldquoUbiquicidin a novel murine microbi-cidal protein present in the cytosolic fraction of macrophagesrdquoJournal of Leukocyte Biology vol 66 no 3 pp 423ndash428 1999
[200] M S Akhtar A Qaisar J Irfanullah et al ldquoAntimicrobialpeptide 99mTc-ubiquicidin 29ndash41 as human infection-imagingagent clinical trialrdquo Journal of Nuclear Medicne vol 46 no 4pp 567ndash573 2005
[201] M Assadi K Vahdat I Nabipour et al ldquoDiagnostic value of99mTc-ubiquicidin scintigraphy for osteomyelitis and compar-isons with 99mTc-methylene diphosphonate scintigraphy andmagnetic resonance imagingrdquo Nuclear Medicine Communica-tions vol 32 no 8 pp 716ndash723 2011
[202] T Emery ldquoExchange of Iron by Gallium in SiderophoresrdquoBiochemistry vol 25 no 16 pp 4629ndash4633 1986
[203] M Petrik C Zhai H Haas and C Decristoforo ldquoSiderophoresfor molecular imaging applicationsrdquo Clinical and TranslationalImaging vol 5 no 1 pp 15ndash27 2017
[204] H J Flint E A BayerM T Rincon R Lamed and B AWhiteldquoPolysaccharide utilization by gut bacteria potential for newinsights from genomic analysisrdquo Nature Reviews Microbiologyvol 6 no 2 pp 121ndash131 2008
[205] GGowrishankarMNamavari E B Jouannot et al ldquoInvestiga-tion of 6-[18F]-fluoromaltose as a novel PET tracer for imagingbacterial infectionrdquo PLoS ONE vol 9 no 9 Article ID e1079512014
[206] N Gholipour M Akhlaghi A M Kheirabadi et al ldquoChelator-free radiolabeling of dextran with 68Ga for PET studiesrdquoJournal of Radioanalytical and Nuclear Chemistry vol 311 no3 pp 1811ndash1817 2017
[207] C Bettegowda C A Foss I Cheong et al ldquoImaging bac-terial infections with radiolabeled 1-(21015840-deoxy-21015840- fluoro-120573-D-arabinofuranosyl)-5-iodouracilrdquo Proceedings of the NationalAcadamy of Sciences of the United States of America vol 102 no4 pp 1145ndash1150 2005
[208] S A Soghomonyan M Doubrovin J Pike et al ldquoPositronemission tomography (PET) imaging of tumor-localizedSalmonella expressing HSV1-TKrdquo Cancer GeneTherapy vol 12no 1 pp 101ndash108 2005
[209] C Palestro K Nichols S Sheikh-Fayyaz S Dewey P Singhaland K Bhargava ldquoCan Gallium-68 PET differentiate acuteinterstitial nephritis from acute tubular necrosisrdquo Journal ofNuclear Medicne vol 57 Supplement 2 p 551 2016
[210] A J Morguet D L Munz V Ivancevic et al ldquoImmunoscintig-raphy using technetium-99m-labeled anti-NCA-95 antigranu-locyte antibodies as an adjunct to echocardiography in subacuteinfective endocarditisrdquo Journal of the American College ofCardiology vol 23 no 5 pp 1171ndash1178 1994
[211] C van der Laken O Boerman W Oyen et al ldquoIn Vivo Expres-sion of Interleukin-1 Receptors during Various ExperimentallyInduced Inflammatory Conditionsrdquo The Journal of InfectiousDiseases vol 177 no 5 pp 1398ndash1401 1998
[212] C J Van Der Laken O C Boerman W J G Oyen M T PVan De Ven J W M Van Der Meer and F H M CorstensldquoScintigraphic detection of infection and inflammation Newdevelopments with special emphasis on receptor interactionrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 25 no 5 pp 535ndash546 1998
[213] C J van der LakenOC BoermanW J GOyenM T P van deVen J W M van der Meer and F H M Corstens ldquoImaging ofinfection in rabbits with radioiodinated interleukin-1 (120572 and 120573)its receptor antagonist and a chemotactic peptide a comparativestudyrdquo European Journal of Nuclear Medicine and MolecularImaging vol 25 no 4 pp 347ndash352 1998
[214] C J Van Der Laken O C BoermanW J G Oyen M T P VanDe Ven F H M Corstens and J W M Ven Der Meer ldquoThekinetics of radiolabelled interleukin-8 in infection and sterileinflammationrdquo Nuclear Medicine Communications vol 19 no3 pp 271ndash282 1998
[215] E Lazzeri P Erba M Perri et al ldquoScintigraphic imaging ofvertebral osteomyelitis with 111in-biotinrdquoThe Spine Journal vol33 no 7 pp E198ndashE204 2008
[216] E Blom B Langstrom and I Velikyan ldquo68Ga-labeling of biotinanalogues and their characterizationrdquo Bioconjugate Chemistryvol 20 no 6 pp 1146ndash1151 2009
[217] O Eriksson F Carlsson E Blom et al ldquoPreclinical evaluationof a 68Ga-labeled biotin analogue for applications in islettransplantationrdquo Nuclear Medicine and Biology vol 39 no 3pp 415ndash421 2012
[218] E A Weinstein A A Ordonez V P DeMarco et alldquoImaging Enterobacteriaceae infection in vivo with 18F-fluoro-deoxysorbitol positron emission tomographyrdquo Science Transla-tional Medicine vol 6 no 259 p 259ra146 2014
[219] K M Nielsen M H Kyneb A K O Alstrup et alldquo68Ga-labeled phage-display selected peptides as tracers forpositron emission tomography imaging of Staphylococcusaureus biofilm-associated infections Selection radiolabellingand preliminary biological evaluationrdquo Nuclear Medicine andBiology vol 43 no 10 pp 593ndash605 2016
[220] T J Makinen P Lankinen T Poyhonen J Jalava H T Aroand A Roivainen ldquoComparison of 18F-FDG and 68Ga PETimaging in the assessment of experimental osteomyelitis due toStaphylococcus aureusrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 32 no 11 pp 1259ndash1268 2005
[221] JMU Silvola I LaitinenH J Sipila et al ldquoUptake of 68galliumin atherosclerotic plaques in LDLRminusminusApoB100100micerdquo EJN-MMI Research vol 1 no 1 pp 1ndash8 2011
Contrast Media amp Molecular Imaging 23
[222] T A Wynn ldquoCellular and molecular mechanisms of fibrosisrdquoThe Journal of Pathology vol 214 no 2 pp 199ndash210 2008
[223] T Derlin D Jonigk J Bauersachs and FM Bengel ldquoMolecularImaging of Chemokine Receptor CXCR4 in NonndashSmall CellLung Cancer Using 68Ga-Pentixafor PETCT ComparisonWith 18F-FDGrdquo Clinical Nuclear Medicine 2016
[224] I Velikyan U Rosenstrom T N Bulenga O Eriksson andG Antoni ldquoFeasibility of multiple examinations using68ga-labelled collagelin analogues Organ distribution in rat forextrapolation to human organ and whole-body radiationdosimetryrdquo Pharmaceuticals vol 9 no 2 article no 31 2016
[225] S Jadhav M Kakela J Makila et al ldquoSynthesis and in VivoPET Imaging of Hyaluronan Conjugates of OligonucleotidesrdquoBioconjugate Chemistry vol 27 no 2 pp 391ndash403 2016
[226] A Autio A Saraste N Kudomi et al ldquoAssessment of bloodflow with (68) Ga-DOTA PET in experimental inflammation avalidation study using (15) O-waterrdquo American Journal ofNuclear Medicine and Molecular Imaging vol 4 no 6 pp 571ndash579 2014
[227] G Davies A Rolle A Maurer et al ldquoTowards translationalimmunoPETMR imaging of invasive pulmonary aspergillosisthe Humanised Monoclonal Antibody JF5 detects in vivordquoTheranostics vol 7 no 14 pp 3398ndash3414 2017
[228] DGoodwin CMeares GDavid et al ldquoMonoclonal antibodiesas reversible equilibrium carriers of radiopharmaceuticalsrdquoInternational Journal of Radiation Applications and Instrumen-tation Part B Nuclear Medicine and Biology vol 13 no 4 pp383ndash391 1986
[229] D A Goodwin C F Mears M McTigue and G S DavidldquoMonoclonal antibody hapten radiopharmaceutical deliveryrdquoNuclear Medicine Communications vol 7 no 8 pp 569ndash5801986
[230] S E Halpern and R O Dillman ldquoProblems associated withradioimmunodetection and possibilities for future solutionsrdquo JBiol Response Mod vol 6 no 3 pp 235ndash262 1987
[231] H Hong J Sun and W Cai ldquoRadionuclide-based cancerimaging targeting the carcinoembryonic antigenrdquo BiomarkerInsights vol 3 pp 435ndash451 2008
[232] G J Forster E B Santos P M Smith-Jones P Zanzonico andS M Larson ldquoPretargeted radioimmunotherapy with a single-chain antibodystreptavidin construct and radiolabeledDOTA-biotin Strategies for reduction of the renal doserdquo Journal ofNuclear Medicine vol 47 no 1 pp 140ndash149 2006
[233] Z Yao M Zhang H Kobayashi et al ldquoImproved targeting ofradiolabeled streptavidin in tumors pretargeted with biotiny-lated monoclonal antibodies through an avidin chaserdquo Journalof Nuclear Medicine vol 36 no 5 pp 837ndash841 1995
[234] C-H Chang R M Sharkey E A Rossi et al ldquoMolecularAdvances in Pretargeting Radioimunotherapy with BispecificAntibodies 1 Supported in part by USPHS Grant R01-CA-84379from the NIH and Department of Energy Grant DE-FG01-00NE22941 (both to R M S)1rdquo Mol Cancer Ther vol 1 no 7pp 553ndash563 2002
[235] R M Sharkey E A Rossi W J McBride C-H Chang andD M Goldenberg ldquoRecombinant Bispecific Monoclonal Anti-bodies Prepared by theDock-and-Lock Strategy for PretargetedRadioimmunotherapyrdquo Seminars in Nuclear Medicine vol 40no 3 pp 190ndash203 2010
[236] R M Sharkey E A Rossi C-H Chang and D M Golden-berg ldquoImproved cancer therapy and molecular imaging withmultivalent multispecific antibodiesrdquo Cancer Biotherapy andRadiopharmaceuticals vol 25 no 1 pp 1ndash12 2010
[237] D M Goldenberg R M Sharkey G Paganelli J Barbet andJ Chatal ldquoAntibody pretargeting advances cancer radioim-munodetection and radioimmunotherapyrdquo Journal of ClinicalOncology vol 24 no 5 pp 823ndash834 2006
[238] O C Boerman F G van Schaijk W J G Oyen and FH M Corstens ldquoPretargeted radioimmunotherapy of cancerprogress step by steprdquo Journal of Nuclear Medicine vol 44 no3 pp 400ndash411 2003
[239] J Schuhmacher S Kaul G Klivenyi et al ldquoImmunoscintigra-phy with positron emission tomography Gallium-68 chelateimaging of breast cancer pretargeted with bispecific anti-MUC1anti-Ga chelate antibodiesrdquo Cancer Research vol 61 no9 pp 3712ndash3717 2001
[240] J Schuhmacher G Klivenyi S Kaul et al ldquoPretargeting ofhuman mammary carcinoma xenografts with bispecific anti-MUC1anti-Ga chelate antibodies and immunoscintigraphywith PETrdquo Nuclear Medicine and Biology vol 28 no 7 pp 821ndash828 2001
[241] C Somasundaram S Matzku J Schuhmacher and M ZollerldquoDevelopment of a bispecific monoclonal antibody against agallium-67 chelate and the human melanoma-associated anti-gen p97 for potential use in pretargeted immunoscintigraphyrdquoCancer Immunology Immunotherapy vol 36 no 5 pp 337ndash3451993
[242] E A Rossi D L Rossi R Stein D M Goldenberg and C-H Chang ldquoA bispecific antibody-IFN1205722b immunocytokine tar-geting CD20 and HLA-DR is highly toxic to human lymphomaandmultiplemyeloma cellsrdquoCancer Research vol 70 no 19 pp7600ndash7609 2010
[243] R M Sharkey H Karacay S Litwin et al ldquoImproved ther-apeutic results by pretargeted radioimmunotherapy of non-Hodgkinrsquos lymphoma with a new recombinant trivalent anti-CD20 bispecific antibodyrdquo Cancer Research vol 68 no 13 pp5282ndash5290 2008
[244] G L Griffiths C-H Chang W J McBride et al ldquoReagentsandmethods for PETusing bispecific antibody pretargeting and68Ga-radiolabeled bivalent hapten-peptide-chelate conjugatesrdquoJournal of Nuclear Medicine vol 45 no 1 pp 30ndash39 2004
[245] J Watine M Miedouge and B Friedberg ldquoCarcinoembryonicantigen as an independent prognostic factor of recurrence andsurvival in patients resected for colorectal liver metastases Asystematic reviewrdquo Diseases of the Colon amp Rectum vol 44 no12 pp 1791ndash1799 2001
[246] M J Goldstein and E P Mitchell ldquoCarcinoembryonic antigenin the staging and follow-up of patients with colorectal cancerrdquoCancer Investigation vol 23 no 4 pp 338ndash351 2005
[247] D V Gold D M Goldenberg H Karacay et al ldquoA novelbispecific trivalent antibody construct for targeting pancreaticcarcinomardquo Cancer Research vol 68 no 12 pp 4819ndash48262008
[248] J Schuhmacher G Klivenyi R Matys et al ldquoMultistep tumortargeting in nudemice using bispecific antibodies and a galliumchelate suitable for immunoscintigraphy with positron emis-sion tomographyrdquo Cancer Research vol 55 no 1 pp 115ndash1231995
[249] G Klivenyi J Schuhmacher E Patzelt et al ldquoGallium-68chelate imaging of human colon carcinoma xenografts pre-targeted with bispecific anti-CD44(V6)anti-gallium chelateantibodiesrdquo Journal ofNuclearMedicine vol 39 no 10 pp 1769ndash1776 1998
[250] M Zoller J Schuhmacher J Reed W Maier-Borst and SMatzku ldquoEstablishment and characterization of monoclonal
24 Contrast Media amp Molecular Imaging
antibodies against an octahedral gallium chelate suitable forimmunoscintigraphy with PETrdquo Journal of Nuclear Medicinevol 33 no 7 pp 1366ndash1372 1992
[251] R M Sharkey T M Cardillo E A Rossi et al ldquoSignal ampli-fication in molecular imaging by pretargeting a multivalentbispecific antibodyrdquo Nature Medicine vol 11 no 11 pp 1250ndash1255 2005
[252] D M Goldenberg and R M Sharkey ldquoNovel radiolabeledantibody conjugatesrdquo Oncogene vol 26 no 25 pp 3734ndash37442007
[253] D M Goldenberg E A Rossi R M Sharkey W J McBrideand C-H Chang ldquoMultifunctional antibodies by the dock-and-lock method for improved cancer imaging and therapy bypretargetingrdquo Journal of NuclearMedicine vol 49 no 1 pp 158ndash163 2008
[254] R Schoffelen R M Sharkey D M Goldenberg et al ldquoPre-targeted immuno-positron emission tomography imaging ofcarcinoembryonic antigen-expressing tumors with a bispecificantibody and a68Ga- And18F-labeled hapten peptide in micewith human tumor xenograftsrdquoMolecular Cancer Therapeuticsvol 9 no 4 pp 1019ndash1027 2010
[255] E S Bos W H Kuijpers M Meesters-Winters et al ldquoIn vitroevaluation of DNA-DNA hybridization as a two-step approachin radioimmunotherapy of cancerrdquoCancer Research vol 54 no13 pp 3479ndash3486 1994
[256] G Paganelli M Bartolomei M Ferrari et al ldquoPre-TargetedLocoregional Radioimmunotherapy withrdquo Cancer biotherapyand radiopharmaceuticals vol 16 no 3 pp 227ndash235 2001
[257] A Forero P L Weiden J M Vose et al ldquoPhase 1 trial of a novelanti-CD20 fusion protein in pretargeted radioimmunotherapyfor B-cell non-Hodgkin lymphomardquo Blood vol 104 no 1 pp227ndash236 2004
[258] DM Goldenberg C-H Chang E A RossiW J McBride andR M Sharkey ldquoPretargeted molecular imaging and radioim-munotherapyrdquoTheranostics vol 2 no 5 pp 523ndash540 2012
[259] H Karacay R M Sharkey W J McBride E A Rossi C-HChang and D M Goldenberg ldquoOptimization of hapten-peptide labeling for pretargeted immunoPET of bispecificantibody using generator-produced 68Gardquo Journal of NuclearMedicine vol 52 no 4 pp 555ndash559 2011
[260] J R Oh and B C Ahn ldquoFalse-positive uptake on radioiodinewhole-body scintigraphy physiologic and pathologic variantsunrelated to thyroid cancerrdquo American Journal of NuclearMedicine and Molecular Imaging vol 2 no 2 pp 141ndash150 2012
[261] E Frampas C Rousseau C Bodet-Milin J Barbet J-F Chataland F Kraeber-Bodere ldquoImprovement of radioimmunotherapyusing pretargetingrdquo Frontiers in Oncology vol 3 Article ID00159 2013
[262] C S McKay and M G Finn ldquoClick chemistry in complexmixtures Bioorthogonal bioconjugationrdquo Chemistry amp Biologyvol 21 no 9 pp 1075ndash1101 2014
[263] B L Oliveira Z Guo and G J Bernardes ldquoInverse electrondemand DielsndashAlder reactions in chemical biologyrdquo ChemicalSociety Reviews vol 46 no 16 pp 4895ndash4950 2017
[264] B Nichols Z Qin J Yang D R Vera and N K Devaraj ldquo68Gachelating bioorthogonal tetrazine polymers for the multisteplabeling of cancer biomarkersrdquo Chemical Communications vol50 no 40 pp 5215ndash5217 2014
[265] R Rossin P R Verkerk S M van den Bosch et al ldquoInvivo chemistry for pretargeted tumor imaging in live micerdquoAngewandte Chemie International Edition vol 49 no 19 pp3375ndash3378 2010
[266] B M Zeglis K K Sevak T Reiner et al ldquoA pretargetedPET imaging strategy based on bioorthogonal diels-alder clickchemistryrdquo Journal of Nuclear Medicine vol 54 no 8 pp 1389ndash1396 2013
[267] J L Houghton R Membreno D Abdel-Atti et al ldquoEstablish-ment of the invivo efficacy of pretargeted radioimmunotherapyutilizing inverse electron demand diels-alder click chemistryrdquoMolecular Cancer Therapeutics vol 16 no 1 pp 124ndash133 2017
[268] J Funkhouser ldquoReinventing pharma the theranostic revolu-tionrdquo Current Drug Discovery pp 17ndash19 2002
[269] J Sorensen I Velikyan A Wennborg et al ldquoMeasuring HER2-expression in metastatic breast cancer using 68Ga-ABY025PETCTrdquo European Journal of Nuclear Medicine and MolecularImaging vol 41 pp S226ndashS226 2014
[270] I Velikyan A Wennborg J Feldwisch et al ldquoGMP compliantpreparation of a 68Gallium-labeled Affibody analogue forbreast cancer patient examination first-in-manrdquoEur JNuclMedMol Imaging vol 41 pp S228ndashS229 2014
[271] K Oberg ldquoMolecular imaging radiotherapy Theranostics forpersonalized patient management of neuroendocrine tumors(NETs)rdquoTheranostics vol 2 no 5 pp 448ndash458 2012
[272] I Velikyan AWennborg J FeldwischH Lindman J Carlssonand J Sorensen ldquoGood manufacturing practice production of [(68) Ga]Ga-ABY-025 for HER2 specific breast cancer imagingrdquoAmerican Journal of Nuclear Medicine and Molecular Imagingvol 6 no 2 pp 135ndash153 2016
[273] M Sandstrom K Lindskog I Velikyan et al ldquoBiodistributionand radiation dosimetry of the anti-HER2 Affibody molecule68Ga-ABY-025 in breast cancer patientsrdquo Journal of NuclearMedicine vol 57 no 6 pp 867ndash871 2016
[274] D Sandberg V Tolmachev I Velikyan et al ldquoIntra-imagereferencing for simplified assessment of HER2-expression inbreast cancer metastases using the Affibody molecule ABY-025with PET and SPECTrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 44 no 8 pp 1337ndash1346 2017
[275] H ZhangM AMoroz I Serganova et al ldquoImaging expressionof the human somatostatin receptor subtype-2 reporter genewith 68Ga-DOTATOCrdquo Journal ofNuclearMedicine vol 52 no1 pp 123ndash131 2011
[276] M Naji and A Al-Nahhas ldquo68Ga-labelled peptides in themanagement of neuroectodermal tumoursrdquo European Journalof Nuclear Medicine and Molecular Imaging vol 39 no 1 ppS61ndashS67 2012
[277] I Velikyan ldquoThe diversity of 68Ga-Based imaging agentsrdquoRecent Results in Cancer Research vol 194 pp 101ndash131 2013
[278] K Ferreira H-Y Hu V Fetz et al ldquoMultivalent siderophore-dotam conjugates as theranostics for imaging and treatment ofbacterial infectionsrdquo Angewandte Chemie International Editionvol 56 no 28 pp 8272ndash8276 2017
E-selectin binding peptide labelled with 99mTc accumu-lated in acute osteomyelitic lesions in rats presumably byinteraction with activated vascular endothelium [132] Ananalogue of P-selectin natural ligand fucoidan labelled with68Ga could discriminate active and inactive atheroschleroticplaques in mice [44]
54 Targeting Vascular Adhesion Protein-1 Vascular adhe-sion protein-1 (VAP-1) and CD73 are endothelial surfaceenzymes involved in the recruitment of leukocytes and theirmovement from the blood into the tissue [109] Endothelialactivation that takes place during inflammation can be uti-lized for specific targeting imaging Several peptide analogues
Contrast Media amp Molecular Imaging 7
300
250
200
150
100
50
0
(kBq
ml)
Inflammation
Kidneys
Muscle
Inflammation
Kidneys
Muscle
Figure 1 PET images of the distribution of [68Ga]Ga-DOTAVAP-P1 [68Ga]Ga-DOTAVAP-PEG-P1 and [68Ga]Ga-DOTA-Siglec-9 inturpentine-induced rat model of sterile inflammation All three peptide analogues showed target-to-nontarget ratio above 6 with rapidaccumulation in the inflammation site and renal clearance Adapted from [57]
labelledwith 68Gawere designed for the visualization ofVAP-1 and showed promising results in animals with inducedinfection and sterile inflammation [7ndash13 133] The bindingwas proven specific and it was possible to differentiate inflam-mation from infection [68Ga]Ga-Siglec targeting VAP-1demonstrated preclinical potential for imaging of synovialinflammation in patients with rheumatic diseases [53] Thesame agent was utilized for respiratory distress syndrome(ARDS an inflammatory lung injury) imaging in a porcinemodel [54] Imaging VAP-1 with [68Ga]Ga-Siglec was foundpromising also for the detection of inflamed atheroscle-rotic lesions [55] and inflammatory response induced bycatheter implantation and staphylococcal infection [56]68Ga-Siglec and two more peptide analogues with affinityto VAP-1 ([68Ga]Ga-DOTAVAP-P1 [68Ga]Ga-DOTAVAP-PEG-P1 and [68Ga]Ga-DOTA-Siglec-9) were investigated inrat model of sterile skinmuscle inflammation (Figure 1) [57]They showed distinct uptake in the affected sites
55 Targeting Chemokines Cytokines are produced bymacrophages B-lymphocytes T-lymphocytes and mast cellsand act through receptors modulating for example immuneresponse to infection and inflammation Cytokines includechemokines interleukins interferons and lymphokines thatcan be classified in broad families exhibiting diverse func-tions for example IL-1 and IL-6 superfamilies and TNFTNFreceptor superfamily Therapeutics targeting cytokines are inclinical use for example inhibiting TNF or IL-6 in rheumaticdiseases
Chemokine receptors are physiologically expressed onB-lymphocytes T-lymphocytes macrophages neutrophilseosinophils monocytes and hematopoietic stem cells [134]Imaging agents targeting CXCR4 are based on inhibitors(AMD3100) or small peptides (NFB T140 pentixafor andTN14003) and comprise 18F 67Ga 68Ga or 64Cu [135ndash148] They were developed and studied for the imaging of
various cancerous diseases lung breast prostate cancersacute myeloid leukemia and glioblastoma
The application of CXCR4 targeting agents was extendedbeyond oncology Clinical caseimage reports [149 150]were published on the utilization of [68Ga]Ga-pentixafor fordetection and quantification of CXCR4 receptor density inischemic heart diseases reflecting the role of the receptorin inflammatory and progenitor cell recruitment [58 59]The same agent was successfully used in the assessment ofmacrophage infiltration in atherosclerotic plaques in rabbitdisease model [151]
56 Targeting Folate Receptors Folate receptors (FRs) areoverexpressed on a variety of cancer cells and activatedmacrophages but not on normal cells [152 153] Theenhanced expression of FR was found in lung macrophagesduring acute inflammation [154] The majority of the nuclearimaging agents based on folic acid or pteroic acid [155] weredeveloped for diagnosis of cancers overexpressing FR recep-tors such as breast cervical ovarian colorectal nasopharyn-geal renal and endometrial cancers Various 68Ga-labelledagents demonstrated accumulation in cell cultures and micebearing folate-receptor positive human nasopharyngeal car-cinoma cell line (KB) xenografts [6 156ndash162] [68Ga]Ga-DOTA-PEG-FA comprising folic acid was investigated forthe detection and quantification of inflammatory response tomedical implants using mice with subcutaneously implantedpolylactic acid and poly(N-isopropylacrylamide) particles asa model [60] The agent was accumulated in the area of theimplant most probably reflecting interaction of [68Ga]Ga-DOTA-PEG-FA with folate receptor expressed on activatedmacrophages Another folic acid based agent [68Ga]Ga-DOTA-folate was successfully tested in an inflammatory pawrat model (Figure 2) [61] Distinct accumulation in inflamedhand and foot joints of rheumatoid arthritis of a 99mTc-labelled folate analogue was observed in a patient while no
8 Contrast Media amp Molecular Imaging
NH ONHONH
OOO
HOHN O
HN
NN
N N
HO
O
N
N
O
O
N
N
O
O
O
Ga+
minus
（3
(a)
2
15
1
05
0
(b)
Figure 2 Accumulation of [68Ga]Ga-DOTA-folate (a) in the site of inflammation of rat inflammatory pawmodel induced by subcutaneouslyinjected Complete Freundrsquos Adjuvant (b) Adapted from [61]
4
2
0
Figure 3 Intense atherosclerotic inflammation (white arrows) was detected by [68Ga]Ga-DOTA-TATE in a patient with acute coronarysyndrome Adapted from [65]
uptake was detected in a nonarthritis patientrsquos hands and feet[163]
57 Targeting Somatostatin Receptors Somatostatin receptor(SSTR) ligand analogues have found an extensive appli-cation in diagnosis and radiotherapy of neuroendocrinetumours The elevated expression of SSTRs is known also insmall cell lung cancer breast cancer renal cell carcinomaprostate cancer and malignant lymphoma A number ofsomatostatin ligand analogues labelled with gamma- andpositron-emitting radionuclides were used clinically foroncological cases [85 164ndash174] 68Ga-labelled somatostatinanalogues demonstrated superior performance in terms ofhigher specificity and sensitivity detection rate shorterexamination time and quantification possibility and havebecome a golden standard for the detection of neuroen-docrine tumours (NETs) taking over that title from [111In]-pentetreotide (OctreoScan) and demonstrating specificityand sensitivity of over 90 [27 175ndash180] 68Ga-labelledagents for the imaging of NETs demonstrated advantages
also over other radionuclides and tracers such as [18F]FDG[174] 123I-metaiodobenzylguanidine ([123I]MIBG) [181 182][18F]DOPA [183] [99mTc]-dicarboxy propane diphosphonate[184] and [18F]NaF
SSTR are also overexpressed on activated macrophagesand T-lymphocytes 68Ga-labelled analogues were used ininflammation related diseases such as idiopathic pulmonaryfibrosis [62] Gravesrsquo and Hashimotorsquos diseases [63] coro-nary artery plaque imaging and characterization [64] andatherosclerotic inflammation with excellent macrophagespecificity (Figure 3) [65] Promising diagnostic potential ofa 99mTc-labelled analogue was demonstrated in patients withrheumatoid arthritis and secondary Sjogrenrsquos syndrome andthe method was suggested for the assistance in anti-TNFalpha antibody treatment planning [185] [68Ga]Ga-DOTA-TOCPET-CT was found superior to 67Ga-CitrateSPECT indetection of sarcoidosis lesions [186] A clinical study demon-strated correlation between uptake of [68Ga]Ga-DOTA-TOCand SST2 mRNA expression and recorded the information ina database [187] providing tools for accurate quantification
Contrast Media amp Molecular Imaging 9
and evaluation of disease progression and treatment responsein cancerous and inflammatory diseases involving SSTRsPreclinical study using atherosclerotic mice demonstratedsuperior targeting properties of [68Ga]Ga-DOTA-NOC ascompared to [18F]FDR-NOC [188] overall confirming thepotential of SSTR targeting for atherosclerotic plaque imag-ing
58 Imaging Neuroinflammation Despite difficulty ofdesigning 68Ga-labelled molecules capable of blood-brainbarrier penetration several agents were suggested for theimaging of neuroinflammation in particular A120573 plaquesdeposited on blood vessels [67ndash69] Bivalent styrylpyridineslabelled with 68Ga demonstrated high specificity and affinityfor A120573 plaques using postmortem Alzheimerrsquos disease (AD)brain sections [67] Benzofuran derivative comprising 68Gashowed promising results in terms of binding specificityand affinity investigated in vitro in sections of Tg2576mice [68] Although the synthesis of a 68Ga-labelledPittsburgh compound analogue was successful the in vitrobinding to amyloid deposits was limited [69] The commondisadvantage of these agents is poor blood-brain barrierpenetration nevertheless the exploration of more successfulanalogues continues Curcumin functions as an antioxidantantimicrobial anti-inflammatory and anticancer agentDiacetyl-curcumin and bis(dehydroxy)curcumin labelledwith 68Ga demonstrated in vitro binding to 120573-amyloid fibrilsand lung cancer cells [189] Potential application of the agentscould include diagnostic imaging of Alzheimerrsquos disease andvarious cancers
6 Imaging Infection
Infection imaging can be indirect utilizing targets involvedin the immune response namely inflammation as presentedin the inflammation targets section above or direct utilizingpathogen related targets The direct imaging is especiallycrucial in cases where inflammatory response is absent Thedifference in biochemistry and structure between bacterialand human cells might exclude physiological uptake byhuman tissuemaking it easier tomeet the favorable character-istics of an imaging agent However discrimination betweenthe various infectious microorganisms pathogenic bacteriaand microbiota targeting specific bacteria type as well asdifficulty of accessing bacteria aggregated in a biofilm makesthe task very challenging [190 191] The specific targetingof infection would require accumulation of the radioactivesignal in the pathogen The radiolabelled targeting agentsfor infection can be roughly divided into several groupsantibiotics based antimicrobial protein and peptide basedsiderophore and other metabolisable compound based andantigen-specific antibodies and antibody fragments (Table 3)
61 Radiolabelled Antibiotics Antimicrobials act on the pro-cesses that are specific to microbes for example bacteria andfungi and thus corresponding imaging agents might distin-guish infection from inflammation [191] They might requireinternalization or may bind to the cell surface dependent on
their biological action mechanism [191ndash193] The possibilityof antibiotic resistance development exists also in the case ofimaging agents even though the amount of such agents wouldbe subnanomolar [194 195] Another complication is possiblenonspecific uptake of antibiotics based agents by leucocytes[196] Considerable number of various antibiotic analogueshave been labelled with 99mTc 111In 131I 11C and 18F[102] and evaluated preclinically and clinically with 99mTc-ciprofloxacin becoming a commercial product (Infecton) [21197 198] However the further improvement of specificityis desirable [191] Antibiotics are accessible and cheap andthey demonstrate high sensitivity [102 191] making thedevelopment of 68Ga-labelled analogues very attractive giventhe earlier mentioned advantages that 68Ga as a radionu-clide in combination with PET provides Two 68Ga-labelledanalogues based on ciprofloxacin demonstrated potential fordiscrimination between bacterial infection and inflammationin rats infected with Staphylococcus aureus [70]
62 Radiolabelled Antimicrobial Proteins and Peptides Anti-microbial proteins and peptides for example serprocidinscathelicidins and defensins produced by the cells of immunesystem target microbial membrane lipids and impose micro-bicidal effect [35 43] They present a large group of poten-tial candidates for microbial imaging including bacteriafungi parasites and viruses Antimicrobial peptides havedemonstrated higher specificity for infection than antibioticanalogues They accumulate at infection but not sterileinflammation sites The most thoroughly studied antimicro-bial peptide ubiquicidin UBI [29ndash41] labelled with 99mTc[199] demonstrated promising results in human clinical trials[200 201] It has the potential for quantification of viableinfecting microorganisms and consequently for monitoringthe efficacy of antimicrobial therapy in patients
Fragments of an antimicrobial peptide ubiquicidin con-jugated to NOTA and labelled with 68Ga [68Ga]Ga-NOTA-UBI29-41 and [68Ga]Ga-NOTA-UBI30-41 demonstratedpossibility for the distinction between infection and inflam-mation in a rabbit model [71 72] Antimicrobial peptidefragments GF-17 and RAWVAWR-NH2 of respectivelyhuman cathelicidin LL-37 andhuman lysozyme active againstE coli and S aureus were labelled with 68Ga and theirbiodistribution in normal rats demonstrated fast clearancefrom liver [75] Antimicrobial depsipeptide based agent[68Ga]Ga-DOTA-TBIA101 targeting bacterial lipopolysac-charides detected muscular E coli-infection in mice (Fig-ure 4) [73] The agent was also studied in healthy rabbitsand various disease model rabbits such as sterile inflam-mation Staphylococcus aureus infection andMycobacteriumtuberculosis [74] The clearance of [68Ga]Ga-DOTA-TBIA101from blood and normal tissue was fast and enhanced uptakein sterile inflammation and Mycobacterium tuberculosis siteswas observed The improvement of the bacterial selectivitywill require modification of the agent structure
63 Radiolabelled Siderophores Bacteria and fungi producevarious siderophores for harvesting iron which is essentialfor their survival and growth [34 98 191] Siderophores
10 Contrast Media amp Molecular Imaging
(a)
(b)
(c) (d)
(e)
Figure 4 Left panel presents maximum intensity projection images of [68Ga]Ga-DOTA-TBIA101 distribution in a healthy mouse (a) and amouse with muscular infection site (MIS) in the right hind muscle tissue (white arrows) Right panel presents coronal (c) sagittal (d) andaxial (e) images with uptake in theMIS (white arrow) and absence of the uptake in the contralateralmuscle tissue Ki and Bl stand respectivelyfor kidney and bladder Reproduced from [73]
can also play a critical role in the development of biofilmsby microbes They are low molecular weight compoundsspecifically chelating Fe(III) and Ga(III) can form stablecomplexes with them mimicking Fe(III) [202 203]
Desferri-triacetylfusarinine C (TAFC) and desferri-ferricrocin (FC) labelled with 68Ga were used for theimaging of invasive pulmonary aspergillosis (IPA) caused byAspergillus fumigatus [15] [68Ga]Ga-TAFC demonstratedsuperior characteristics in terms of specific target bindingmetabolic stability and fast blood clearance in a rat modelof A fumigatus infection Seven analogues were developedin another study with TAFC and ferrioxamine E (FOXE)showing favorable binding clearance elimination andstability characteristics [16] as well as lung uptake inrat of invasive aspergillosis model wherein the uptakeextent was correlated with disease severity [17] [68Ga]Ga-triacetylfusarinine C and [68Ga]Ga-ferrioxamine E wereinvestigated in rat model of A fumigatus and demonstratedrapid uptake in the lungs (Figure 5) [76]
64 Radiolabelled Metabolisable Agents Mammalian micro-biota consumes (poly)saccharides in particular maltose andmaltodextrins [204] The transport mechanism is specific
to bacteria and is absent in mammalian cells making itpossible to utilize these (poly)saccharides for imaging agentdevelopment Maltodextrin functionalized with a fluorescentdye was internalized through the bacteria-specific maltodex-trin transport pathway and discriminated between activebacteria and inflammation in vivo [192] Maltose labelledwith 18F localized specifically bacterial infection in mice[205] Potential to label polysaccharides directly with 68Gamight be utilized extensively
As mentioned above the chemical properties of Ga(III)provide the potential for direct labelling of polysaccharidesDextran was labelled directly and resulting complex demon-strated sufficient stability in human serum however thefeasibility of the bacterial imaging was not demonstrated[206]
Trapping of nucleosides that are substrates of thymidinekinase occurring within bacteria was explored using 18Fand 125I labelled analogues of uracil [207] Promising resultswere obtained in seven bacterial species in mice Anotherstudy in the context of therapeutic bacteria developmentdemonstrated possibility of detecting Salmonella vectorswithin tumours using 18F-labelled uracil [208] However
Contrast Media amp Molecular Imaging 11
N
O
N
ON
HN
O
O
O
OO O
NH
O
O
O
O
NH
O
OGa
（3
（3
（3
（3
（3
（3
（2
(a) (b) (c)
Figure 5 Molecular structure of [68Ga]Ga-triacetylfusarinine C (a) used for the in vivo imaging of a rat with Aspergillus fumigatus infection(b) and negative control of noninfected rat (c) White arrows point at the infected (b) and normal (c) lungs Adapted from [76]
the development of 68Ga-labelled nucleosides that wouldmaintain their biological activity is challenging and fewexamples known from the literature confirm that [4 6]
7 68Ga-Citrate
As mentioned above 68GaPET provides a number of advan-tages over 67GaSPECT and following publications demon-strate it in clinical and preclinical studies [68Ga]Ga-citratedemonstrated high diagnostic accuracy of 90of osteomyeli-tis and diskitis in clinical studies (Figure 6) [18 19] Thisstudy demonstrates that [68Ga]Ga-citrate can be employedfor monitoring the response to treatment [68Ga]Ga-citratewas used clinically to follow-up surgical intervention inpatients with acute osteomyelitis and intra-abdominal infec-tion [77] The agent was also used to successfully visualizelungmalignancy and tuberculosis in patients however in caseof high prevalence of granulomatous diseases the distinctionbetween malignant and benign lung lesions was unclear [7879] Another clinical study conducted head-to-head compar-ison of [68Ga]Ga-citrate (Figure 7) and [18F]FDG in patientswith Staphylococcus aureus bacteremia [80] The detectionrate of osteomyelitis was similar and further investigationof [68Ga]Ga-citrate applicability in cases of osteomyelitisinduced by other pathogens as well as for monitoring healingprocess is warranted
Comparative study of [68Ga]Ga-citrate and [67Ga]Ga-citrate was performed in healthy and infection model rats[77] The performance of [68Ga]Ga-citrate was found supe-rior in terms of image contrast in the lower abdomen and
extremities Potential of [68Ga]Ga-citrate for the differentia-tion of acute interstitial nephritis from acute tubular necrosiswas studied in rat model of the disease and it was demon-strated that the kidney uptake correlated with the extentof mononuclear cell infiltration accompanying inflammation[209] 68Ga-labelled Apo-transferrin demonstrated bacterialinfection detection capacity in rat model with Staphylococcusaureus wherein the infection site was visualized 1 h afteradministration of the agent [14]
71 Radiolabelled Antibodies and Antibody FragmentsHuman immunoglobulin (HIG) binds to bacteria but alsoaccumulates at the sites of fungal and viral infection aswell as sterile inflammation due to binding to leukocytesThe improved specificity for bacteria was achieved for thefragments of HIG It is feasible to develop specific antibodiesto various antigens present on the bacterial cell surface [102]Monoclonal antibodies labelled with 99mTc were used forinfection imaging via granulocytes targeting NCA-95 [210]Various cytokines of interleukin family (IL-1 IL-8) labelledwith 123I or 99mTc demonstrated accumulation in the sitesof infection in various animal models [111 112 211ndash214]Registered antigranulocyte radiopharmaceuticals suchas LeuTech Scintimun and Leukoscan are based on99mTc-labelled antibodies This experience can be translatedto 68Ga however either the size of the antibodies mustbe reduced or pretargeting techniques must be appliedin order to overcome the discrepancy between the shortphysical half-life of 68Ga and slow pharmacokinetics ofantibodies
12 Contrast Media amp Molecular Imaging
(a) (b) (c) (d)
Figure 6 [68Ga]Ga-citrate PETCT examination of a patient affected by acute osteomyelitis before (left panel) and after (right panel) surgicalcurettage showing uptake in the transaxial (a c) and 3D reconstruction images (b d red area) Absence of the uptake after the therapyconfirms complete response to the treatment Adapted from [19]
Figure 7 Vertebral osteomyelitis (spondylodiscitis red arrow-heads) and abscesses in the iliopsoas and paravertebral area (redarrows) were detected by [68Ga]Ga-citrate in a patient admittedto the hospital with back pain and general symptoms The PETacquisition was performed 88min after administration of 245MBqof [68Ga]Ga-citrate Adapted from [80]
72 Radiolabelled Biotin Biotin is a growth factor utilizedin many bacteria An 111In-labelled analogue of biotin wassuccessfully utilized for diagnosis of vertebral infections ina clinical study [215] It would be rational to explore therelevance of 68Ga-labelled analogues given the advantagesof 68Ga over 111In and promising [68Ga]Ga-DOTA-Biotinanalogues [216 217] developed for monitoring survival oftransplanted avidin-coated islets
8 Miscellaneous
Stable Ga(III) complex with thiosemicarbazones demon-strated antimicrobial effect against P aeruginosa and Calbicans due to most probably both displacement of essentialFe(III) with Ga(III) and thiosemicarbazones [101] Substitu-tion of the stable Ga(III) by radioactive 68Ga might result ina specific infection imaging agent
Selective imaging of Enterobacteriaceae using 2-[18F]-fluorodeoxysorbitol (18F-FDS)was demonstrated in amurine
myositis model [218] The uptake of 18F-FDS was correlatedwith bacterial burden moreover the agent differentiatedinfection from sterile inflammation Given the potential of68Ga for the labelling of small biologically active molecules[4] it might be plausible to develop a respective analoguewith added value of the advantages that 68Ga offers includingsimpler production chemistry lowered radiation dose repet-itive examination and accessibility at clinical centers withoutcyclotrons and remote from [18F]-FDG distribution sites Asmentioned above the poor access to bacteria aggregated ina biofilm might make the imaging task challenging Severalpeptide candidates with affinity for S aureus biofilm weredesigned and labelled with 68Ga [219] The resulting agentsdemonstrated binding in vitro however it was not possible toblock the binding with excess of the cold peptide
Ionic 68Ga was found superior to [18F]-FDG in infectiondetection in the rat model with diffuse osteomyelitis [220] Inanother study the uptake of ionic 68Ga was observed in theaortic plaques of atherosclerotic mice specifically at the sitesrich inmacrophages [221] However the slow blood clearanceof ionic 68Ga presents a limitation
Chronic inflammation is the major reason of fibro-sis [222] 68Ga-labelled SST analogue ([68Ga]Ga-DOTA-NOC) demonstrated uptake in pathogenic areas in patientsaffected by idiopathic pulmonary fibrosis with potentialfor monitoring response to treatment and drug develop-ment [62] Another clinical study using [68Ga]Ga-pentixaforalso showed potential of the agent for monitoring dis-ease activity and response to treatment in idiopathic pul-monary fibrosis [223] Peptide based agents CNO2A-PEG2-c[CPGRVMHGLHLGDDEGPC] and [68Ga]Ga-NODAGA-PEG2-c[CPGRVMHGLHLGDDEGPC] for the imaging andquantification of fibrosis by PET were developed and char-acterized preclinically showing fast clearance from normal
Contrast Media amp Molecular Imaging 13
tissue and blood and binding specificity [89] Dosimetrycalculations demonstrated possibility of six examinations peryear in humans assuring disease monitoring in longitudinalstudies and routine clinical setup [224]
Several hyaluronan conjugates of oligonucleotides target-ing CD44 positive cells were developed and tested in healthyrats sham-operated rats and rats with myocardial infarction[225]The uptake of the agents was higher for the latter groupand varied dependent on the difference in the oligonucleotidestructure
TLR2 and TLR4 expression levels in neutrophils werefound higher in individuals with bacterial and viral infectionsthan those in control samples There is a possibility that IL-4IL-8 IL-10 IL-12 and TNF-a might serve as biomarkers forinfections and that IL-2 IL-8 or IL-10 is potentially able todistinguish between bacterial and viral infections [22]
Mannosylated human serum albumin labelled with 68Gavia NOTA chelator moiety ([68Ga]Ga-NOTA-MSA) wastested in a rat model of myocarditis targetingmannose recep-tors expressed onmacrophages infiltratingmyocardium [66]The uptake in the diseased myocardium was considerablyhigher than that of the normal one and it was precludedby administration of excess of nonlabelled MSA indicatingbinding specificity The tracer build-up was also observed inthe organs of macrophage accumulation
[68Ga]Ga-DOTA was investigated for the quantificationof increased blood flow which is one of the key events ininflammation [226] The uptake kinetics of [68Ga]Ga-DOTAin the site of inflammation in rats with induced inflamma-tion correlated well with that of 15O-water suggesting highrelevance [68Ga]Ga-DOTA
9 Pretargeted Imaging
The half-life of 68Ga is shorter than that of 64Cu 67Ga 99mTc89Zr 111In and 123124125I and thus in contrast to the latterit is not compatible with slow pharmacokinetics of largemolecules such as antibodies and glycoproteins The rangeof antigen-specific antibodies relevant to inflammation andinfection is broad and a number of 99mTc-labelled antibodieswere used clinically [20 21 227] The respective range of68Ga-based agents could be similarThe solution to overcomethe incompatibility of half-life time frames could be eitherthe reduction of the antibody size or the application of thepretargeting concept
The history of the pretargeting concept spans threedecades predominantly in the field of oncology [228ndash230]It was developed to improve image contrast and dosimetryin immunoimaging and radioimmunotherapy when usingradiolabelled antibody ligands with slow pharmacokinetics[231] The arsenal of antibodies is vast and diverse encourag-ing extensive investment into development of techniques thatwould allow their exploration to the fullest Pretargeting con-siders at least two major steps wherein a functionalized anti-body is first administered for target localization and clearancefrom blood and normal tissue and thereafter a radiolabelledsmall molecule capable of binding to the functionalized
antibody due to high affinity or covalent interaction is admin-istered The key properties of the radiolabelled molecules arefast pharmacokinetic and clearance Several techniques havebeen developed for the realization of pretargeting conceptincluding avidinstreptavidin-biotin systems [216 217 232233] bispecific antibodies (bsmAb) with haptens [232 234ndash254] antibody-oligonucleotide conjugates with complemen-tary oligonucleotides [255] biorthogonal systems allowingcovalent chemical reactions in vivo (Figure 8)
The high affinity of biotin to avidin and streptavidinproteins was utilized clinically and preclinically in pretar-geting approach for the imaging and therapy of pancreaticadenocarcinoma [232] glioblastoma [256] and lymphoma[257] However this pretargeting technique may requirethree steps in order to eliminate the excess of antibody-(strept)avidin conjugate circulating in the blood and notbound to the target by adding clearing agent Anotherapplication of the technique was monitoring transplantationof islets of Langerhans in the treatment for type 1 diabetesmellitus wherein the cells or cellmimetics were conjugated to(strept)avidin prior to the transplantation [216 217] Severalanalogues of biotin comprising DOTA chelate moiety forlabelling with 68Ga and ethylene glycol linker of variouslength demonstrated the influence of the latter on the affinitytowards avidin
Particular example of hapten molecules is the ones com-prising histamine-succinyl-glycine (HSG) motif and chelatemoiety [251ndash253 258] for the complexationwith 68Ga Severalanalogues were developed for the imaging of carcinoem-bryonic antigen (CEA) pretargeted with anti-CEA bsmAb[254 259 260] and two clinical studies of medullary thyroidcarcinoma and breast carcinoma positive for CEA using68Ga-labelled hapten molecules and bsmAb were initiated[261]
Bioorthogonal reactions are fast regioselective requiringsmall reagent concentration and occurring under mild con-ditions often in aqueous solution and temperature below 37∘C[262 263] Amongst various biorthogonal reaction types thecycloaddition of tetrazines and various dienophiles referredto as inverse-electron-demandDiels-Alder (IEDDA) reactionis themost successful in the context of pretargeting Antibod-ies functionalized with trans-cyclooctene (TCO) and a radi-olabelled tetrazine that can interact in vivo based on IEDDAreaction were studied [264ndash267] In particular 68Ga-labelledtetrazine dextran demonstrated favorable pharmacokineticsin a healthy mouse [264] However the proof of concept is tobe performed in a xenografted animal Accumulation of anti-TAG72 [265] and anti-A33 [266] antibodies functionalizedwith TCO in mouse xenografts was visualized respectivelyby an 111In and 64Cu-labelled tetrazine analogues Anti-CA199 antibody-TCO in combination with 177Lu-labelledtetrazine demonstrated radiotherapeutic effect in pancreaticcancer murine model [267]
Thepretargeted imaging techniquesmay contribute to theexpansion of immuno-PET with 68Ga providing the intrinsicadvantages of 68Ga and PET As mentioned above mostof the developed radiolabelled counterparts of pretargetingtechniques have demonstrated promising results There are
14 Contrast Media amp Molecular Imaging
H
ON
NN
O
OO
OO
NH
NS
NH
ONH
O
HO
ONH
O
Ga
HN
NH
NH
O
OO
HNN
HN
NH
NH
O
OO
HNN
（2
(a)
NH
O
O
NH
N
NNGa
O O
O O
O
O
O
N N
NN
OO
（2
(b)
N
N
O
O
N
N
O
O
O
NH
O
O
ONH
NHS
O
H
HO
NH
+
minus
(c)
Figure 8 Schematic presentation of pretargeting techniques (a) bispecific antibodies engineered to specifically bind with radiolabelledhapten molecules (b) bioorthogonal click chemistry for fast and specific covalent binding between for example a trans-cyclooctenefunctionalized antibody and a radiolabelled tetrazine (c) interaction between antibody-(strept)avidin conjugate and radiolabelled biotinutilizing extremely high affinity of (strept)avidin and biotin
Contrast Media amp Molecular Imaging 15
a considerable number of potential antibody biomarkersthat could be considered for the imaging of infection andinflammation
10 Theranostics Potential
Theranostics [268] embraces realization of personalizedmedicine by conducting diagnosis on individual basis andproviding possibility of predicting the efficacy of a specifictreatment and following up the response to the treatmentenabling adjustment of the latter very early in the processIn the context of nuclear medicine wherein the radiophar-maceuticals targeted at biomarkers specific to a disease cancarry either diagnostic radionuclides or therapeutic ones theconcept can be denoted as radiotheranostics [28] The tar-geted molecular imaging such as PET can offer noninvasivediagnosis specific to the disease for example tumour-typespecific and provide accurate localization of the lesions Thestrongest advantage of PET is the potential for quantificationof the target for example receptor expression investigationof the uptake kinetics and estimation of the dosimetryThesecharacteristics of PET allow for individualized treatmentselection and planning monitoring of treatment responseand detection of recurrent diseaseThe individualized patientmanagement provides such advantages as optimization ofthe treatment regimen for the improved response and exclu-sion of futile treatments minimization of risks and toxicitywith overall outcome of reduced cost and patient distressThe importance of individualized patient management wasdemonstrated by clinical studies wherein the influence ofdose of the administered radiopharmaceutical targeted atreceptors overexpressed in cancer lesions on the diagnosticoutcome was investigated in the same patient [85 269270] 68Ga-labelled SST analogues [26ndash28 271] and Affibodymolecules [5 272ndash274] used respectively in NENs andbreast cancer patients are the most prominent examplesof (radio)theranostics involving 68GaPET wherein 68Ga-labelled analogues were used not only for localization of thelesions but also for staging patient stratification prognosistherapy selection and monitoring of the response to thetreatment of NETs and other cancer types [2ndash4 6 85 176275ndash277]
The methodology can be translated to inflammationand infection allowing for accurate and specific selection oftreatment regimen and for follow-up and evaluation of theresponse to therapy resulting in improved treatment efficacyand decreased cost and side effects The accommodation ofboth imaging function and antibiotic function in the samemolecule is a novel example of a theranostic agent [278]A series of siderophores conjugated with DOTA moiety forthe radiolabelling and with antibiotics for the treatmentof bacterial infection were investigated preclinically Theaccumulation of the intravenously administered ampicillinconjugate in the site of subcutaneously injected P aeruginosain mice was clearly and focally visualized within 06 h withretention for at least 24 h These results obtained usinganalogues carrying dye for optical imaging can be translatedto 68Ga-labelled counterparts for PET
11 Conclusions
The medical need for specific agents for noninvasive quan-titative and whole-body imaging of inflammation and infec-tion has not been met yet despite decades of research How-ever the prerequisites in terms of identification of potentialtargets design and synthesis of the respective ligands andimaging technologies are evolving very fast The potentialof accurate and quantitative lesion localization as well asmonitoring of the treatment response promises personalizedpatient management
The use of 68Ga in oncology is established proving thestrong potential of 68Ga for the promotion of PET technol-ogy for effective and efficient diagnostics and personalizedmedicineThe experience of oncological 68Ga-based agents isgetting translated to inflammation and infection Pretargetedimaging technology opens wide possibilities based on anti-body biomarkers
Conflicts of Interest
The author declares that there are no conflicts of interestregarding the publication of this article
References
[1] I Velikyan ldquoContinued rapid growth inGa applications update2013 to June 2014rdquo Journal of Labelled CompoundsampRadiophar-maceuticals pp 99ndash121 2015
[2] I Velikyan ldquo 68Ga-based radiopharmaceuticals Production andapplication relationshiprdquo Molecules vol 20 no 7 pp 12913ndash12943 2015
[3] M Fani P Peitl and I Velikyan ldquoCurrent status of radiophar-maceuticals for the theranostics of neuroendocrine neoplasmsrdquoPharmaceuticals vol 10 no 1 article no 30 2017
[4] I Velikyan ldquoPositron emitting [68Ga]Ga-based imaging agentsChemistry and diversityrdquoMedicinal Chemistry vol 7 no 5 pp345ndash379 2011
[5] J Sorensen I Velikyan D Sandberg et al ldquoMeasuringHER2-receptor expression in metastatic breast cancer using[68Ga]ABY-025 Affibody PETCTrdquo Theranostics vol 6 no 2pp 262ndash271 2016
[6] I Velikyan ldquoProspective of 68Ga-Radiopharmaceutical devel-opmentrdquoTheranostics vol 4 no 1 pp 47ndash80 2014
[7] P Lankinen T J Makinen T A Poyhonen et al ldquo68Ga-DOTAVAP-P1 PET imaging capable of demonstrating the phaseof inflammation in healing bones and the progress of infectionin osteomyelitic bonesrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 35 no 2 pp 352ndash364 2008
[8] T UjulaMHuttunen P Luoto et al ldquoMatrixmetalloproteinase9 targeting peptides Syntheses 68Ga-labeling and preliminaryevaluation in a rat melanoma xenograft modelrdquo BioconjugateChemistry vol 21 no 9 pp 1612ndash1621 2010
[9] A Autio T Ujula P Luoto S Salomaki S Jalkanen and ARoivainen ldquoPET imaging of inflammation and adenocarcinomaxenografts using vascular adhesion protein 1 targeting peptide68Ga-DOTAVAP-P1 Comparison with 18F-FDGrdquo EuropeanJournal of Nuclear Medicine and Molecular Imaging vol 37 no10 pp 1918ndash1925 2010
16 Contrast Media amp Molecular Imaging
[10] J Silvola A Autio P Luoto S Jalkanen andA Roivainen ldquoPre-liminary evaluation of novel 68Ga-DOTAVAP-PEG-P2 peptidetargeting vascular adhesion protein-1rdquo Clinical Physiology andFunctional Imaging vol 30 no 1 pp 75ndash78 2010
[11] T Ujula S Salomaki P Virsu et al ldquoSynthesis 68Ga labelingand preliminary evaluation of DOTA peptide binding vascularadhesion protein-1 a potential PET imaging agent for diagnos-ing osteomyelitisrdquo Nuclear Medicine and Biology vol 36 no 6pp 631ndash641 2009
[12] A Autio T Henttinen H J Sipila S Jalkanen and ARoivainen ldquoMini-PEG spacering of VAP-1-targeting 68Ga-DOTAVAP-P1 peptide improves PET imaging of inflamma-tionrdquo EJNMMI Research vol 1 no 1 pp 1ndash7 2011
[13] K Aalto A Autio E A Kiss et al ldquoSiglec-9 is a novel leukocyteligand for vascular adhesion protein-1 and can be used in PETimaging of inflammation and cancerrdquo Blood vol 118 no 13 pp3725ndash3733 2011
[14] V Kumar D K Boddeti S G Evans F Roesch and RHowman-Giles ldquoPotential use of 68Ga-apo-transferrin as a PETimaging agent for detecting Staphylococcus aureus infectionrdquoNuclear Medicine and Biology vol 38 no 3 pp 393ndash398 2011
[15] M Petrik H Haas G Dobrozemsky et al ldquo68Ga-siderophoresfor PET imaging of invasive pulmonary aspergillosis Proof ofprinciplerdquo Journal of Nuclear Medicine vol 51 no 4 pp 639ndash645 2010
[16] M Petrik H Haas M Schrettl A Helbok M Blatzer and CDecristoforo ldquoIn vitro and in vivo evaluation of selected 68Ga-siderophores for infection imagingrdquo Nuclear Medicine andBiology vol 39 no 3 pp 361ndash369 2012
[17] M Petrik GM Franssen H Haas et al ldquoPreclinical evaluationof two 68Ga-siderophores as potential radiopharmaceuticals forAspergillus fumigatus infection imagingrdquo European Journal ofNuclearMedicine andMolecular Imaging vol 39 no 7 pp 1175ndash1183 2012
[18] A Rizzello D Di Pierro F Lodi et al ldquoSynthesis and qualitycontrol of 68Ga citrate for routine clinical PETrdquo NuclearMedicine Communications vol 30 no 7 pp 542ndash545 2009
[19] C Nanni C Errani and L Boriani ldquo 68Ga-citrate PETCT forevaluating patients with infections of the bone preliminaryresultsrdquo Journal of Nuclear Medicine vol 51 no 12 pp 1932ndash1936 2010
[20] S S Das A V Hall D W Wareham and K E Britton ldquoInfec-tion imaging with radiopharmaceuticals in the 21st centuryrdquoBrazilian Archives of Biology and Technology vol 45 no spepp 25ndash37 2002
[21] A Signore and A W J M Glaudemans ldquoThe molecularimaging approach to image infections and inflammation bynuclear medicine techniquesrdquo Annals of Nuclear Medicine vol25 no 10 pp 681ndash700 2011
[22] T Yusa K Tateda A Ohara and S Miyazaki ldquoNew possiblebiomarkers for diagnosis of infections and diagnostic distinc-tion between bacterial and viral infections in childrenrdquo Journalof Infection and Chemotherapy vol 23 no 2 pp 96ndash100 2017
[23] A Signore A W J M Glaudemans O Gheysens C Lauriand O A Catalano ldquoNuclear Medicine Imaging in PediatricInfection or Chronic Inflammatory Diseasesrdquo Seminars inNuclear Medicine vol 47 no 3 pp 286ndash303 2017
[24] I Velikyan ldquoMolecular imaging and radiotherapyTheranosticsfor personalized patient managementrdquo Theranostics vol 2 no5 pp 424ndash426 2012
[25] F Rosch and R P Baum ldquoGenerator-based PET radiophar-maceuticals for molecular imaging of tumours On the way
to THERANOSTICSrdquo Dalton Transactions vol 40 no 23 pp6104ndash6111 2011
[26] R P Baum H R Kulkarni and C Carreras ldquoPeptides andreceptors in image-guided therapy Theranostics for neuroen-docrine neoplasmsrdquo Seminars in Nuclear Medicine vol 42 no3 pp 190ndash207 2012
[27] R P Baum and H R Kulkarni ldquoTheranostics From molecularimaging using Ga-68 labeled tracers and PETCT to per-sonalized radionuclide therapy - the bad berka experiencerdquoTheranostics vol 2 no 5 pp 437ndash447 2012
[28] I Velikyan ldquoRadionuclides for Imaging andTherapy in Oncol-ogyrdquo Cancer Theranostics pp 285ndash325 2014
[29] J Czernin andWAWeber ldquoIssues and controversies in nuclearmedicine Introductionrdquo Journal of Nuclear Medicine vol 52no Supplement 2 pp 1Sndash2S 2011
[30] S J Goldsmith and S Vallabhajosula ldquoClinically proven radio-pharmaceuticals for infection imaging mechanisms and appli-cationsrdquo Seminars in Nuclear Medicine vol 39 no 1 pp 2ndash102009
[31] M F Tsan ldquoMechanism of gallium-67 accumulation in inflam-matory lesionsrdquo Journal of Nuclear Medicine vol 26 no 1 pp88ndash92 1985
[32] S L Kipper ldquoRadiolabelled leukocyte imaging of the abdomenrdquoin Nuclear Medicine Annual J Freeman Ed pp 81ndash126 RavenPress New York NY USA 1995
[33] F Jamar J Buscombe A Chiti et al ldquoEANMSNMMI guidelinefor 18F-FDG use in inflammation and infectionrdquo Journal ofNuclear Medicine vol 54 no 4 pp 647ndash658 2013
[34] C J Palestro ldquoThe current role of gallium imaging in infectionrdquoSeminars in Nuclear Medicine vol 24 no 2 pp 128ndash141 1994
[35] M S Akhtar M B Imran M A Nadeem and A ShahidldquoAntimicrobial peptides as infection imaging agents better thanradiolabeled antibioticsrdquo International Journal of Peptides vol2012 Article ID 965238 19 pages 2012
[36] D Delbeke and G M Segall ldquoStatus of and trends in nuclearmedicine in the United Statesrdquo Journal of Nuclear Medicine vol52 no 2 2011
[37] S S Gambhir J Czernin J Schwimmer D H Silverman R EColeman and M E Phelps ldquoA tabulated summary of the FDGPET literaturerdquo Journal of Nuclear Medicine vol 42 pp 1Sndash93S2001
[38] M J Lindsay B A Siegel S R Tunis et al ldquoThe NationalOncologic PET Registry ExpandedMedicare coverage for PETunder coverage with evidence developmentrdquo American Journalof Roentgenology vol 188 no 4 pp 1109ndash1113 2007
[39] F Gemmel H Van Den Wyngaert C Love M M Welling PGemmel and C J Palestro ldquoProsthetic joint infectionsradionuclide state-of-the-art imagingrdquo European Journal ofNuclearMedicine andMolecular Imaging vol 39 no 5 pp 892ndash909 2012
[40] J Sorensen ldquoHow does the patient benefit from clinical PETrdquoTheranostics vol 2 no 5 pp 427ndash436 2012
[41] S L Rice C A Roney P Daumar and J S Lewis ldquoThe nextgeneration of positron emission tomography radiopharmaceu-ticals in oncologyrdquo Seminars in Nuclear Medicine vol 41 no 4pp 265ndash282 2011
[42] R LWahl JMHerman and E Ford ldquoThePromise and Pitfallsof Positron Emission Tomography and Single-Photon EmissionComputed Tomography Molecular Imaging-Guided RadiationTherapyrdquo Seminars in Radiation Oncology vol 21 no 2 pp 88ndash100 2011
Contrast Media amp Molecular Imaging 17
[43] A W J M Glaudemans R H J A Slart J M Van Dijl MVan Oosten and G M Van Dam ldquoMolecular imaging of infec-tious and inflammatory diseases A terra incognitardquo Journal ofNuclear Medicine vol 56 no 5 pp 659ndash661 2015
[44] X Li W Bauer I Israel et al ldquoTargeting p-selectin by gallium-68-labeled fucoidan positron emission tomography for nonin-vasive characterization of vulnerable plaques Correlation within vivo 176t mrirdquo Arteriosclerosis Thrombosis and VascularBiology vol 34 no 8 pp 1661ndash1667 2014
[45] S Eichendorff P Svendsen D Bender et al ldquoBiodistributionand PET Imaging of a Novel [68Ga]-Anti-CD163-AntibodyConjugate in Rats with Collagen-Induced Arthritis and inControlsrdquoMolecular Imaging and Biology vol 17 no 1 pp 87ndash93 2014
[46] Z Zhu Y Yin K Zheng et al ldquoEvaluation of synovial angiogen-esis in patients with rheumatoid arthritis using 68Ga-PRGD2PETCT A prospective proof-of-concept cohort studyrdquo Annalsof the Rheumatic Diseases vol 73 no 6 pp 1269ndash1272 2014
[47] J S Eo J C Paeng S Lee et al ldquoAngiogenesis imaging inmyocardial infarction using 68Ga-NOTA- RGD PET Charac-terization and application to therapeutic efficacy monitoring inratsrdquo Coronary Artery Disease vol 24 no 4 pp 303ndash311 2013
[48] J H Kim Y-H Kim Y J Kim et al ldquoQuantitative positronemission tomography imaging of angiogenesis in rats with fore-limb ischemia using 68Ga-NOTA-c(RGDyK)rdquo Angiogenesisvol 16 no 4 pp 837ndash846 2013
[49] I Laitinen J Notni K Pohle et al ldquoComparison of cyclicRGD peptides for 120572v1205733 integrin detection in a rat model ofmyocardial infarctionrdquo EJNMMI Research vol 3 no 1 pp 1ndash9 2013
[50] M Kiugel I Dijkgraaf V Kyto et al ldquoDimeric [68Ga]DOTA-RGD Peptide Targeting 120572 ltinfgtvltinfgt 120573 ltinfgt3ltinfgt Inte-grin Reveals Extracellular Matrix Alterations after MyocardialInfarctionrdquo Molecular Imaging and Biology vol 16 no 6 pp793ndash801 2014
[51] M Gronman M Tarkia T Kiviniemi et al ldquoImaging of 120572v1205733integrin expression in experimental myocardial ischemia with[68Ga]NODAGA-RGD positron emission tomographyrdquo Jour-nal of Translational Medicine vol 15 no 1 p 144 2017
[52] J Haukkala I Laitinen P Luoto et al ldquo68Ga-DOTA-RGDpep-tide Biodistribution and binding into atherosclerotic plaquesin micerdquo European Journal of Nuclear Medicine and MolecularImaging vol 36 no 12 pp 2058ndash2067 2009
[53] H Virtanen A Autio R Siitonen et al ldquo68Ga-DOTA-Siglec-9- a new imaging tool to detect synovitisrdquo Arthritis Research ampTherapy vol 17 no 1 article no 308 2015
[54] J Retamal J Sorensen M Lubberink et al ldquoFeasibility of(68) Ga-labeled Siglec-9 peptide for the imaging of acutelung inflammation a pilot study in a porcine model of acuterespiratory distress syndromerdquoAm JNuclMedMol Imaging vol6 no 1 pp 18ndash31 2016
[55] J M U Silvola H Virtanen R Siitonen et al ldquoLeukocytetrafficking-associated vascular adhesion protein 1 is expressedand functionally active in atherosclerotic plaquesrdquo ScientificReports vol 6 Article ID 35089 2016
[56] H Ahtinen J Kulkova L Lindholm et al ldquo68Ga-DOTA-Siglec-9 PETCT imaging of peri-implant tissue responses andstaphylococcal infectionsrdquo EJNMMI Research vol 4 no 1article no 45 pp 1ndash11 2014
[57] A Autio S Jalkanen and A Roivainen ldquoNuclear imaging ofinflammation Homing-associated molecules as targetsrdquo EJN-MMI Research vol 3 no 1 pp 1ndash7 2013
[58] J TThackeray T Derlin AHaghikia et al ldquoMolecular Imagingof the Chemokine Receptor CXCR4 after Acute MyocardialInfarctionrdquo JACC Cardiovascular Imaging vol 8 no 12 pp1417ndash1426 2015
[59] J S Schmid A Schirbel A K Buck S Kropf H-J Westerand C Lapa ldquoPentixafor-Positron Emission TomographyComputed Tomography Detects Chemokine Receptor CXCR4Expression after Ischemic Strokerdquo Circulation CardiovascularImaging vol 9 no 9 Article ID e005217 2016
[60] J Zhou G Hao H Weng et al ldquoIn vivo evaluation ofmedical device-associated inflammation using a macrophage-specific positron emission tomography (PET) imaging proberdquoBioorganic amp Medicinal Chemistry Letters vol 23 no 7 pp2044ndash2047 2013
[61] S A Kularatne M-J Belanger X Meng et al ldquoComparativeanalysis of folate derived PET imaging agents with [ 18F]-2-fluoro-2-deoxy-d-glucose using a rodent inflammatory pawmodelrdquo Molecular Pharmaceutics vol 10 no 8 pp 3103ndash31112013
[62] V Ambrosini M Zompatori F De Luca et al ldquo68Ga-DOTANOCPETCTAllows Somatostatin Receptor Imaging inIdiopathic Pulmonary Fibrosis Preliminary Resultsrdquo Journal ofNuclear Medicine vol 51 no 12 pp 1950ndash1955 2010
[63] T Lincke J Singer R Kluge O Sabri and R Paschke ldquoRela-tive quantification of indium-111 pentetreotide and gallium-68DOTATOC uptake in the thyroid gland and association withthyroid pathologiesrdquoThyroid vol 19 no 4 pp 381ndash389 2009
[64] A Rominger T Saam E Vogl et al ldquoIn vivo imaging ofmacrophage activity in the coronary arteries using 68Ga-DOTATATE PETCT correlation with coronary calcium bur-den and risk factorsrdquo Journal of Nuclear Medicine vol 51 no 2pp 193ndash197 2010
[65] J M Tarkin F R Joshi N R Evans et al ldquoDetection ofAtherosclerotic Inflammation by 68Ga-DOTATATE PET Com-pared to [18F]FDG PET Imagingrdquo Journal of the AmericanCollege of Cardiology vol 69 no 14 pp 1774ndash1791 2017
[66] S-P Lee H-J Im S Kang et al ldquoNoninvasive imaging ofmyocardial inflammation in myocarditis using 68Ga-taggedmannosylated human serum albumin positron emissiontomographyrdquoTheranostics vol 7 no 2 pp 413ndash424 2017
[67] Z Zha J Song S R Choi et al ldquo68Ga-Bivalent PolypegylatedStyrylpyridine Conjugates for Imaging A120573 Plaques in CerebralAmyloid Angiopathyrdquo Bioconjugate Chemistry vol 27 no 5 pp1314ndash1323 2016
[68] H Watanabe M Ono S Iikuni et al ldquoA 68Ga complex basedon benzofuran scaffold for the detection of 120573-amyloid plaquesrdquoBioorganic amp Medicinal Chemistry Letters vol 24 no 20 pp4834ndash4837 2014
[69] D Cressier M Dhilly T T Cao Pham et al ldquoGallium-68 Com-plexes Conjugated to Pittsburgh Compound B Radiolabelingand Biological EvaluationrdquoMolecular Imaging and Biology vol18 no 3 pp 334ndash343 2016
[70] D Satpati CArjun R KrishnamohanG Samuel and S Baner-jee ldquo68Ga-labeledCiprofloxacinConjugates as Radiotracers forTargeting Bacterial InfectionrdquoChemical Biology ampDrug Designvol 87 no 5 pp 680ndash686 2016
[71] T Ebenhan N Chadwick and M M Sathekge ldquoPeptidesynthesis characterization and 68Ga-radiolabeling of NOTA-conjugated ubiquicidin fragments for prospective infectionimaging with PETCTrdquo Nuclear Medicine and Biology vol 41no 5 pp 390ndash400 2014
18 Contrast Media amp Molecular Imaging
[72] T Ebenhan J R Zeevaart and J D Venter ldquoPreclinicalevaluation of 68Ga-labeled 1 4 7-triazacyclononane-1 4 7-triacetic acid-ubiquicidin as a radioligand for PET infectionimagingrdquo Journal of Nuclear Medicine vol 55 no 2 pp 308ndash314 2014
[73] B B Mokaleng T Ebenhan S Ramesh et al ldquoSynthesis 68Ga-radiolabeling and preliminary in vivo assessment of adepsipeptide-derived compound as a potential PETCTinfection imaging agentrdquo BioMed Research International vol2015 Article ID 284354 2015
[74] T Ebenhan B Mokaleng J Venter H Kruger J Zeevaart andM Sathekge ldquoPreclinical Assessment of a 68Ga-DOTA-Functionalized Depsipeptide as a Radiodiagnostic InfectionImaging AgentrdquoMolecules vol 22 no 9 p 1403 2017
[75] S Chopra B Singh A Koul A Mishra and H Wester ldquoSyn-thesis of DOTA conjugated GF-17 and RAWVAWR-NH2 andradiolabeling with 68Ga as a potential PET tracer for infectionimagingrdquo J Nucl Med vol 57 Supplement 2 p 1115 2016
[76] M Petrik HHaas P Laverman et al ldquo 68Ga-triacetylfusarinineC and 68Ga-ferrioxamine e for aspergillus infection imaginguptake specificity in various microorganismsrdquoMolecular Imag-ing and Biology vol 16 no 1 pp 102ndash108 2014
[77] V Kumar and D K Boddeti ldquo 68Ga-radiopharmaceuticals forPET imaging of infection and inflammationrdquo Recent Results inCancer Research vol 194 pp 189ndash219 2013
[78] M Vorster A Maes A Jacobs et al ldquoEvaluating the possiblerole of 68Ga-citrate PETCT in the characterization of indeter-minate lung lesionsrdquo Annals of Nuclear Medicine vol 28 no 6pp 523ndash530 2014
[79] M Vorster B Mokaleng M M Sathekge and T Ebenhan ldquoAmodified technique for efficient radiolabeling of 68Ga-citratefrom a SnO2-based 68Ge68Ga generator for better infectionimagingrdquoHellenic Journal of Nuclear Medicine vol 16 no 3 pp193ndash198 2013
[80] S Salomaeki J Kemppainen U Hohenthal et al ldquoHead-to-head comparison of 68Ga-Citrate and 18F-FDG PETCT fordetection of infectious foci in patients with staphylococcusaureus bacteraemiardquo Contrast Media amp Molecular Imaging vol2017 p 8 2017
[81] L Fass ldquoImaging and cancer a reviewrdquoMolecular Oncology vol2 no 2 pp 115ndash152 2008
[82] A Chopra L Shan W C Eckelman et al ldquoMolecular imagingand contrast agent database (MICAD) Evolution and progressrdquoMolecular Imaging and Biology vol 14 no 1 pp 4ndash13 2012
[83] A Sanchez-Crespo P Andreo and S A Larsson ldquoPositronflight in human tissues and its influence on PET image spatialresolutionrdquo European Journal of Nuclear Medicine and Molecu-lar Imaging vol 31 no 1 pp 44ndash51 2004
[84] H W A M De Jong L Perk G W M Visser R Boellaard GAM S Van Dongen and A A Lammertsma ldquoHigh resolutionPET imaging characteristics of68Ga 124i and89Zr comparedto18Frdquo in Proceedings of the Nuclear Science Symposium Con-ference Record 2005 IEEE pp 1624ndash1627 Puerto Rico October2005
[85] I Velikyan A Sundin B Eriksson et al ldquoIn vivo bindingof [68Ga]-DOTATOC to somatostatin receptors in neuroen-docrine tumours - impact of peptide massrdquo Nuclear Medicineand Biology vol 37 no 3 pp 265ndash275 2010
[86] U Eberlein and M Lassmann ldquoDosimetry of [68Ga]-labeledcompoundsrdquo Applied Radiation and Isotopes vol 76 pp 70ndash742013
[87] C PettinatoA SarnelliMDiDonna et al ldquo68Ga-DOTANOCBiodistribution and dosimetry in patients affected by neuroen-docrine tumorsrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 35 no 1 pp 72ndash79 2008
[88] B P Burke G S Clemente and S J Archibald ldquoRecentadvances in chelator design and labelling methodology for68Ga radiopharmaceuticalsrdquo Journal of Labelled Compoundsand Radiopharmaceuticals vol 57 no 4 pp 239ndash243 2014
[89] I Velikyan U Rosenstrom S Estrada et al ldquoSynthesis andpreclinical evaluation of 68Ga-labeled collagelin analogs forimaging and quantification of fibrosisrdquo Nuclear Medicine andBiology vol 41 no 9 pp 728ndash736 2014
[90] M F Ferreira G Pereira J P Andre and etal C ldquoGa[NO2A-N-(120572-amino)propionate] chelates Synthesis and evaluation aspotential tracers for 68Ga PETrdquoDalton Transactions vol 43 no21 pp 8037ndash8047 2014
[91] J Notni J Simecek and H-J Wester ldquoPhosphinic acid func-tionalized polyazacycloalkane chelators for radiodiagnosticsand radiotherapeutics Unique characteristics and applicationsrdquoChemMedChem vol 9 no 6 pp 1107ndash1115 2014
[92] J Simecek O Zemek P Hermann J Notni and H J WesterldquoTailored gallium( III) chelator NOPO synthesis characteriza-tion bioconjugation and application in preclinical Ga-68-PETimagingrdquoMolecular Pharmaceutics 2013
[93] D Parker B P Waldron and D S Yufit ldquoCrystallographicand solution NMR structural analyses of four hexacoordinatedgallium(iii) complexes based on ligands derived from 6-amino-perhydro-14-diazepinerdquo Dalton Transactions vol 42 no 22pp 8001ndash8008 2013
[94] B P Waldron D Parker C Burchardt D S Yufit M ZimnyandF Roesch ldquoStructure and stability of hexadentate complexesof ligands based on AAZTA for efficient PET labelling withgallium-68rdquo Chemical Communications vol 49 no 6 pp 579ndash581 2013
[95] D Parker and B PWaldron ldquoConformational analysis and syn-thetic approaches to polydentate perhydro-diazepine ligandsfor the complexation of gallium(iii)rdquo Organic amp BiomolecularChemistry vol 11 no 17 pp 2827ndash2838 2013
[96] I Velikyan H Maecke and B Langstrom ldquoConvenient prepa-ration of 68Ga-based PET-radiopharmaceuticals at room tem-peraturerdquo Bioconjugate Chemistry vol 19 no 2 pp 569ndash5732008
[97] J Erchegyi R Cescato B Waser J E Rivier and J C ReubildquoN-Imidazolebenzyl-histidine substitution in somatostatin andin its octapeptide analogue modulates receptor selectivity andfunctionrdquo Journal of Medicinal Chemistry vol 54 no 17 pp5981ndash5987 2011
[98] R Saha N Saha R S Donofrio and L L Bestervelt ldquoMicrobialsiderophores Amini reviewrdquo Journal of Basic Microbiology vol53 no 4 pp 303ndash317 2013
[99] V Nikolova S Angelova N Markova and T Dudev ldquoGalliumas a Therapeutic Agent A Thermodynamic Evaluation of theCompetition between Ga3+ and Fe3+ Ions in MetalloproteinsrdquoThe Journal of Physical Chemistry B vol 120 no 9 pp 2241ndash2248 2016
[100] C R Chitambar ldquoGallium and its competing roles with ironin biological systemsrdquo Biochimica et Biophysica Acta (BBA) -Molecular Cell Research vol 1863 no 8 pp 2044ndash2053 2016
[101] J A Lessa M A Soares and R G dos Santos ldquoGallium(III)complexes with 2-acetylpyridine-derived thiosemicarbazonesantimicrobial and cytotoxic effects and investigation on theinteractions with tubulinrdquo BioMetals vol 26 pp 151ndash165 2013
Contrast Media amp Molecular Imaging 19
[102] M van Oosten M Hahn L M A Crane et al ldquoTargetedimaging of bacterial infections Advances hurdles and hopesrdquoFEMS Microbiology Reviews vol 39 no 6 pp 892ndash916 2015
[103] M Vorster AMaes C V DWiele andM Sathekge ldquoGallium-68 PET A Powerful Generator-based Alternative to Infectionand Inflammation Imagingrdquo Seminars in Nuclear Medicine vol46 no 5 pp 436ndash447 2016
[104] M Kircher and C Lapa ldquoNovel Noninvasive Nuclear MedicineImaging Techniques for Cardiac Inflammationrdquo Current Car-diovascular Imaging Reports vol 10 no 2 article no 6 2017
[105] D AHammoud ldquoMolecular imaging of inflammation Currentstatusrdquo Journal of Nuclear Medicine vol 57 no 8 pp 1161ndash11652016
[106] D R Brenner D Scherer K Muir et al ldquoA review of the appli-cation of inflammatory biomarkers in epidemiologic cancerresearchrdquo Cancer Epidemiology Biomarkers amp Prevention vol23 no 9 pp 1729ndash1751 2014
[107] M D Turner B Nedjai T Hurst and D J PenningtonldquoCytokines and chemokines at the crossroads of cell signallingand inflammatory diseaserdquo Biochimica et Biophysica Acta (BBA)- Molecular Cell Research vol 1843 no 11 pp 2563ndash2582 2014
[108] L Werner H Guzner-Gur and I Dotan ldquoInvolvement ofCXCR4CXCR7CXCL12 interactions in inflammatory boweldiseaserdquoTheranostics vol 3 no 1 pp 40ndash46 2013
[109] S Jalkanen and M Salmi ldquoVAP-1 and CD73 endothelial cellsurface enzymes in leukocyte extravasationrdquo ArteriosclerosisThrombosis and Vascular Biology vol 28 no 1 pp 18ndash26 2008
[110] G Malviya F Galli I Sonni and A Signore ldquoImaging T-lymphocytes in inflammatory diseases A nuclear medicineapproachrdquo The Quarterly Journal of Nuclear Medicine andMolecular Imaging vol 58 no 3 pp 237ndash257 2014
[111] S Gratz H J RennenO C BoermanW J Oyen and P Burmaldquo(99m)Tc-interleukin-8 for imaging acute osteomyelitisrdquo Jour-nal of Nuclear Medicine vol 42 no 8 pp 1257ndash1264 2001
[112] S Gratz H J Rennen O C Boerman W J Oyen andF H Corstens ldquoRapid imaging of experimental colitis with(99m)Tc-interleukin-8 in rabbitsrdquo Journal of Nuclear Medicnevol 42 no 6 pp 917ndash923 2001
[113] C Alkim H Alkim A R Koksal S Boga and I SenldquoAngiogenesis in inflammatory bowel diseaserdquo InternationalJournal of Inflammation vol 2015 Article ID 970890 2015
[114] I S Alam T H Witney G Tomasi et al ldquoRadiolabeled RGDtracer kinetics annotates differential 120572v1205733 integrin expressionlinked to cell intrinsic and vessel expressionrdquoMolecular Imagingand Biology vol 16 no 4 pp 558ndash566 2014
[115] J Notni K Pohle and H-J Wester ldquoBe spoilt for choice withradiolabelled RGD peptides Preclinical evaluation of 68Ga-TRAP(RGD)3rdquoNuclear Medicine and Biology vol 40 no 1 pp33ndash41 2013
[116] J Oxboel M Brandt-Larsen C Schjoeth-Eskesen et al ldquoCom-parison of two new angiogenesis PET tracers 68Ga-NODAGA-E[c(RGDyK)]2 and 64Cu-NODAGA-E[c(RGDyK)]2 in vivoimaging studies in human xenograft tumorsrdquo Nuclear Medicineand Biology vol 41 no 3 pp 259ndash267 2014
[117] J Simecek J Notni T G Kapp H Kessler and H-J WesterldquoBenefits of NOPO as chelator in gallium-68 peptides exempli-fied by preclinical characterization of 68Ga-NOPO-c(RGDfK)rdquoMolecular Pharmaceutics vol 11 no 5 pp 1687ndash1695 2014
[118] M Trajkovic-Arsic P Mohajerani A Sarantopoulos et alldquoMultimodal molecular imaging of integrin avb3 for in vivodetection of pancreatic cancerrdquo Journal of NuclearMedicine vol55 no 3 pp 446ndash451 2014
[119] H Cai and P S Conti ldquoRGD-based PET tracers for imagingreceptor integrin 120572 v1205733 expressionrdquo Journal of Labelled Com-pounds and Radiopharmaceuticals vol 56 no 5 pp 264ndash2792013
[120] I Dijkgraaf S Y A Terry W J Mcbride et al ldquoImagingintegrin alpha-v-beta-3 expression in tumors with an 18F-labeled dimeric RGD peptiderdquo Contrast Media amp MolecularImaging vol 8 no 3 pp 238ndash245 2013
[121] P A Knetsch M Petrik C Rangger et al ldquo[68Ga]NS3-RGD and [68Ga] Oxo-DO3A-RGD for imaging 120572v1205733 integrinexpression Synthesis evaluation and comparisonrdquo NuclearMedicine and Biology vol 40 no 1 pp 65ndash72 2013
[122] Z Liu and F Wang ldquoDevelopment of RGD-based radiotracersfor tumor imaging and therapy Translating from bench tobedsiderdquo Current Molecular Medicine vol 13 no 10 pp 1487ndash1505 2013
[123] H Choi J H Phi J C Paeng et al ldquoImaging of integrin 120572v1205733expression using 68Ga-RGD positron emission tomography inpediatric cerebral infarctrdquoMolecular Imaging vol 12 no 4 pp213ndash217 2013
[124] H-J Yoon K W Kang I K Chun et al ldquoCorrelation of breastcancer subtypes based on estrogen receptor progesteronereceptor and HER2 with functional imaging parameters from68Ga-RGD PETCT and 18F-FDG PETCTrdquo European Journalof Nuclear Medicine and Molecular Imaging vol 41 no 8 pp1534ndash1543 2014
[125] R P Baum H R Kulkarni D Muller et al ldquoFirst-in-human study demonstrating tumor-angiogenesis by PETCTimaging with 68Ga-NODAGA-THERANOST a high-affinitypeptidomimetic for 120572v1205733 integrin receptor targetingrdquo CancerBiotherapy andRadiopharmaceuticals vol 30 no 4 pp 152ndash1592015
[126] R Haubner A Finkenstedt A Stegmayr et alldquo[68Ga]NODAGA-RGD ndash Metabolic stability biodistributionand dosimetry data from patients with hepatocellularcarcinoma and liver cirrhosisrdquo European Journal of NuclearMedicine and Molecular Imaging vol 43 no 11 pp 2005ndash20132016
[127] V Lopez-Rodrıguez C Galindo-Sarco F O Garcıa-Perez GFerro-Flores O Arrieta and M A Avila-Rodrıguez ldquoPET-based human dosimetry of the dimeric 120572v1205733 integrin ligand68Ga-DOTA-E-[c(RGDfK)]2 a potential tracer for imagingtumor angiogenesisrdquo Journal of Nuclear Medicine vol 57 no 3pp 404ndash409 2016
[128] M V Backer Z Levashova V Patel et al ldquoMolecular imagingof VEGF receptors in angiogenic vasculature with single-chainVEGF-based probesrdquo Nature Medicine vol 13 no 4 pp 504ndash509 2007
[129] MV Backer Z Levashova R Levenson F G Blankenberg andJ M Backer ldquoCysteine-containing fusion tag for site-specificconjugation of therapeutic and imaging agents to targetingproteinsrdquoMethods in Molecular Biology (Clifton NJ) vol 494pp 275ndash294 2008
[130] M Eder A V Krivoshein M Backer J M Backer UHaberkorn and M Eisenhut ldquoScVEGF-PEG-HBED-CC andscVEGF-PEG-NOTA conjugates comparison of easy-to-labelrecombinant proteins for [68Ga]PET imaging of VEGF recep-tors in angiogenic vasculaturerdquo Nuclear Medicine and Biologyvol 37 no 4 pp 405ndash412 2010
[131] E Blom I Velikyan A Monazzam P Razifar et al ldquoSynthe-sis and characterization of scVEGF-PEG-[ 68Ga]NOTA andscVEGF-PEG-[ 68Ga]DOTA PET tracersrdquo Journal of Labelled
20 Contrast Media amp Molecular Imaging
Compounds and Radiopharmaceuticals vol 54 no 11 pp 685ndash692 2011
[132] S Gratz M Behe and O C Boerman ldquo 99119898Tc-E-selectinbinding peptide for imaging acute osteomyelitis in a novel ratmodelrdquo Nuclear Medicine Communications vol 22 no 9 pp1003ndash1013 2001
[133] S B Jensen M Kakela L Joslashdal et al ldquoExploring the radiosyn-thesis and in vitro characteristics of [68Ga]Ga-DOTA-Siglec-9rdquoJournal of Labelled Compounds and Radiopharmaceuticals vol60 no 9 pp 439ndash449 2017
[134] B A Teicher and S P Fricker ldquoCXCL12 (SDF-1)CXCR4pathway in cancerrdquo Clinical Cancer Research vol 16 no 11 pp2927ndash2931 2010
[135] O Jacobson I D Weiss D O Kiesewetter J M Farber andX Chen ldquoPET of tumor CXCR4 expression with 4-18F-T140rdquoJournal of Nuclear Medicine vol 51 no 11 pp 1796ndash1804 2010
[136] A Aghanejad A R Jalilian Y Fazaeli et al ldquoSynthesis andevaluation of [67Ga]-AMD3100 A novel imaging agent fortargeting the chemokine receptorCXCR4rdquo Scientia Pharmaceu-tica vol 82 no 1 pp 29ndash42 2014
[137] O Jacobson I D Weiss L P Szajek et al ldquoPET imaging ofCXCR4 using copper-64 labeled peptide antagonistrdquoTheranos-tics vol 1 pp 251ndash262 2011
[138] O Jacobson I D Weiss L P Szajek et al ldquoImprovement ofCXCR4 tracer specificity for PET imagingrdquo Journal of Con-trolled Release vol 157 no 2 pp 216ndash223 2012
[139] H J Wester U Keller M Schottelius et al ldquoDisclosing theCXCR4 expression in lymphoproliferative diseases by targetedmolecular imagingrdquo Theranostics vol 5 no 6 pp 618ndash6302015
[140] E Gourni O Demmer M Schottelius et al ldquoPET of CXCR4expression by a 68Ga-labeled highly specific targeted contrastagentrdquo Journal of NuclearMedicine vol 52 no 11 pp 1803ndash18102011
[141] O Demmer I Dijkgraaf U Schumacher et al ldquoDesignsynthesis and functionalization of dimeric peptides targetingchemokine receptor CXCR4rdquo Journal of Medicinal Chemistryvol 54 no 21 pp 7648ndash7662 2011
[142] O Demmer E Gourni U Schumacher H Kessler and H-JWester ldquoPET Imaging of CXCR4 Receptors in Cancer by a NewOptimized Ligandrdquo ChemMedChem vol 6 no 10 pp 1789ndash1791 2011
[143] U Hennrich L Seyler M Schafer et al ldquoSynthesis and invitro evaluation of 68Ga-DOTA-4-FBn-TN14003 a novel tracerfor the imaging of CXCR4 expressionrdquo Bioorganic amp MedicinalChemistry vol 20 no 4 pp 1502ndash1510 2012
[144] G P C George E Stevens O Aberg et al ldquoPreclinical evalua-tion of a CXCR4-specific 68Ga-labelled TN14003 derivative forcancer PET imagingrdquo Bioorganic amp Medicinal Chemistry vol22 no 2 pp 796ndash803 2014
[145] S Poty E Gourni P Desogere et al ldquoAMD3100 A VersatilePlatform for CXCR4 Targeting 68Ga-Based Radiopharmaceu-ticalsrdquo Bioconjugate Chemistry vol 27 no 3 pp 752ndash761 2016
[146] K Philipp-Abbrederis K Herrmann S Knop et al ldquoIn vivomolecular imaging of chemokine receptor CXCR4 expressionin patients with advancedmultiple myelomardquo EMBOMolecularMedicine vol 7 no 4 pp 477ndash487 2015
[147] Z Wang M Zhang L Wang et al ldquoProspective study of 68Ga-NOTA-NFB Radiation dosimetry in healthy volunteers andfirst application in glioma patientsrdquo Theranostics vol 5 no 8pp 882ndash889 2015
[148] I M Jackson P J Scott and S Thompson ldquoClinical Applica-tions of Radiolabeled Peptides for PETrdquo Seminars in NuclearMedicine vol 47 no 5 pp 493ndash523 2017
[149] C Lapa T Reiter R A Werner et al ldquo[68Ga]Pentixafor-PETCT for Imaging of Chemokine Receptor 4 Expression afterMyocardial Infarctionrdquo JACC Cardiovascular Imaging vol 8no 12 pp 1466ndash1468 2015
[150] C Rischpler S G Nekolla H Kossmann et al ldquoUpregu-lated myocardial CXCR4-expression after myocardial infarc-tion assessed by simultaneous GA-68 pentixafor PETMRIrdquoJournal of Nuclear Cardiology vol 23 no 1 pp 131ndash133 2016
[151] F Hyafil J Pelisek I Laitinen et al ldquoImaging the CytokineReceptorCXCR4 in atherosclerotic plaqueswith the radiotracer68Ga-Pentixafor for PETrdquo Journal of Nuclear Medicine vol 58no 3 pp 499ndash506 2017
[152] Y Yi ldquoFolate receptor-targeted diagnostics and therapeutics forinflammatory diseasesrdquo ImmuneNetwork vol 16 no 6 pp 337ndash343 2016
[153] C M Paulos M J Turk G J Breur and P S Low ldquoFolatereceptor-mediated targeting of therapeutic and imaging agentsto activated macrophages in rheumatoid arthritisrdquo AdvancedDrug Delivery Reviews vol 56 no 8 pp 1205ndash1217 2004
[154] W Han R Zaynagetdinov F E Yull et al ldquoMolecular imagingof folate receptor 120573-positive macrophages during acute lunginflammationrdquo American Journal of Respiratory Cell and Molec-ular Biology vol 53 no 1 pp 50ndash59 2015
[155] B Kuhle C Muller and T L Ross ldquoA Novel 68Ga-Labeledpteroic acid-based PET tracer for tumor imaging via the folatereceptorrdquo Recent Results in Cancer Research vol 194 pp 257ndash267 2013
[156] C Brand V A Longo M Groaning W A Weber and TReiner ldquoDevelopment of a New Folate-Derived Ga-68-BasedPET Imaging AgentrdquoMolecular Imaging and Biology vol 19 no5 pp 754ndash761 2017
[157] M Fani XWang G Nicolas et al ldquoDevelopment of new folate-based PET radiotracers Preclinical evaluation of 68Ga-DOTA-folate conjugatesrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 38 no 1 pp 108ndash119 2011
[158] C J Mathias M R Lewis D E Reichert et al ldquoPreparationof 66Ga- and 68Ga-labeled Ga(III)-deferoxamine-folate aspotential folate-receptor-targeted PET radiopharmaceuticalsrdquoNuclear Medicine and Biology vol 30 no 7 pp 725ndash731 2003
[159] S-M Kim N Choi S Hwang et al ldquoFolate receptor-specific positron emission tomography imaging with folic acid-conjugated tissue inhibitor of metalloproteinase-2rdquo Bulletin ofthe Korean Chemical Society vol 34 no 11 pp 3243ndash3248 2013
[160] M Fani M-L Tamma G P Nicolas et al ldquoIn vivo imagingof folate receptor positive tumor xenografts using novel 68Ga-NODAGA-folate conjugatesrdquo Molecular Pharmaceutics vol 9no 5 pp 1136ndash1145 2012
[161] C Muller and R Schibli ldquoProspects in folate receptor-targetedradionuclide therapyrdquo Frontiers in Oncology vol 3 Article IDArticle 249 2013
[162] A Jain A Mathur U Pandey et al ldquoSynthesis and evaluationof a 68Ga labeled folic acid derivative for targeting folatereceptorsrdquo Applied Radiation and Isotopes vol 116 pp 77ndash842016
[163] W Xia A R Hilgenbrink E L Matteson M B Lockwood J-X Cheng and P S Low ldquoA functional folate receptor is inducedduring macrophage activation and can be used to target drugsto activated macrophagesrdquo Blood vol 113 no 2 pp 438ndash4462009
Contrast Media amp Molecular Imaging 21
[164] E P Krenning W A P Breeman P P M Kooij et alldquoLocalisation of endocrine-related tumours with radioiodi-nated analogue of somatostatinrdquoThe Lancet vol 1 no 8632 pp242ndash244 1989
[165] E P Krenning D J KwekkeboomWH Bakker et al ldquoSomato-statin receptor scintigraphy with [111In-DTPA-d-Phe1]- and[123I-Tyr3]-octreotide the Rotterdam experience with morethan 1000 patientsrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 20 no 8 pp 716ndash731 1993
[166] A Stahl G Meisetschlager M Schottelius et al ldquo[123I]Mtr-TOCA a radioiodinated and carbohydrated analogue ofoctreotide Scintigraphic comparison with [111In]octreotiderdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 33 no 1 pp 45ndash52 2006
[167] R Lebtahi J le Cloirec C Houzard et al ldquoDetection of neu-roendocrine tumors 99mTc-P829 scintigraphy compared with111In-pentetreotide scintigraphyrdquo Journal of Nuclear Medicinevol 43 no 7 pp 889ndash895 2002
[168] C Decristoforo T Maina B Nock M Gabriel P Cordopatisand R Moncayo ldquo99mTc-demotate 1 First data in tumourpatients - Results of a pilotphase I studyrdquo European Journal ofNuclearMedicine andMolecular Imaging vol 30 no 9 pp 1211ndash1219 2003
[169] C Decristoforo S J Mather W Cholewinski E DonnemillerG Riccabona and R Moncayo ldquo(99m)Tc-EDDAHYNIC-TOC A new (99m)Tc-labelled radiopharmaceutical forimaging somatostatin receptor-positive tumours First clinicalresults and intra-patient comparison with 111In-labelledoctreotide derivativesrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 27 no 9 pp 1318ndash1325 2000
[170] A Hubalewska-Dydejczyk K Fross-Baron R Mikołajczak etal ldquo99mTc-EDDAHYNIC-octreotate scintigraphy an efficientmethod for the detection and staging of carcinoid tumoursResults of 3 yearsrsquo experiencerdquo European Journal of NuclearMedicine and Molecular Imaging vol 33 no 10 pp 1123ndash11332006
[171] M Bangard M Behe S Guhlke et al ldquoDetection of somato-statin receptor-positive tumours using the new 99mC-tricine-HYNIC-D-Phe1-Tyr3-octreotide First results in patients andcomparison with 111In-DTPA-D-Phe1-octreotiderdquo EuropeanJournal of Nuclear Medicine and Molecular Imaging vol 27 no6 pp 628ndash637 2000
[172] A Helisch G J Forster H Reber et al ldquoPre-therapeuticdosimetry and biodistribution of 86Y-DOTA- Phe1-Tyr3-octreotide versus 111In-pentetreotide in patients with advancedneuroendocrine tumoursrdquo European Journal of NuclearMedicine and Molecular Imaging vol 31 no 10 pp 1386ndash13922004
[173] M Henze J Schuhmacher P Hipp et al ldquoPET imaging ofsomatostatin receptors using [68GA]DOTA-D-Phe1-Tyr3-Octreotide First results in patients with meningiomasrdquo Journalof Nuclear Medicine vol 42 no 7 pp 1053ndash1056 2001
[174] I Kayani J B Bomanji A Groves et al ldquoFunctional imaging ofneuroendocrine tumors with combined PETCT using 68Ga-DOTATATE (Dota-DPhe1 Tyr3-octreotate) and 18F-FDGrdquoCancer vol 112 no 11 pp 2447ndash2455 2008
[175] A Al-Nahhas ldquoNuclear medicine imaging of neuroendocrinetumoursrdquo Clinical Medicine vol 12 no 4 pp 377ndash380 2012
[176] V Ambrosini S Nicolini P Caroli et al ldquoPETCT imaging indifferent types of lung cancer an overviewrdquo European Journal ofRadiology vol 81 no 5 pp 988ndash1001 2012
[177] V Ambrosini D Campana P Tomassetti and S Fanti ldquo68Ga-labelled peptides for diagnosis of gastroenteropancreatic NETrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 39 no 1 pp S52ndashS60 2012
[178] K E Oberg J-C Reubi D J Kwekkeboom and E P KrenningldquoRole of somatostatins in gastroenteropancreatic neuroen-docrine tumor development and therapyrdquoGastroenterology vol139 no 3 pp 753-753 2010
[179] K Oberg ldquoGallium-68 somatostatin receptor PETCT Is ittime to replace 111Indium DTPA octreotide for patients withneuroendocrine tumorsrdquo Endocrine Journal vol 42 no 1 pp3-4 2012
[180] R Srirajaskanthan I Kayani A M Quigley J Soh M ECaplin and J Bomanji ldquoThe role of 68Ga-DOTATATE PET inpatients with neuroendocrine tumors and negative or equivocalfindings on 111In-DTPA-octreotide scintigraphyrdquo Journal ofNuclear Medicine vol 51 no 6 pp 875ndash882 2010
[181] A Kroiss D Putzer and C Uprimny ldquoFunctional imag-ing in phaeochromocytoma and neuroblastoma with 68Ga-DOTA-Tyr3-octreotide positron emission tomography and123I-metaiodobenzylguanidinerdquo European Journal of NuclearMedicine and Molecular Imaging vol 38 no 5 pp 865ndash8732011
[182] M Naji C Zhao S J Welsh et al ldquo68Ga-DOTA-TATE PETvs 123I-MIBG in identifying malignant neural crest tumoursrdquoMolecular Imaging and Biology vol 13 no 4 pp 769ndash775 2011
[183] V Ambrosini P Tomassetti P Castellucci et al ldquoComparisonbetween 68Ga-DOTA-NOC and 18F-DOPA PET for the detec-tion of gastro-entero-pancreatic and lung neuro-endocrinetumoursrdquo European Journal of Nuclear Medicine and MolecularImaging vol 35 no 8 pp 1431ndash1438 2008
[184] D Putzer M Gabriel B Henninger et al ldquoBone metastasesin patients with neuroendocrine tumor 68Ga- DOTA-Tyr3-octreotide PET in comparison to CT and bone scintigraphyrdquoJournal of Nuclear Medicine vol 50 no 8 pp 1214ndash1221 2009
[185] L K Anzola-Fuentes M Chianelli F Galli et al ldquoSomatostatinreceptor scintigraphy in patients with rheumatoid arthritis andsecondary Sjogrenrsquos syndrome treated with Infliximab a pilotstudyrdquo EJNMMI Research vol 6 no 1 article no 49 2016
[186] T Nobashi Y Nakamoto T Kubo et al ldquoThe utility of PETCTwith 68Ga-DOTATOC in sarcoidosis comparison with 67Ga-scintigraphyrdquoAnnals ofNuclearMedicine vol 30 no 8 pp 544ndash552 2016
[187] C Boy T A Heusner T D Poeppel et al ldquo68Ga-DOTATOCPETCT and somatostatin receptor (sst1-sst5) expression innormal human tissue Correlation of sst2mRNAand SUVmaxrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 38 no 7 pp 1224ndash1236 2011
[188] P Rinne S Hellberg M Kiugel et al ldquoComparison of Somato-statin Receptor 2-Targeting PET Tracers in the Detection ofMouse Atherosclerotic Plaquesrdquo Molecular Imaging and Biol-ogy vol 18 no 1 pp 99ndash108 2016
[189] M Asti E Ferrari S Croci et al ldquoSynthesis and characteri-zation of 68Ga-labeled curcumin and curcuminoid complexesas potential radiotracers for imaging of cancer and alzheimersdiseaserdquo Inorganic Chemistry vol 53 no 10 pp 4922ndash49332014
[190] A Signore I Santino and A W J M Glaudemans ldquoIn vivoimaging of microorganismsrdquo Clinical and Translational Imag-ing vol 4 no 3 pp 161-162 2016
[191] S Auletta F Galli C Lauri D Martinelli I Santino andA Signore ldquoImaging bacteria with radiolabelled quinolones
22 Contrast Media amp Molecular Imaging
cephalosporins and siderophores for imaging infection a sys-tematic reviewrdquo Clinical and Translational Imaging vol 4 no 4pp 229ndash252 2016
[192] X Ning S Lee Z Wang et al ldquoMaltodextrin-based imagingprobes detect bacteria in vivo with high sensitivity and speci-ficityrdquo Nature Materials vol 10 no 8 pp 602ndash607 2011
[193] J Ady andY Fong ldquoImaging for infection Fromvisualization ofinflammation to visualization of microbesrdquo Surgical Infectionsvol 15 no 6 pp 700ndash707 2014
[194] J M Sierra D Rodriguez-Puig A Soriano J Mensa C Pieraand J Vila ldquoAccumulation of 99mTc-ciprofloxacin in Staphy-lococcus aureus and Pseudomonas aeruginosardquo AntimicrobialAgents and Chemotherapy vol 52 no 7 pp 2691-2692 2008
[195] D I Andersson and D Hughes ldquoMicrobiological effects ofsublethal levels of antibioticsrdquoNature ReviewsMicrobiology vol12 no 7 pp 465ndash478 2014
[196] N Dumarey D Blocklet T Appelboom L Tant and ASchoutens ldquoInfecton is not specific for bacterial osteo-articularinfective pathologyrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 29 no 4 pp 530ndash535 2002
[197] K E Britton D W Wareham S S Das et al ldquoImaging bacte-rial infection with 99mTc-ciprofloxacin (Infecton)rdquo Journal ofClinical Pathology vol 55 no 11 pp 817ndash823 2002
[198] G Ferro-Flores M A Avila-Rodrıguez and F O Garcıa-PerezldquoImaging of bacteria with radiolabeled ubiquicidin by SPECTand PET techniquesrdquo Clinical and Translational Imaging vol 4no 3 pp 175ndash182 2016
[199] P S Hiemstra M T van den Barselaar M Roest P H Nibber-ing and R van Furth ldquoUbiquicidin a novel murine microbi-cidal protein present in the cytosolic fraction of macrophagesrdquoJournal of Leukocyte Biology vol 66 no 3 pp 423ndash428 1999
[200] M S Akhtar A Qaisar J Irfanullah et al ldquoAntimicrobialpeptide 99mTc-ubiquicidin 29ndash41 as human infection-imagingagent clinical trialrdquo Journal of Nuclear Medicne vol 46 no 4pp 567ndash573 2005
[201] M Assadi K Vahdat I Nabipour et al ldquoDiagnostic value of99mTc-ubiquicidin scintigraphy for osteomyelitis and compar-isons with 99mTc-methylene diphosphonate scintigraphy andmagnetic resonance imagingrdquo Nuclear Medicine Communica-tions vol 32 no 8 pp 716ndash723 2011
[202] T Emery ldquoExchange of Iron by Gallium in SiderophoresrdquoBiochemistry vol 25 no 16 pp 4629ndash4633 1986
[203] M Petrik C Zhai H Haas and C Decristoforo ldquoSiderophoresfor molecular imaging applicationsrdquo Clinical and TranslationalImaging vol 5 no 1 pp 15ndash27 2017
[204] H J Flint E A BayerM T Rincon R Lamed and B AWhiteldquoPolysaccharide utilization by gut bacteria potential for newinsights from genomic analysisrdquo Nature Reviews Microbiologyvol 6 no 2 pp 121ndash131 2008
[205] GGowrishankarMNamavari E B Jouannot et al ldquoInvestiga-tion of 6-[18F]-fluoromaltose as a novel PET tracer for imagingbacterial infectionrdquo PLoS ONE vol 9 no 9 Article ID e1079512014
[206] N Gholipour M Akhlaghi A M Kheirabadi et al ldquoChelator-free radiolabeling of dextran with 68Ga for PET studiesrdquoJournal of Radioanalytical and Nuclear Chemistry vol 311 no3 pp 1811ndash1817 2017
[207] C Bettegowda C A Foss I Cheong et al ldquoImaging bac-terial infections with radiolabeled 1-(21015840-deoxy-21015840- fluoro-120573-D-arabinofuranosyl)-5-iodouracilrdquo Proceedings of the NationalAcadamy of Sciences of the United States of America vol 102 no4 pp 1145ndash1150 2005
[208] S A Soghomonyan M Doubrovin J Pike et al ldquoPositronemission tomography (PET) imaging of tumor-localizedSalmonella expressing HSV1-TKrdquo Cancer GeneTherapy vol 12no 1 pp 101ndash108 2005
[209] C Palestro K Nichols S Sheikh-Fayyaz S Dewey P Singhaland K Bhargava ldquoCan Gallium-68 PET differentiate acuteinterstitial nephritis from acute tubular necrosisrdquo Journal ofNuclear Medicne vol 57 Supplement 2 p 551 2016
[210] A J Morguet D L Munz V Ivancevic et al ldquoImmunoscintig-raphy using technetium-99m-labeled anti-NCA-95 antigranu-locyte antibodies as an adjunct to echocardiography in subacuteinfective endocarditisrdquo Journal of the American College ofCardiology vol 23 no 5 pp 1171ndash1178 1994
[211] C van der Laken O Boerman W Oyen et al ldquoIn Vivo Expres-sion of Interleukin-1 Receptors during Various ExperimentallyInduced Inflammatory Conditionsrdquo The Journal of InfectiousDiseases vol 177 no 5 pp 1398ndash1401 1998
[212] C J Van Der Laken O C Boerman W J G Oyen M T PVan De Ven J W M Van Der Meer and F H M CorstensldquoScintigraphic detection of infection and inflammation Newdevelopments with special emphasis on receptor interactionrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 25 no 5 pp 535ndash546 1998
[213] C J van der LakenOC BoermanW J GOyenM T P van deVen J W M van der Meer and F H M Corstens ldquoImaging ofinfection in rabbits with radioiodinated interleukin-1 (120572 and 120573)its receptor antagonist and a chemotactic peptide a comparativestudyrdquo European Journal of Nuclear Medicine and MolecularImaging vol 25 no 4 pp 347ndash352 1998
[214] C J Van Der Laken O C BoermanW J G Oyen M T P VanDe Ven F H M Corstens and J W M Ven Der Meer ldquoThekinetics of radiolabelled interleukin-8 in infection and sterileinflammationrdquo Nuclear Medicine Communications vol 19 no3 pp 271ndash282 1998
[215] E Lazzeri P Erba M Perri et al ldquoScintigraphic imaging ofvertebral osteomyelitis with 111in-biotinrdquoThe Spine Journal vol33 no 7 pp E198ndashE204 2008
[216] E Blom B Langstrom and I Velikyan ldquo68Ga-labeling of biotinanalogues and their characterizationrdquo Bioconjugate Chemistryvol 20 no 6 pp 1146ndash1151 2009
[217] O Eriksson F Carlsson E Blom et al ldquoPreclinical evaluationof a 68Ga-labeled biotin analogue for applications in islettransplantationrdquo Nuclear Medicine and Biology vol 39 no 3pp 415ndash421 2012
[218] E A Weinstein A A Ordonez V P DeMarco et alldquoImaging Enterobacteriaceae infection in vivo with 18F-fluoro-deoxysorbitol positron emission tomographyrdquo Science Transla-tional Medicine vol 6 no 259 p 259ra146 2014
[219] K M Nielsen M H Kyneb A K O Alstrup et alldquo68Ga-labeled phage-display selected peptides as tracers forpositron emission tomography imaging of Staphylococcusaureus biofilm-associated infections Selection radiolabellingand preliminary biological evaluationrdquo Nuclear Medicine andBiology vol 43 no 10 pp 593ndash605 2016
[220] T J Makinen P Lankinen T Poyhonen J Jalava H T Aroand A Roivainen ldquoComparison of 18F-FDG and 68Ga PETimaging in the assessment of experimental osteomyelitis due toStaphylococcus aureusrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 32 no 11 pp 1259ndash1268 2005
[221] JMU Silvola I LaitinenH J Sipila et al ldquoUptake of 68galliumin atherosclerotic plaques in LDLRminusminusApoB100100micerdquo EJN-MMI Research vol 1 no 1 pp 1ndash8 2011
Contrast Media amp Molecular Imaging 23
[222] T A Wynn ldquoCellular and molecular mechanisms of fibrosisrdquoThe Journal of Pathology vol 214 no 2 pp 199ndash210 2008
[223] T Derlin D Jonigk J Bauersachs and FM Bengel ldquoMolecularImaging of Chemokine Receptor CXCR4 in NonndashSmall CellLung Cancer Using 68Ga-Pentixafor PETCT ComparisonWith 18F-FDGrdquo Clinical Nuclear Medicine 2016
[224] I Velikyan U Rosenstrom T N Bulenga O Eriksson andG Antoni ldquoFeasibility of multiple examinations using68ga-labelled collagelin analogues Organ distribution in rat forextrapolation to human organ and whole-body radiationdosimetryrdquo Pharmaceuticals vol 9 no 2 article no 31 2016
[225] S Jadhav M Kakela J Makila et al ldquoSynthesis and in VivoPET Imaging of Hyaluronan Conjugates of OligonucleotidesrdquoBioconjugate Chemistry vol 27 no 2 pp 391ndash403 2016
[226] A Autio A Saraste N Kudomi et al ldquoAssessment of bloodflow with (68) Ga-DOTA PET in experimental inflammation avalidation study using (15) O-waterrdquo American Journal ofNuclear Medicine and Molecular Imaging vol 4 no 6 pp 571ndash579 2014
[227] G Davies A Rolle A Maurer et al ldquoTowards translationalimmunoPETMR imaging of invasive pulmonary aspergillosisthe Humanised Monoclonal Antibody JF5 detects in vivordquoTheranostics vol 7 no 14 pp 3398ndash3414 2017
[228] DGoodwin CMeares GDavid et al ldquoMonoclonal antibodiesas reversible equilibrium carriers of radiopharmaceuticalsrdquoInternational Journal of Radiation Applications and Instrumen-tation Part B Nuclear Medicine and Biology vol 13 no 4 pp383ndash391 1986
[229] D A Goodwin C F Mears M McTigue and G S DavidldquoMonoclonal antibody hapten radiopharmaceutical deliveryrdquoNuclear Medicine Communications vol 7 no 8 pp 569ndash5801986
[230] S E Halpern and R O Dillman ldquoProblems associated withradioimmunodetection and possibilities for future solutionsrdquo JBiol Response Mod vol 6 no 3 pp 235ndash262 1987
[231] H Hong J Sun and W Cai ldquoRadionuclide-based cancerimaging targeting the carcinoembryonic antigenrdquo BiomarkerInsights vol 3 pp 435ndash451 2008
[232] G J Forster E B Santos P M Smith-Jones P Zanzonico andS M Larson ldquoPretargeted radioimmunotherapy with a single-chain antibodystreptavidin construct and radiolabeledDOTA-biotin Strategies for reduction of the renal doserdquo Journal ofNuclear Medicine vol 47 no 1 pp 140ndash149 2006
[233] Z Yao M Zhang H Kobayashi et al ldquoImproved targeting ofradiolabeled streptavidin in tumors pretargeted with biotiny-lated monoclonal antibodies through an avidin chaserdquo Journalof Nuclear Medicine vol 36 no 5 pp 837ndash841 1995
[234] C-H Chang R M Sharkey E A Rossi et al ldquoMolecularAdvances in Pretargeting Radioimunotherapy with BispecificAntibodies 1 Supported in part by USPHS Grant R01-CA-84379from the NIH and Department of Energy Grant DE-FG01-00NE22941 (both to R M S)1rdquo Mol Cancer Ther vol 1 no 7pp 553ndash563 2002
[235] R M Sharkey E A Rossi W J McBride C-H Chang andD M Goldenberg ldquoRecombinant Bispecific Monoclonal Anti-bodies Prepared by theDock-and-Lock Strategy for PretargetedRadioimmunotherapyrdquo Seminars in Nuclear Medicine vol 40no 3 pp 190ndash203 2010
[236] R M Sharkey E A Rossi C-H Chang and D M Golden-berg ldquoImproved cancer therapy and molecular imaging withmultivalent multispecific antibodiesrdquo Cancer Biotherapy andRadiopharmaceuticals vol 25 no 1 pp 1ndash12 2010
[237] D M Goldenberg R M Sharkey G Paganelli J Barbet andJ Chatal ldquoAntibody pretargeting advances cancer radioim-munodetection and radioimmunotherapyrdquo Journal of ClinicalOncology vol 24 no 5 pp 823ndash834 2006
[238] O C Boerman F G van Schaijk W J G Oyen and FH M Corstens ldquoPretargeted radioimmunotherapy of cancerprogress step by steprdquo Journal of Nuclear Medicine vol 44 no3 pp 400ndash411 2003
[239] J Schuhmacher S Kaul G Klivenyi et al ldquoImmunoscintigra-phy with positron emission tomography Gallium-68 chelateimaging of breast cancer pretargeted with bispecific anti-MUC1anti-Ga chelate antibodiesrdquo Cancer Research vol 61 no9 pp 3712ndash3717 2001
[240] J Schuhmacher G Klivenyi S Kaul et al ldquoPretargeting ofhuman mammary carcinoma xenografts with bispecific anti-MUC1anti-Ga chelate antibodies and immunoscintigraphywith PETrdquo Nuclear Medicine and Biology vol 28 no 7 pp 821ndash828 2001
[241] C Somasundaram S Matzku J Schuhmacher and M ZollerldquoDevelopment of a bispecific monoclonal antibody against agallium-67 chelate and the human melanoma-associated anti-gen p97 for potential use in pretargeted immunoscintigraphyrdquoCancer Immunology Immunotherapy vol 36 no 5 pp 337ndash3451993
[242] E A Rossi D L Rossi R Stein D M Goldenberg and C-H Chang ldquoA bispecific antibody-IFN1205722b immunocytokine tar-geting CD20 and HLA-DR is highly toxic to human lymphomaandmultiplemyeloma cellsrdquoCancer Research vol 70 no 19 pp7600ndash7609 2010
[243] R M Sharkey H Karacay S Litwin et al ldquoImproved ther-apeutic results by pretargeted radioimmunotherapy of non-Hodgkinrsquos lymphoma with a new recombinant trivalent anti-CD20 bispecific antibodyrdquo Cancer Research vol 68 no 13 pp5282ndash5290 2008
[244] G L Griffiths C-H Chang W J McBride et al ldquoReagentsandmethods for PETusing bispecific antibody pretargeting and68Ga-radiolabeled bivalent hapten-peptide-chelate conjugatesrdquoJournal of Nuclear Medicine vol 45 no 1 pp 30ndash39 2004
[245] J Watine M Miedouge and B Friedberg ldquoCarcinoembryonicantigen as an independent prognostic factor of recurrence andsurvival in patients resected for colorectal liver metastases Asystematic reviewrdquo Diseases of the Colon amp Rectum vol 44 no12 pp 1791ndash1799 2001
[246] M J Goldstein and E P Mitchell ldquoCarcinoembryonic antigenin the staging and follow-up of patients with colorectal cancerrdquoCancer Investigation vol 23 no 4 pp 338ndash351 2005
[247] D V Gold D M Goldenberg H Karacay et al ldquoA novelbispecific trivalent antibody construct for targeting pancreaticcarcinomardquo Cancer Research vol 68 no 12 pp 4819ndash48262008
[248] J Schuhmacher G Klivenyi R Matys et al ldquoMultistep tumortargeting in nudemice using bispecific antibodies and a galliumchelate suitable for immunoscintigraphy with positron emis-sion tomographyrdquo Cancer Research vol 55 no 1 pp 115ndash1231995
[249] G Klivenyi J Schuhmacher E Patzelt et al ldquoGallium-68chelate imaging of human colon carcinoma xenografts pre-targeted with bispecific anti-CD44(V6)anti-gallium chelateantibodiesrdquo Journal ofNuclearMedicine vol 39 no 10 pp 1769ndash1776 1998
[250] M Zoller J Schuhmacher J Reed W Maier-Borst and SMatzku ldquoEstablishment and characterization of monoclonal
24 Contrast Media amp Molecular Imaging
antibodies against an octahedral gallium chelate suitable forimmunoscintigraphy with PETrdquo Journal of Nuclear Medicinevol 33 no 7 pp 1366ndash1372 1992
[251] R M Sharkey T M Cardillo E A Rossi et al ldquoSignal ampli-fication in molecular imaging by pretargeting a multivalentbispecific antibodyrdquo Nature Medicine vol 11 no 11 pp 1250ndash1255 2005
[252] D M Goldenberg and R M Sharkey ldquoNovel radiolabeledantibody conjugatesrdquo Oncogene vol 26 no 25 pp 3734ndash37442007
[253] D M Goldenberg E A Rossi R M Sharkey W J McBrideand C-H Chang ldquoMultifunctional antibodies by the dock-and-lock method for improved cancer imaging and therapy bypretargetingrdquo Journal of NuclearMedicine vol 49 no 1 pp 158ndash163 2008
[254] R Schoffelen R M Sharkey D M Goldenberg et al ldquoPre-targeted immuno-positron emission tomography imaging ofcarcinoembryonic antigen-expressing tumors with a bispecificantibody and a68Ga- And18F-labeled hapten peptide in micewith human tumor xenograftsrdquoMolecular Cancer Therapeuticsvol 9 no 4 pp 1019ndash1027 2010
[255] E S Bos W H Kuijpers M Meesters-Winters et al ldquoIn vitroevaluation of DNA-DNA hybridization as a two-step approachin radioimmunotherapy of cancerrdquoCancer Research vol 54 no13 pp 3479ndash3486 1994
[256] G Paganelli M Bartolomei M Ferrari et al ldquoPre-TargetedLocoregional Radioimmunotherapy withrdquo Cancer biotherapyand radiopharmaceuticals vol 16 no 3 pp 227ndash235 2001
[257] A Forero P L Weiden J M Vose et al ldquoPhase 1 trial of a novelanti-CD20 fusion protein in pretargeted radioimmunotherapyfor B-cell non-Hodgkin lymphomardquo Blood vol 104 no 1 pp227ndash236 2004
[258] DM Goldenberg C-H Chang E A RossiW J McBride andR M Sharkey ldquoPretargeted molecular imaging and radioim-munotherapyrdquoTheranostics vol 2 no 5 pp 523ndash540 2012
[259] H Karacay R M Sharkey W J McBride E A Rossi C-HChang and D M Goldenberg ldquoOptimization of hapten-peptide labeling for pretargeted immunoPET of bispecificantibody using generator-produced 68Gardquo Journal of NuclearMedicine vol 52 no 4 pp 555ndash559 2011
[260] J R Oh and B C Ahn ldquoFalse-positive uptake on radioiodinewhole-body scintigraphy physiologic and pathologic variantsunrelated to thyroid cancerrdquo American Journal of NuclearMedicine and Molecular Imaging vol 2 no 2 pp 141ndash150 2012
[261] E Frampas C Rousseau C Bodet-Milin J Barbet J-F Chataland F Kraeber-Bodere ldquoImprovement of radioimmunotherapyusing pretargetingrdquo Frontiers in Oncology vol 3 Article ID00159 2013
[262] C S McKay and M G Finn ldquoClick chemistry in complexmixtures Bioorthogonal bioconjugationrdquo Chemistry amp Biologyvol 21 no 9 pp 1075ndash1101 2014
[263] B L Oliveira Z Guo and G J Bernardes ldquoInverse electrondemand DielsndashAlder reactions in chemical biologyrdquo ChemicalSociety Reviews vol 46 no 16 pp 4895ndash4950 2017
[264] B Nichols Z Qin J Yang D R Vera and N K Devaraj ldquo68Gachelating bioorthogonal tetrazine polymers for the multisteplabeling of cancer biomarkersrdquo Chemical Communications vol50 no 40 pp 5215ndash5217 2014
[265] R Rossin P R Verkerk S M van den Bosch et al ldquoInvivo chemistry for pretargeted tumor imaging in live micerdquoAngewandte Chemie International Edition vol 49 no 19 pp3375ndash3378 2010
[266] B M Zeglis K K Sevak T Reiner et al ldquoA pretargetedPET imaging strategy based on bioorthogonal diels-alder clickchemistryrdquo Journal of Nuclear Medicine vol 54 no 8 pp 1389ndash1396 2013
[267] J L Houghton R Membreno D Abdel-Atti et al ldquoEstablish-ment of the invivo efficacy of pretargeted radioimmunotherapyutilizing inverse electron demand diels-alder click chemistryrdquoMolecular Cancer Therapeutics vol 16 no 1 pp 124ndash133 2017
[268] J Funkhouser ldquoReinventing pharma the theranostic revolu-tionrdquo Current Drug Discovery pp 17ndash19 2002
[269] J Sorensen I Velikyan A Wennborg et al ldquoMeasuring HER2-expression in metastatic breast cancer using 68Ga-ABY025PETCTrdquo European Journal of Nuclear Medicine and MolecularImaging vol 41 pp S226ndashS226 2014
[270] I Velikyan A Wennborg J Feldwisch et al ldquoGMP compliantpreparation of a 68Gallium-labeled Affibody analogue forbreast cancer patient examination first-in-manrdquoEur JNuclMedMol Imaging vol 41 pp S228ndashS229 2014
[271] K Oberg ldquoMolecular imaging radiotherapy Theranostics forpersonalized patient management of neuroendocrine tumors(NETs)rdquoTheranostics vol 2 no 5 pp 448ndash458 2012
[272] I Velikyan AWennborg J FeldwischH Lindman J Carlssonand J Sorensen ldquoGood manufacturing practice production of [(68) Ga]Ga-ABY-025 for HER2 specific breast cancer imagingrdquoAmerican Journal of Nuclear Medicine and Molecular Imagingvol 6 no 2 pp 135ndash153 2016
[273] M Sandstrom K Lindskog I Velikyan et al ldquoBiodistributionand radiation dosimetry of the anti-HER2 Affibody molecule68Ga-ABY-025 in breast cancer patientsrdquo Journal of NuclearMedicine vol 57 no 6 pp 867ndash871 2016
[274] D Sandberg V Tolmachev I Velikyan et al ldquoIntra-imagereferencing for simplified assessment of HER2-expression inbreast cancer metastases using the Affibody molecule ABY-025with PET and SPECTrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 44 no 8 pp 1337ndash1346 2017
[275] H ZhangM AMoroz I Serganova et al ldquoImaging expressionof the human somatostatin receptor subtype-2 reporter genewith 68Ga-DOTATOCrdquo Journal ofNuclearMedicine vol 52 no1 pp 123ndash131 2011
[276] M Naji and A Al-Nahhas ldquo68Ga-labelled peptides in themanagement of neuroectodermal tumoursrdquo European Journalof Nuclear Medicine and Molecular Imaging vol 39 no 1 ppS61ndashS67 2012
[277] I Velikyan ldquoThe diversity of 68Ga-Based imaging agentsrdquoRecent Results in Cancer Research vol 194 pp 101ndash131 2013
[278] K Ferreira H-Y Hu V Fetz et al ldquoMultivalent siderophore-dotam conjugates as theranostics for imaging and treatment ofbacterial infectionsrdquo Angewandte Chemie International Editionvol 56 no 28 pp 8272ndash8276 2017
Computational and Mathematical Methods in Medicine
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Research and TreatmentAIDS
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Parkinsonrsquos Disease
Evidence-Based Complementary andAlternative Medicine
Volume 2018Hindawiwwwhindawicom
Submit your manuscripts atwwwhindawicom
Contrast Media amp Molecular Imaging 7
300
250
200
150
100
50
0
(kBq
ml)
Inflammation
Kidneys
Muscle
Inflammation
Kidneys
Muscle
Figure 1 PET images of the distribution of [68Ga]Ga-DOTAVAP-P1 [68Ga]Ga-DOTAVAP-PEG-P1 and [68Ga]Ga-DOTA-Siglec-9 inturpentine-induced rat model of sterile inflammation All three peptide analogues showed target-to-nontarget ratio above 6 with rapidaccumulation in the inflammation site and renal clearance Adapted from [57]
labelledwith 68Gawere designed for the visualization ofVAP-1 and showed promising results in animals with inducedinfection and sterile inflammation [7ndash13 133] The bindingwas proven specific and it was possible to differentiate inflam-mation from infection [68Ga]Ga-Siglec targeting VAP-1demonstrated preclinical potential for imaging of synovialinflammation in patients with rheumatic diseases [53] Thesame agent was utilized for respiratory distress syndrome(ARDS an inflammatory lung injury) imaging in a porcinemodel [54] Imaging VAP-1 with [68Ga]Ga-Siglec was foundpromising also for the detection of inflamed atheroscle-rotic lesions [55] and inflammatory response induced bycatheter implantation and staphylococcal infection [56]68Ga-Siglec and two more peptide analogues with affinityto VAP-1 ([68Ga]Ga-DOTAVAP-P1 [68Ga]Ga-DOTAVAP-PEG-P1 and [68Ga]Ga-DOTA-Siglec-9) were investigated inrat model of sterile skinmuscle inflammation (Figure 1) [57]They showed distinct uptake in the affected sites
55 Targeting Chemokines Cytokines are produced bymacrophages B-lymphocytes T-lymphocytes and mast cellsand act through receptors modulating for example immuneresponse to infection and inflammation Cytokines includechemokines interleukins interferons and lymphokines thatcan be classified in broad families exhibiting diverse func-tions for example IL-1 and IL-6 superfamilies and TNFTNFreceptor superfamily Therapeutics targeting cytokines are inclinical use for example inhibiting TNF or IL-6 in rheumaticdiseases
Chemokine receptors are physiologically expressed onB-lymphocytes T-lymphocytes macrophages neutrophilseosinophils monocytes and hematopoietic stem cells [134]Imaging agents targeting CXCR4 are based on inhibitors(AMD3100) or small peptides (NFB T140 pentixafor andTN14003) and comprise 18F 67Ga 68Ga or 64Cu [135ndash148] They were developed and studied for the imaging of
various cancerous diseases lung breast prostate cancersacute myeloid leukemia and glioblastoma
The application of CXCR4 targeting agents was extendedbeyond oncology Clinical caseimage reports [149 150]were published on the utilization of [68Ga]Ga-pentixafor fordetection and quantification of CXCR4 receptor density inischemic heart diseases reflecting the role of the receptorin inflammatory and progenitor cell recruitment [58 59]The same agent was successfully used in the assessment ofmacrophage infiltration in atherosclerotic plaques in rabbitdisease model [151]
56 Targeting Folate Receptors Folate receptors (FRs) areoverexpressed on a variety of cancer cells and activatedmacrophages but not on normal cells [152 153] Theenhanced expression of FR was found in lung macrophagesduring acute inflammation [154] The majority of the nuclearimaging agents based on folic acid or pteroic acid [155] weredeveloped for diagnosis of cancers overexpressing FR recep-tors such as breast cervical ovarian colorectal nasopharyn-geal renal and endometrial cancers Various 68Ga-labelledagents demonstrated accumulation in cell cultures and micebearing folate-receptor positive human nasopharyngeal car-cinoma cell line (KB) xenografts [6 156ndash162] [68Ga]Ga-DOTA-PEG-FA comprising folic acid was investigated forthe detection and quantification of inflammatory response tomedical implants using mice with subcutaneously implantedpolylactic acid and poly(N-isopropylacrylamide) particles asa model [60] The agent was accumulated in the area of theimplant most probably reflecting interaction of [68Ga]Ga-DOTA-PEG-FA with folate receptor expressed on activatedmacrophages Another folic acid based agent [68Ga]Ga-DOTA-folate was successfully tested in an inflammatory pawrat model (Figure 2) [61] Distinct accumulation in inflamedhand and foot joints of rheumatoid arthritis of a 99mTc-labelled folate analogue was observed in a patient while no
8 Contrast Media amp Molecular Imaging
NH ONHONH
OOO
HOHN O
HN
NN
N N
HO
O
N
N
O
O
N
N
O
O
O
Ga+
minus
（3
(a)
2
15
1
05
0
(b)
Figure 2 Accumulation of [68Ga]Ga-DOTA-folate (a) in the site of inflammation of rat inflammatory pawmodel induced by subcutaneouslyinjected Complete Freundrsquos Adjuvant (b) Adapted from [61]
4
2
0
Figure 3 Intense atherosclerotic inflammation (white arrows) was detected by [68Ga]Ga-DOTA-TATE in a patient with acute coronarysyndrome Adapted from [65]
uptake was detected in a nonarthritis patientrsquos hands and feet[163]
57 Targeting Somatostatin Receptors Somatostatin receptor(SSTR) ligand analogues have found an extensive appli-cation in diagnosis and radiotherapy of neuroendocrinetumours The elevated expression of SSTRs is known also insmall cell lung cancer breast cancer renal cell carcinomaprostate cancer and malignant lymphoma A number ofsomatostatin ligand analogues labelled with gamma- andpositron-emitting radionuclides were used clinically foroncological cases [85 164ndash174] 68Ga-labelled somatostatinanalogues demonstrated superior performance in terms ofhigher specificity and sensitivity detection rate shorterexamination time and quantification possibility and havebecome a golden standard for the detection of neuroen-docrine tumours (NETs) taking over that title from [111In]-pentetreotide (OctreoScan) and demonstrating specificityand sensitivity of over 90 [27 175ndash180] 68Ga-labelledagents for the imaging of NETs demonstrated advantages
also over other radionuclides and tracers such as [18F]FDG[174] 123I-metaiodobenzylguanidine ([123I]MIBG) [181 182][18F]DOPA [183] [99mTc]-dicarboxy propane diphosphonate[184] and [18F]NaF
SSTR are also overexpressed on activated macrophagesand T-lymphocytes 68Ga-labelled analogues were used ininflammation related diseases such as idiopathic pulmonaryfibrosis [62] Gravesrsquo and Hashimotorsquos diseases [63] coro-nary artery plaque imaging and characterization [64] andatherosclerotic inflammation with excellent macrophagespecificity (Figure 3) [65] Promising diagnostic potential ofa 99mTc-labelled analogue was demonstrated in patients withrheumatoid arthritis and secondary Sjogrenrsquos syndrome andthe method was suggested for the assistance in anti-TNFalpha antibody treatment planning [185] [68Ga]Ga-DOTA-TOCPET-CT was found superior to 67Ga-CitrateSPECT indetection of sarcoidosis lesions [186] A clinical study demon-strated correlation between uptake of [68Ga]Ga-DOTA-TOCand SST2 mRNA expression and recorded the information ina database [187] providing tools for accurate quantification
Contrast Media amp Molecular Imaging 9
and evaluation of disease progression and treatment responsein cancerous and inflammatory diseases involving SSTRsPreclinical study using atherosclerotic mice demonstratedsuperior targeting properties of [68Ga]Ga-DOTA-NOC ascompared to [18F]FDR-NOC [188] overall confirming thepotential of SSTR targeting for atherosclerotic plaque imag-ing
58 Imaging Neuroinflammation Despite difficulty ofdesigning 68Ga-labelled molecules capable of blood-brainbarrier penetration several agents were suggested for theimaging of neuroinflammation in particular A120573 plaquesdeposited on blood vessels [67ndash69] Bivalent styrylpyridineslabelled with 68Ga demonstrated high specificity and affinityfor A120573 plaques using postmortem Alzheimerrsquos disease (AD)brain sections [67] Benzofuran derivative comprising 68Gashowed promising results in terms of binding specificityand affinity investigated in vitro in sections of Tg2576mice [68] Although the synthesis of a 68Ga-labelledPittsburgh compound analogue was successful the in vitrobinding to amyloid deposits was limited [69] The commondisadvantage of these agents is poor blood-brain barrierpenetration nevertheless the exploration of more successfulanalogues continues Curcumin functions as an antioxidantantimicrobial anti-inflammatory and anticancer agentDiacetyl-curcumin and bis(dehydroxy)curcumin labelledwith 68Ga demonstrated in vitro binding to 120573-amyloid fibrilsand lung cancer cells [189] Potential application of the agentscould include diagnostic imaging of Alzheimerrsquos disease andvarious cancers
6 Imaging Infection
Infection imaging can be indirect utilizing targets involvedin the immune response namely inflammation as presentedin the inflammation targets section above or direct utilizingpathogen related targets The direct imaging is especiallycrucial in cases where inflammatory response is absent Thedifference in biochemistry and structure between bacterialand human cells might exclude physiological uptake byhuman tissuemaking it easier tomeet the favorable character-istics of an imaging agent However discrimination betweenthe various infectious microorganisms pathogenic bacteriaand microbiota targeting specific bacteria type as well asdifficulty of accessing bacteria aggregated in a biofilm makesthe task very challenging [190 191] The specific targetingof infection would require accumulation of the radioactivesignal in the pathogen The radiolabelled targeting agentsfor infection can be roughly divided into several groupsantibiotics based antimicrobial protein and peptide basedsiderophore and other metabolisable compound based andantigen-specific antibodies and antibody fragments (Table 3)
61 Radiolabelled Antibiotics Antimicrobials act on the pro-cesses that are specific to microbes for example bacteria andfungi and thus corresponding imaging agents might distin-guish infection from inflammation [191] They might requireinternalization or may bind to the cell surface dependent on
their biological action mechanism [191ndash193] The possibilityof antibiotic resistance development exists also in the case ofimaging agents even though the amount of such agents wouldbe subnanomolar [194 195] Another complication is possiblenonspecific uptake of antibiotics based agents by leucocytes[196] Considerable number of various antibiotic analogueshave been labelled with 99mTc 111In 131I 11C and 18F[102] and evaluated preclinically and clinically with 99mTc-ciprofloxacin becoming a commercial product (Infecton) [21197 198] However the further improvement of specificityis desirable [191] Antibiotics are accessible and cheap andthey demonstrate high sensitivity [102 191] making thedevelopment of 68Ga-labelled analogues very attractive giventhe earlier mentioned advantages that 68Ga as a radionu-clide in combination with PET provides Two 68Ga-labelledanalogues based on ciprofloxacin demonstrated potential fordiscrimination between bacterial infection and inflammationin rats infected with Staphylococcus aureus [70]
62 Radiolabelled Antimicrobial Proteins and Peptides Anti-microbial proteins and peptides for example serprocidinscathelicidins and defensins produced by the cells of immunesystem target microbial membrane lipids and impose micro-bicidal effect [35 43] They present a large group of poten-tial candidates for microbial imaging including bacteriafungi parasites and viruses Antimicrobial peptides havedemonstrated higher specificity for infection than antibioticanalogues They accumulate at infection but not sterileinflammation sites The most thoroughly studied antimicro-bial peptide ubiquicidin UBI [29ndash41] labelled with 99mTc[199] demonstrated promising results in human clinical trials[200 201] It has the potential for quantification of viableinfecting microorganisms and consequently for monitoringthe efficacy of antimicrobial therapy in patients
Fragments of an antimicrobial peptide ubiquicidin con-jugated to NOTA and labelled with 68Ga [68Ga]Ga-NOTA-UBI29-41 and [68Ga]Ga-NOTA-UBI30-41 demonstratedpossibility for the distinction between infection and inflam-mation in a rabbit model [71 72] Antimicrobial peptidefragments GF-17 and RAWVAWR-NH2 of respectivelyhuman cathelicidin LL-37 andhuman lysozyme active againstE coli and S aureus were labelled with 68Ga and theirbiodistribution in normal rats demonstrated fast clearancefrom liver [75] Antimicrobial depsipeptide based agent[68Ga]Ga-DOTA-TBIA101 targeting bacterial lipopolysac-charides detected muscular E coli-infection in mice (Fig-ure 4) [73] The agent was also studied in healthy rabbitsand various disease model rabbits such as sterile inflam-mation Staphylococcus aureus infection andMycobacteriumtuberculosis [74] The clearance of [68Ga]Ga-DOTA-TBIA101from blood and normal tissue was fast and enhanced uptakein sterile inflammation and Mycobacterium tuberculosis siteswas observed The improvement of the bacterial selectivitywill require modification of the agent structure
63 Radiolabelled Siderophores Bacteria and fungi producevarious siderophores for harvesting iron which is essentialfor their survival and growth [34 98 191] Siderophores
10 Contrast Media amp Molecular Imaging
(a)
(b)
(c) (d)
(e)
Figure 4 Left panel presents maximum intensity projection images of [68Ga]Ga-DOTA-TBIA101 distribution in a healthy mouse (a) and amouse with muscular infection site (MIS) in the right hind muscle tissue (white arrows) Right panel presents coronal (c) sagittal (d) andaxial (e) images with uptake in theMIS (white arrow) and absence of the uptake in the contralateralmuscle tissue Ki and Bl stand respectivelyfor kidney and bladder Reproduced from [73]
can also play a critical role in the development of biofilmsby microbes They are low molecular weight compoundsspecifically chelating Fe(III) and Ga(III) can form stablecomplexes with them mimicking Fe(III) [202 203]
Desferri-triacetylfusarinine C (TAFC) and desferri-ferricrocin (FC) labelled with 68Ga were used for theimaging of invasive pulmonary aspergillosis (IPA) caused byAspergillus fumigatus [15] [68Ga]Ga-TAFC demonstratedsuperior characteristics in terms of specific target bindingmetabolic stability and fast blood clearance in a rat modelof A fumigatus infection Seven analogues were developedin another study with TAFC and ferrioxamine E (FOXE)showing favorable binding clearance elimination andstability characteristics [16] as well as lung uptake inrat of invasive aspergillosis model wherein the uptakeextent was correlated with disease severity [17] [68Ga]Ga-triacetylfusarinine C and [68Ga]Ga-ferrioxamine E wereinvestigated in rat model of A fumigatus and demonstratedrapid uptake in the lungs (Figure 5) [76]
64 Radiolabelled Metabolisable Agents Mammalian micro-biota consumes (poly)saccharides in particular maltose andmaltodextrins [204] The transport mechanism is specific
to bacteria and is absent in mammalian cells making itpossible to utilize these (poly)saccharides for imaging agentdevelopment Maltodextrin functionalized with a fluorescentdye was internalized through the bacteria-specific maltodex-trin transport pathway and discriminated between activebacteria and inflammation in vivo [192] Maltose labelledwith 18F localized specifically bacterial infection in mice[205] Potential to label polysaccharides directly with 68Gamight be utilized extensively
As mentioned above the chemical properties of Ga(III)provide the potential for direct labelling of polysaccharidesDextran was labelled directly and resulting complex demon-strated sufficient stability in human serum however thefeasibility of the bacterial imaging was not demonstrated[206]
Trapping of nucleosides that are substrates of thymidinekinase occurring within bacteria was explored using 18Fand 125I labelled analogues of uracil [207] Promising resultswere obtained in seven bacterial species in mice Anotherstudy in the context of therapeutic bacteria developmentdemonstrated possibility of detecting Salmonella vectorswithin tumours using 18F-labelled uracil [208] However
Contrast Media amp Molecular Imaging 11
N
O
N
ON
HN
O
O
O
OO O
NH
O
O
O
O
NH
O
OGa
（3
（3
（3
（3
（3
（3
（2
(a) (b) (c)
Figure 5 Molecular structure of [68Ga]Ga-triacetylfusarinine C (a) used for the in vivo imaging of a rat with Aspergillus fumigatus infection(b) and negative control of noninfected rat (c) White arrows point at the infected (b) and normal (c) lungs Adapted from [76]
the development of 68Ga-labelled nucleosides that wouldmaintain their biological activity is challenging and fewexamples known from the literature confirm that [4 6]
7 68Ga-Citrate
As mentioned above 68GaPET provides a number of advan-tages over 67GaSPECT and following publications demon-strate it in clinical and preclinical studies [68Ga]Ga-citratedemonstrated high diagnostic accuracy of 90of osteomyeli-tis and diskitis in clinical studies (Figure 6) [18 19] Thisstudy demonstrates that [68Ga]Ga-citrate can be employedfor monitoring the response to treatment [68Ga]Ga-citratewas used clinically to follow-up surgical intervention inpatients with acute osteomyelitis and intra-abdominal infec-tion [77] The agent was also used to successfully visualizelungmalignancy and tuberculosis in patients however in caseof high prevalence of granulomatous diseases the distinctionbetween malignant and benign lung lesions was unclear [7879] Another clinical study conducted head-to-head compar-ison of [68Ga]Ga-citrate (Figure 7) and [18F]FDG in patientswith Staphylococcus aureus bacteremia [80] The detectionrate of osteomyelitis was similar and further investigationof [68Ga]Ga-citrate applicability in cases of osteomyelitisinduced by other pathogens as well as for monitoring healingprocess is warranted
Comparative study of [68Ga]Ga-citrate and [67Ga]Ga-citrate was performed in healthy and infection model rats[77] The performance of [68Ga]Ga-citrate was found supe-rior in terms of image contrast in the lower abdomen and
extremities Potential of [68Ga]Ga-citrate for the differentia-tion of acute interstitial nephritis from acute tubular necrosiswas studied in rat model of the disease and it was demon-strated that the kidney uptake correlated with the extentof mononuclear cell infiltration accompanying inflammation[209] 68Ga-labelled Apo-transferrin demonstrated bacterialinfection detection capacity in rat model with Staphylococcusaureus wherein the infection site was visualized 1 h afteradministration of the agent [14]
71 Radiolabelled Antibodies and Antibody FragmentsHuman immunoglobulin (HIG) binds to bacteria but alsoaccumulates at the sites of fungal and viral infection aswell as sterile inflammation due to binding to leukocytesThe improved specificity for bacteria was achieved for thefragments of HIG It is feasible to develop specific antibodiesto various antigens present on the bacterial cell surface [102]Monoclonal antibodies labelled with 99mTc were used forinfection imaging via granulocytes targeting NCA-95 [210]Various cytokines of interleukin family (IL-1 IL-8) labelledwith 123I or 99mTc demonstrated accumulation in the sitesof infection in various animal models [111 112 211ndash214]Registered antigranulocyte radiopharmaceuticals suchas LeuTech Scintimun and Leukoscan are based on99mTc-labelled antibodies This experience can be translatedto 68Ga however either the size of the antibodies mustbe reduced or pretargeting techniques must be appliedin order to overcome the discrepancy between the shortphysical half-life of 68Ga and slow pharmacokinetics ofantibodies
12 Contrast Media amp Molecular Imaging
(a) (b) (c) (d)
Figure 6 [68Ga]Ga-citrate PETCT examination of a patient affected by acute osteomyelitis before (left panel) and after (right panel) surgicalcurettage showing uptake in the transaxial (a c) and 3D reconstruction images (b d red area) Absence of the uptake after the therapyconfirms complete response to the treatment Adapted from [19]
Figure 7 Vertebral osteomyelitis (spondylodiscitis red arrow-heads) and abscesses in the iliopsoas and paravertebral area (redarrows) were detected by [68Ga]Ga-citrate in a patient admittedto the hospital with back pain and general symptoms The PETacquisition was performed 88min after administration of 245MBqof [68Ga]Ga-citrate Adapted from [80]
72 Radiolabelled Biotin Biotin is a growth factor utilizedin many bacteria An 111In-labelled analogue of biotin wassuccessfully utilized for diagnosis of vertebral infections ina clinical study [215] It would be rational to explore therelevance of 68Ga-labelled analogues given the advantagesof 68Ga over 111In and promising [68Ga]Ga-DOTA-Biotinanalogues [216 217] developed for monitoring survival oftransplanted avidin-coated islets
8 Miscellaneous
Stable Ga(III) complex with thiosemicarbazones demon-strated antimicrobial effect against P aeruginosa and Calbicans due to most probably both displacement of essentialFe(III) with Ga(III) and thiosemicarbazones [101] Substitu-tion of the stable Ga(III) by radioactive 68Ga might result ina specific infection imaging agent
Selective imaging of Enterobacteriaceae using 2-[18F]-fluorodeoxysorbitol (18F-FDS)was demonstrated in amurine
myositis model [218] The uptake of 18F-FDS was correlatedwith bacterial burden moreover the agent differentiatedinfection from sterile inflammation Given the potential of68Ga for the labelling of small biologically active molecules[4] it might be plausible to develop a respective analoguewith added value of the advantages that 68Ga offers includingsimpler production chemistry lowered radiation dose repet-itive examination and accessibility at clinical centers withoutcyclotrons and remote from [18F]-FDG distribution sites Asmentioned above the poor access to bacteria aggregated ina biofilm might make the imaging task challenging Severalpeptide candidates with affinity for S aureus biofilm weredesigned and labelled with 68Ga [219] The resulting agentsdemonstrated binding in vitro however it was not possible toblock the binding with excess of the cold peptide
Ionic 68Ga was found superior to [18F]-FDG in infectiondetection in the rat model with diffuse osteomyelitis [220] Inanother study the uptake of ionic 68Ga was observed in theaortic plaques of atherosclerotic mice specifically at the sitesrich inmacrophages [221] However the slow blood clearanceof ionic 68Ga presents a limitation
Chronic inflammation is the major reason of fibro-sis [222] 68Ga-labelled SST analogue ([68Ga]Ga-DOTA-NOC) demonstrated uptake in pathogenic areas in patientsaffected by idiopathic pulmonary fibrosis with potentialfor monitoring response to treatment and drug develop-ment [62] Another clinical study using [68Ga]Ga-pentixaforalso showed potential of the agent for monitoring dis-ease activity and response to treatment in idiopathic pul-monary fibrosis [223] Peptide based agents CNO2A-PEG2-c[CPGRVMHGLHLGDDEGPC] and [68Ga]Ga-NODAGA-PEG2-c[CPGRVMHGLHLGDDEGPC] for the imaging andquantification of fibrosis by PET were developed and char-acterized preclinically showing fast clearance from normal
Contrast Media amp Molecular Imaging 13
tissue and blood and binding specificity [89] Dosimetrycalculations demonstrated possibility of six examinations peryear in humans assuring disease monitoring in longitudinalstudies and routine clinical setup [224]
Several hyaluronan conjugates of oligonucleotides target-ing CD44 positive cells were developed and tested in healthyrats sham-operated rats and rats with myocardial infarction[225]The uptake of the agents was higher for the latter groupand varied dependent on the difference in the oligonucleotidestructure
TLR2 and TLR4 expression levels in neutrophils werefound higher in individuals with bacterial and viral infectionsthan those in control samples There is a possibility that IL-4IL-8 IL-10 IL-12 and TNF-a might serve as biomarkers forinfections and that IL-2 IL-8 or IL-10 is potentially able todistinguish between bacterial and viral infections [22]
Mannosylated human serum albumin labelled with 68Gavia NOTA chelator moiety ([68Ga]Ga-NOTA-MSA) wastested in a rat model of myocarditis targetingmannose recep-tors expressed onmacrophages infiltratingmyocardium [66]The uptake in the diseased myocardium was considerablyhigher than that of the normal one and it was precludedby administration of excess of nonlabelled MSA indicatingbinding specificity The tracer build-up was also observed inthe organs of macrophage accumulation
[68Ga]Ga-DOTA was investigated for the quantificationof increased blood flow which is one of the key events ininflammation [226] The uptake kinetics of [68Ga]Ga-DOTAin the site of inflammation in rats with induced inflamma-tion correlated well with that of 15O-water suggesting highrelevance [68Ga]Ga-DOTA
9 Pretargeted Imaging
The half-life of 68Ga is shorter than that of 64Cu 67Ga 99mTc89Zr 111In and 123124125I and thus in contrast to the latterit is not compatible with slow pharmacokinetics of largemolecules such as antibodies and glycoproteins The rangeof antigen-specific antibodies relevant to inflammation andinfection is broad and a number of 99mTc-labelled antibodieswere used clinically [20 21 227] The respective range of68Ga-based agents could be similarThe solution to overcomethe incompatibility of half-life time frames could be eitherthe reduction of the antibody size or the application of thepretargeting concept
The history of the pretargeting concept spans threedecades predominantly in the field of oncology [228ndash230]It was developed to improve image contrast and dosimetryin immunoimaging and radioimmunotherapy when usingradiolabelled antibody ligands with slow pharmacokinetics[231] The arsenal of antibodies is vast and diverse encourag-ing extensive investment into development of techniques thatwould allow their exploration to the fullest Pretargeting con-siders at least two major steps wherein a functionalized anti-body is first administered for target localization and clearancefrom blood and normal tissue and thereafter a radiolabelledsmall molecule capable of binding to the functionalized
antibody due to high affinity or covalent interaction is admin-istered The key properties of the radiolabelled molecules arefast pharmacokinetic and clearance Several techniques havebeen developed for the realization of pretargeting conceptincluding avidinstreptavidin-biotin systems [216 217 232233] bispecific antibodies (bsmAb) with haptens [232 234ndash254] antibody-oligonucleotide conjugates with complemen-tary oligonucleotides [255] biorthogonal systems allowingcovalent chemical reactions in vivo (Figure 8)
The high affinity of biotin to avidin and streptavidinproteins was utilized clinically and preclinically in pretar-geting approach for the imaging and therapy of pancreaticadenocarcinoma [232] glioblastoma [256] and lymphoma[257] However this pretargeting technique may requirethree steps in order to eliminate the excess of antibody-(strept)avidin conjugate circulating in the blood and notbound to the target by adding clearing agent Anotherapplication of the technique was monitoring transplantationof islets of Langerhans in the treatment for type 1 diabetesmellitus wherein the cells or cellmimetics were conjugated to(strept)avidin prior to the transplantation [216 217] Severalanalogues of biotin comprising DOTA chelate moiety forlabelling with 68Ga and ethylene glycol linker of variouslength demonstrated the influence of the latter on the affinitytowards avidin
Particular example of hapten molecules is the ones com-prising histamine-succinyl-glycine (HSG) motif and chelatemoiety [251ndash253 258] for the complexationwith 68Ga Severalanalogues were developed for the imaging of carcinoem-bryonic antigen (CEA) pretargeted with anti-CEA bsmAb[254 259 260] and two clinical studies of medullary thyroidcarcinoma and breast carcinoma positive for CEA using68Ga-labelled hapten molecules and bsmAb were initiated[261]
Bioorthogonal reactions are fast regioselective requiringsmall reagent concentration and occurring under mild con-ditions often in aqueous solution and temperature below 37∘C[262 263] Amongst various biorthogonal reaction types thecycloaddition of tetrazines and various dienophiles referredto as inverse-electron-demandDiels-Alder (IEDDA) reactionis themost successful in the context of pretargeting Antibod-ies functionalized with trans-cyclooctene (TCO) and a radi-olabelled tetrazine that can interact in vivo based on IEDDAreaction were studied [264ndash267] In particular 68Ga-labelledtetrazine dextran demonstrated favorable pharmacokineticsin a healthy mouse [264] However the proof of concept is tobe performed in a xenografted animal Accumulation of anti-TAG72 [265] and anti-A33 [266] antibodies functionalizedwith TCO in mouse xenografts was visualized respectivelyby an 111In and 64Cu-labelled tetrazine analogues Anti-CA199 antibody-TCO in combination with 177Lu-labelledtetrazine demonstrated radiotherapeutic effect in pancreaticcancer murine model [267]
Thepretargeted imaging techniquesmay contribute to theexpansion of immuno-PET with 68Ga providing the intrinsicadvantages of 68Ga and PET As mentioned above mostof the developed radiolabelled counterparts of pretargetingtechniques have demonstrated promising results There are
14 Contrast Media amp Molecular Imaging
H
ON
NN
O
OO
OO
NH
NS
NH
ONH
O
HO
ONH
O
Ga
HN
NH
NH
O
OO
HNN
HN
NH
NH
O
OO
HNN
（2
(a)
NH
O
O
NH
N
NNGa
O O
O O
O
O
O
N N
NN
OO
（2
(b)
N
N
O
O
N
N
O
O
O
NH
O
O
ONH
NHS
O
H
HO
NH
+
minus
(c)
Figure 8 Schematic presentation of pretargeting techniques (a) bispecific antibodies engineered to specifically bind with radiolabelledhapten molecules (b) bioorthogonal click chemistry for fast and specific covalent binding between for example a trans-cyclooctenefunctionalized antibody and a radiolabelled tetrazine (c) interaction between antibody-(strept)avidin conjugate and radiolabelled biotinutilizing extremely high affinity of (strept)avidin and biotin
Contrast Media amp Molecular Imaging 15
a considerable number of potential antibody biomarkersthat could be considered for the imaging of infection andinflammation
10 Theranostics Potential
Theranostics [268] embraces realization of personalizedmedicine by conducting diagnosis on individual basis andproviding possibility of predicting the efficacy of a specifictreatment and following up the response to the treatmentenabling adjustment of the latter very early in the processIn the context of nuclear medicine wherein the radiophar-maceuticals targeted at biomarkers specific to a disease cancarry either diagnostic radionuclides or therapeutic ones theconcept can be denoted as radiotheranostics [28] The tar-geted molecular imaging such as PET can offer noninvasivediagnosis specific to the disease for example tumour-typespecific and provide accurate localization of the lesions Thestrongest advantage of PET is the potential for quantificationof the target for example receptor expression investigationof the uptake kinetics and estimation of the dosimetryThesecharacteristics of PET allow for individualized treatmentselection and planning monitoring of treatment responseand detection of recurrent diseaseThe individualized patientmanagement provides such advantages as optimization ofthe treatment regimen for the improved response and exclu-sion of futile treatments minimization of risks and toxicitywith overall outcome of reduced cost and patient distressThe importance of individualized patient management wasdemonstrated by clinical studies wherein the influence ofdose of the administered radiopharmaceutical targeted atreceptors overexpressed in cancer lesions on the diagnosticoutcome was investigated in the same patient [85 269270] 68Ga-labelled SST analogues [26ndash28 271] and Affibodymolecules [5 272ndash274] used respectively in NENs andbreast cancer patients are the most prominent examplesof (radio)theranostics involving 68GaPET wherein 68Ga-labelled analogues were used not only for localization of thelesions but also for staging patient stratification prognosistherapy selection and monitoring of the response to thetreatment of NETs and other cancer types [2ndash4 6 85 176275ndash277]
The methodology can be translated to inflammationand infection allowing for accurate and specific selection oftreatment regimen and for follow-up and evaluation of theresponse to therapy resulting in improved treatment efficacyand decreased cost and side effects The accommodation ofboth imaging function and antibiotic function in the samemolecule is a novel example of a theranostic agent [278]A series of siderophores conjugated with DOTA moiety forthe radiolabelling and with antibiotics for the treatmentof bacterial infection were investigated preclinically Theaccumulation of the intravenously administered ampicillinconjugate in the site of subcutaneously injected P aeruginosain mice was clearly and focally visualized within 06 h withretention for at least 24 h These results obtained usinganalogues carrying dye for optical imaging can be translatedto 68Ga-labelled counterparts for PET
11 Conclusions
The medical need for specific agents for noninvasive quan-titative and whole-body imaging of inflammation and infec-tion has not been met yet despite decades of research How-ever the prerequisites in terms of identification of potentialtargets design and synthesis of the respective ligands andimaging technologies are evolving very fast The potentialof accurate and quantitative lesion localization as well asmonitoring of the treatment response promises personalizedpatient management
The use of 68Ga in oncology is established proving thestrong potential of 68Ga for the promotion of PET technol-ogy for effective and efficient diagnostics and personalizedmedicineThe experience of oncological 68Ga-based agents isgetting translated to inflammation and infection Pretargetedimaging technology opens wide possibilities based on anti-body biomarkers
Conflicts of Interest
The author declares that there are no conflicts of interestregarding the publication of this article
References
[1] I Velikyan ldquoContinued rapid growth inGa applications update2013 to June 2014rdquo Journal of Labelled CompoundsampRadiophar-maceuticals pp 99ndash121 2015
[2] I Velikyan ldquo 68Ga-based radiopharmaceuticals Production andapplication relationshiprdquo Molecules vol 20 no 7 pp 12913ndash12943 2015
[3] M Fani P Peitl and I Velikyan ldquoCurrent status of radiophar-maceuticals for the theranostics of neuroendocrine neoplasmsrdquoPharmaceuticals vol 10 no 1 article no 30 2017
[4] I Velikyan ldquoPositron emitting [68Ga]Ga-based imaging agentsChemistry and diversityrdquoMedicinal Chemistry vol 7 no 5 pp345ndash379 2011
[5] J Sorensen I Velikyan D Sandberg et al ldquoMeasuringHER2-receptor expression in metastatic breast cancer using[68Ga]ABY-025 Affibody PETCTrdquo Theranostics vol 6 no 2pp 262ndash271 2016
[6] I Velikyan ldquoProspective of 68Ga-Radiopharmaceutical devel-opmentrdquoTheranostics vol 4 no 1 pp 47ndash80 2014
[7] P Lankinen T J Makinen T A Poyhonen et al ldquo68Ga-DOTAVAP-P1 PET imaging capable of demonstrating the phaseof inflammation in healing bones and the progress of infectionin osteomyelitic bonesrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 35 no 2 pp 352ndash364 2008
[8] T UjulaMHuttunen P Luoto et al ldquoMatrixmetalloproteinase9 targeting peptides Syntheses 68Ga-labeling and preliminaryevaluation in a rat melanoma xenograft modelrdquo BioconjugateChemistry vol 21 no 9 pp 1612ndash1621 2010
[9] A Autio T Ujula P Luoto S Salomaki S Jalkanen and ARoivainen ldquoPET imaging of inflammation and adenocarcinomaxenografts using vascular adhesion protein 1 targeting peptide68Ga-DOTAVAP-P1 Comparison with 18F-FDGrdquo EuropeanJournal of Nuclear Medicine and Molecular Imaging vol 37 no10 pp 1918ndash1925 2010
16 Contrast Media amp Molecular Imaging
[10] J Silvola A Autio P Luoto S Jalkanen andA Roivainen ldquoPre-liminary evaluation of novel 68Ga-DOTAVAP-PEG-P2 peptidetargeting vascular adhesion protein-1rdquo Clinical Physiology andFunctional Imaging vol 30 no 1 pp 75ndash78 2010
[11] T Ujula S Salomaki P Virsu et al ldquoSynthesis 68Ga labelingand preliminary evaluation of DOTA peptide binding vascularadhesion protein-1 a potential PET imaging agent for diagnos-ing osteomyelitisrdquo Nuclear Medicine and Biology vol 36 no 6pp 631ndash641 2009
[12] A Autio T Henttinen H J Sipila S Jalkanen and ARoivainen ldquoMini-PEG spacering of VAP-1-targeting 68Ga-DOTAVAP-P1 peptide improves PET imaging of inflamma-tionrdquo EJNMMI Research vol 1 no 1 pp 1ndash7 2011
[13] K Aalto A Autio E A Kiss et al ldquoSiglec-9 is a novel leukocyteligand for vascular adhesion protein-1 and can be used in PETimaging of inflammation and cancerrdquo Blood vol 118 no 13 pp3725ndash3733 2011
[14] V Kumar D K Boddeti S G Evans F Roesch and RHowman-Giles ldquoPotential use of 68Ga-apo-transferrin as a PETimaging agent for detecting Staphylococcus aureus infectionrdquoNuclear Medicine and Biology vol 38 no 3 pp 393ndash398 2011
[15] M Petrik H Haas G Dobrozemsky et al ldquo68Ga-siderophoresfor PET imaging of invasive pulmonary aspergillosis Proof ofprinciplerdquo Journal of Nuclear Medicine vol 51 no 4 pp 639ndash645 2010
[16] M Petrik H Haas M Schrettl A Helbok M Blatzer and CDecristoforo ldquoIn vitro and in vivo evaluation of selected 68Ga-siderophores for infection imagingrdquo Nuclear Medicine andBiology vol 39 no 3 pp 361ndash369 2012
[17] M Petrik GM Franssen H Haas et al ldquoPreclinical evaluationof two 68Ga-siderophores as potential radiopharmaceuticals forAspergillus fumigatus infection imagingrdquo European Journal ofNuclearMedicine andMolecular Imaging vol 39 no 7 pp 1175ndash1183 2012
[18] A Rizzello D Di Pierro F Lodi et al ldquoSynthesis and qualitycontrol of 68Ga citrate for routine clinical PETrdquo NuclearMedicine Communications vol 30 no 7 pp 542ndash545 2009
[19] C Nanni C Errani and L Boriani ldquo 68Ga-citrate PETCT forevaluating patients with infections of the bone preliminaryresultsrdquo Journal of Nuclear Medicine vol 51 no 12 pp 1932ndash1936 2010
[20] S S Das A V Hall D W Wareham and K E Britton ldquoInfec-tion imaging with radiopharmaceuticals in the 21st centuryrdquoBrazilian Archives of Biology and Technology vol 45 no spepp 25ndash37 2002
[21] A Signore and A W J M Glaudemans ldquoThe molecularimaging approach to image infections and inflammation bynuclear medicine techniquesrdquo Annals of Nuclear Medicine vol25 no 10 pp 681ndash700 2011
[22] T Yusa K Tateda A Ohara and S Miyazaki ldquoNew possiblebiomarkers for diagnosis of infections and diagnostic distinc-tion between bacterial and viral infections in childrenrdquo Journalof Infection and Chemotherapy vol 23 no 2 pp 96ndash100 2017
[23] A Signore A W J M Glaudemans O Gheysens C Lauriand O A Catalano ldquoNuclear Medicine Imaging in PediatricInfection or Chronic Inflammatory Diseasesrdquo Seminars inNuclear Medicine vol 47 no 3 pp 286ndash303 2017
[24] I Velikyan ldquoMolecular imaging and radiotherapyTheranosticsfor personalized patient managementrdquo Theranostics vol 2 no5 pp 424ndash426 2012
[25] F Rosch and R P Baum ldquoGenerator-based PET radiophar-maceuticals for molecular imaging of tumours On the way
to THERANOSTICSrdquo Dalton Transactions vol 40 no 23 pp6104ndash6111 2011
[26] R P Baum H R Kulkarni and C Carreras ldquoPeptides andreceptors in image-guided therapy Theranostics for neuroen-docrine neoplasmsrdquo Seminars in Nuclear Medicine vol 42 no3 pp 190ndash207 2012
[27] R P Baum and H R Kulkarni ldquoTheranostics From molecularimaging using Ga-68 labeled tracers and PETCT to per-sonalized radionuclide therapy - the bad berka experiencerdquoTheranostics vol 2 no 5 pp 437ndash447 2012
[28] I Velikyan ldquoRadionuclides for Imaging andTherapy in Oncol-ogyrdquo Cancer Theranostics pp 285ndash325 2014
[29] J Czernin andWAWeber ldquoIssues and controversies in nuclearmedicine Introductionrdquo Journal of Nuclear Medicine vol 52no Supplement 2 pp 1Sndash2S 2011
[30] S J Goldsmith and S Vallabhajosula ldquoClinically proven radio-pharmaceuticals for infection imaging mechanisms and appli-cationsrdquo Seminars in Nuclear Medicine vol 39 no 1 pp 2ndash102009
[31] M F Tsan ldquoMechanism of gallium-67 accumulation in inflam-matory lesionsrdquo Journal of Nuclear Medicine vol 26 no 1 pp88ndash92 1985
[32] S L Kipper ldquoRadiolabelled leukocyte imaging of the abdomenrdquoin Nuclear Medicine Annual J Freeman Ed pp 81ndash126 RavenPress New York NY USA 1995
[33] F Jamar J Buscombe A Chiti et al ldquoEANMSNMMI guidelinefor 18F-FDG use in inflammation and infectionrdquo Journal ofNuclear Medicine vol 54 no 4 pp 647ndash658 2013
[34] C J Palestro ldquoThe current role of gallium imaging in infectionrdquoSeminars in Nuclear Medicine vol 24 no 2 pp 128ndash141 1994
[35] M S Akhtar M B Imran M A Nadeem and A ShahidldquoAntimicrobial peptides as infection imaging agents better thanradiolabeled antibioticsrdquo International Journal of Peptides vol2012 Article ID 965238 19 pages 2012
[36] D Delbeke and G M Segall ldquoStatus of and trends in nuclearmedicine in the United Statesrdquo Journal of Nuclear Medicine vol52 no 2 2011
[37] S S Gambhir J Czernin J Schwimmer D H Silverman R EColeman and M E Phelps ldquoA tabulated summary of the FDGPET literaturerdquo Journal of Nuclear Medicine vol 42 pp 1Sndash93S2001
[38] M J Lindsay B A Siegel S R Tunis et al ldquoThe NationalOncologic PET Registry ExpandedMedicare coverage for PETunder coverage with evidence developmentrdquo American Journalof Roentgenology vol 188 no 4 pp 1109ndash1113 2007
[39] F Gemmel H Van Den Wyngaert C Love M M Welling PGemmel and C J Palestro ldquoProsthetic joint infectionsradionuclide state-of-the-art imagingrdquo European Journal ofNuclearMedicine andMolecular Imaging vol 39 no 5 pp 892ndash909 2012
[40] J Sorensen ldquoHow does the patient benefit from clinical PETrdquoTheranostics vol 2 no 5 pp 427ndash436 2012
[41] S L Rice C A Roney P Daumar and J S Lewis ldquoThe nextgeneration of positron emission tomography radiopharmaceu-ticals in oncologyrdquo Seminars in Nuclear Medicine vol 41 no 4pp 265ndash282 2011
[42] R LWahl JMHerman and E Ford ldquoThePromise and Pitfallsof Positron Emission Tomography and Single-Photon EmissionComputed Tomography Molecular Imaging-Guided RadiationTherapyrdquo Seminars in Radiation Oncology vol 21 no 2 pp 88ndash100 2011
Contrast Media amp Molecular Imaging 17
[43] A W J M Glaudemans R H J A Slart J M Van Dijl MVan Oosten and G M Van Dam ldquoMolecular imaging of infec-tious and inflammatory diseases A terra incognitardquo Journal ofNuclear Medicine vol 56 no 5 pp 659ndash661 2015
[44] X Li W Bauer I Israel et al ldquoTargeting p-selectin by gallium-68-labeled fucoidan positron emission tomography for nonin-vasive characterization of vulnerable plaques Correlation within vivo 176t mrirdquo Arteriosclerosis Thrombosis and VascularBiology vol 34 no 8 pp 1661ndash1667 2014
[45] S Eichendorff P Svendsen D Bender et al ldquoBiodistributionand PET Imaging of a Novel [68Ga]-Anti-CD163-AntibodyConjugate in Rats with Collagen-Induced Arthritis and inControlsrdquoMolecular Imaging and Biology vol 17 no 1 pp 87ndash93 2014
[46] Z Zhu Y Yin K Zheng et al ldquoEvaluation of synovial angiogen-esis in patients with rheumatoid arthritis using 68Ga-PRGD2PETCT A prospective proof-of-concept cohort studyrdquo Annalsof the Rheumatic Diseases vol 73 no 6 pp 1269ndash1272 2014
[47] J S Eo J C Paeng S Lee et al ldquoAngiogenesis imaging inmyocardial infarction using 68Ga-NOTA- RGD PET Charac-terization and application to therapeutic efficacy monitoring inratsrdquo Coronary Artery Disease vol 24 no 4 pp 303ndash311 2013
[48] J H Kim Y-H Kim Y J Kim et al ldquoQuantitative positronemission tomography imaging of angiogenesis in rats with fore-limb ischemia using 68Ga-NOTA-c(RGDyK)rdquo Angiogenesisvol 16 no 4 pp 837ndash846 2013
[49] I Laitinen J Notni K Pohle et al ldquoComparison of cyclicRGD peptides for 120572v1205733 integrin detection in a rat model ofmyocardial infarctionrdquo EJNMMI Research vol 3 no 1 pp 1ndash9 2013
[50] M Kiugel I Dijkgraaf V Kyto et al ldquoDimeric [68Ga]DOTA-RGD Peptide Targeting 120572 ltinfgtvltinfgt 120573 ltinfgt3ltinfgt Inte-grin Reveals Extracellular Matrix Alterations after MyocardialInfarctionrdquo Molecular Imaging and Biology vol 16 no 6 pp793ndash801 2014
[51] M Gronman M Tarkia T Kiviniemi et al ldquoImaging of 120572v1205733integrin expression in experimental myocardial ischemia with[68Ga]NODAGA-RGD positron emission tomographyrdquo Jour-nal of Translational Medicine vol 15 no 1 p 144 2017
[52] J Haukkala I Laitinen P Luoto et al ldquo68Ga-DOTA-RGDpep-tide Biodistribution and binding into atherosclerotic plaquesin micerdquo European Journal of Nuclear Medicine and MolecularImaging vol 36 no 12 pp 2058ndash2067 2009
[53] H Virtanen A Autio R Siitonen et al ldquo68Ga-DOTA-Siglec-9- a new imaging tool to detect synovitisrdquo Arthritis Research ampTherapy vol 17 no 1 article no 308 2015
[54] J Retamal J Sorensen M Lubberink et al ldquoFeasibility of(68) Ga-labeled Siglec-9 peptide for the imaging of acutelung inflammation a pilot study in a porcine model of acuterespiratory distress syndromerdquoAm JNuclMedMol Imaging vol6 no 1 pp 18ndash31 2016
[55] J M U Silvola H Virtanen R Siitonen et al ldquoLeukocytetrafficking-associated vascular adhesion protein 1 is expressedand functionally active in atherosclerotic plaquesrdquo ScientificReports vol 6 Article ID 35089 2016
[56] H Ahtinen J Kulkova L Lindholm et al ldquo68Ga-DOTA-Siglec-9 PETCT imaging of peri-implant tissue responses andstaphylococcal infectionsrdquo EJNMMI Research vol 4 no 1article no 45 pp 1ndash11 2014
[57] A Autio S Jalkanen and A Roivainen ldquoNuclear imaging ofinflammation Homing-associated molecules as targetsrdquo EJN-MMI Research vol 3 no 1 pp 1ndash7 2013
[58] J TThackeray T Derlin AHaghikia et al ldquoMolecular Imagingof the Chemokine Receptor CXCR4 after Acute MyocardialInfarctionrdquo JACC Cardiovascular Imaging vol 8 no 12 pp1417ndash1426 2015
[59] J S Schmid A Schirbel A K Buck S Kropf H-J Westerand C Lapa ldquoPentixafor-Positron Emission TomographyComputed Tomography Detects Chemokine Receptor CXCR4Expression after Ischemic Strokerdquo Circulation CardiovascularImaging vol 9 no 9 Article ID e005217 2016
[60] J Zhou G Hao H Weng et al ldquoIn vivo evaluation ofmedical device-associated inflammation using a macrophage-specific positron emission tomography (PET) imaging proberdquoBioorganic amp Medicinal Chemistry Letters vol 23 no 7 pp2044ndash2047 2013
[61] S A Kularatne M-J Belanger X Meng et al ldquoComparativeanalysis of folate derived PET imaging agents with [ 18F]-2-fluoro-2-deoxy-d-glucose using a rodent inflammatory pawmodelrdquo Molecular Pharmaceutics vol 10 no 8 pp 3103ndash31112013
[62] V Ambrosini M Zompatori F De Luca et al ldquo68Ga-DOTANOCPETCTAllows Somatostatin Receptor Imaging inIdiopathic Pulmonary Fibrosis Preliminary Resultsrdquo Journal ofNuclear Medicine vol 51 no 12 pp 1950ndash1955 2010
[63] T Lincke J Singer R Kluge O Sabri and R Paschke ldquoRela-tive quantification of indium-111 pentetreotide and gallium-68DOTATOC uptake in the thyroid gland and association withthyroid pathologiesrdquoThyroid vol 19 no 4 pp 381ndash389 2009
[64] A Rominger T Saam E Vogl et al ldquoIn vivo imaging ofmacrophage activity in the coronary arteries using 68Ga-DOTATATE PETCT correlation with coronary calcium bur-den and risk factorsrdquo Journal of Nuclear Medicine vol 51 no 2pp 193ndash197 2010
[65] J M Tarkin F R Joshi N R Evans et al ldquoDetection ofAtherosclerotic Inflammation by 68Ga-DOTATATE PET Com-pared to [18F]FDG PET Imagingrdquo Journal of the AmericanCollege of Cardiology vol 69 no 14 pp 1774ndash1791 2017
[66] S-P Lee H-J Im S Kang et al ldquoNoninvasive imaging ofmyocardial inflammation in myocarditis using 68Ga-taggedmannosylated human serum albumin positron emissiontomographyrdquoTheranostics vol 7 no 2 pp 413ndash424 2017
[67] Z Zha J Song S R Choi et al ldquo68Ga-Bivalent PolypegylatedStyrylpyridine Conjugates for Imaging A120573 Plaques in CerebralAmyloid Angiopathyrdquo Bioconjugate Chemistry vol 27 no 5 pp1314ndash1323 2016
[68] H Watanabe M Ono S Iikuni et al ldquoA 68Ga complex basedon benzofuran scaffold for the detection of 120573-amyloid plaquesrdquoBioorganic amp Medicinal Chemistry Letters vol 24 no 20 pp4834ndash4837 2014
[69] D Cressier M Dhilly T T Cao Pham et al ldquoGallium-68 Com-plexes Conjugated to Pittsburgh Compound B Radiolabelingand Biological EvaluationrdquoMolecular Imaging and Biology vol18 no 3 pp 334ndash343 2016
[70] D Satpati CArjun R KrishnamohanG Samuel and S Baner-jee ldquo68Ga-labeledCiprofloxacinConjugates as Radiotracers forTargeting Bacterial InfectionrdquoChemical Biology ampDrug Designvol 87 no 5 pp 680ndash686 2016
[71] T Ebenhan N Chadwick and M M Sathekge ldquoPeptidesynthesis characterization and 68Ga-radiolabeling of NOTA-conjugated ubiquicidin fragments for prospective infectionimaging with PETCTrdquo Nuclear Medicine and Biology vol 41no 5 pp 390ndash400 2014
18 Contrast Media amp Molecular Imaging
[72] T Ebenhan J R Zeevaart and J D Venter ldquoPreclinicalevaluation of 68Ga-labeled 1 4 7-triazacyclononane-1 4 7-triacetic acid-ubiquicidin as a radioligand for PET infectionimagingrdquo Journal of Nuclear Medicine vol 55 no 2 pp 308ndash314 2014
[73] B B Mokaleng T Ebenhan S Ramesh et al ldquoSynthesis 68Ga-radiolabeling and preliminary in vivo assessment of adepsipeptide-derived compound as a potential PETCTinfection imaging agentrdquo BioMed Research International vol2015 Article ID 284354 2015
[74] T Ebenhan B Mokaleng J Venter H Kruger J Zeevaart andM Sathekge ldquoPreclinical Assessment of a 68Ga-DOTA-Functionalized Depsipeptide as a Radiodiagnostic InfectionImaging AgentrdquoMolecules vol 22 no 9 p 1403 2017
[75] S Chopra B Singh A Koul A Mishra and H Wester ldquoSyn-thesis of DOTA conjugated GF-17 and RAWVAWR-NH2 andradiolabeling with 68Ga as a potential PET tracer for infectionimagingrdquo J Nucl Med vol 57 Supplement 2 p 1115 2016
[76] M Petrik HHaas P Laverman et al ldquo 68Ga-triacetylfusarinineC and 68Ga-ferrioxamine e for aspergillus infection imaginguptake specificity in various microorganismsrdquoMolecular Imag-ing and Biology vol 16 no 1 pp 102ndash108 2014
[77] V Kumar and D K Boddeti ldquo 68Ga-radiopharmaceuticals forPET imaging of infection and inflammationrdquo Recent Results inCancer Research vol 194 pp 189ndash219 2013
[78] M Vorster A Maes A Jacobs et al ldquoEvaluating the possiblerole of 68Ga-citrate PETCT in the characterization of indeter-minate lung lesionsrdquo Annals of Nuclear Medicine vol 28 no 6pp 523ndash530 2014
[79] M Vorster B Mokaleng M M Sathekge and T Ebenhan ldquoAmodified technique for efficient radiolabeling of 68Ga-citratefrom a SnO2-based 68Ge68Ga generator for better infectionimagingrdquoHellenic Journal of Nuclear Medicine vol 16 no 3 pp193ndash198 2013
[80] S Salomaeki J Kemppainen U Hohenthal et al ldquoHead-to-head comparison of 68Ga-Citrate and 18F-FDG PETCT fordetection of infectious foci in patients with staphylococcusaureus bacteraemiardquo Contrast Media amp Molecular Imaging vol2017 p 8 2017
[81] L Fass ldquoImaging and cancer a reviewrdquoMolecular Oncology vol2 no 2 pp 115ndash152 2008
[82] A Chopra L Shan W C Eckelman et al ldquoMolecular imagingand contrast agent database (MICAD) Evolution and progressrdquoMolecular Imaging and Biology vol 14 no 1 pp 4ndash13 2012
[83] A Sanchez-Crespo P Andreo and S A Larsson ldquoPositronflight in human tissues and its influence on PET image spatialresolutionrdquo European Journal of Nuclear Medicine and Molecu-lar Imaging vol 31 no 1 pp 44ndash51 2004
[84] H W A M De Jong L Perk G W M Visser R Boellaard GAM S Van Dongen and A A Lammertsma ldquoHigh resolutionPET imaging characteristics of68Ga 124i and89Zr comparedto18Frdquo in Proceedings of the Nuclear Science Symposium Con-ference Record 2005 IEEE pp 1624ndash1627 Puerto Rico October2005
[85] I Velikyan A Sundin B Eriksson et al ldquoIn vivo bindingof [68Ga]-DOTATOC to somatostatin receptors in neuroen-docrine tumours - impact of peptide massrdquo Nuclear Medicineand Biology vol 37 no 3 pp 265ndash275 2010
[86] U Eberlein and M Lassmann ldquoDosimetry of [68Ga]-labeledcompoundsrdquo Applied Radiation and Isotopes vol 76 pp 70ndash742013
[87] C PettinatoA SarnelliMDiDonna et al ldquo68Ga-DOTANOCBiodistribution and dosimetry in patients affected by neuroen-docrine tumorsrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 35 no 1 pp 72ndash79 2008
[88] B P Burke G S Clemente and S J Archibald ldquoRecentadvances in chelator design and labelling methodology for68Ga radiopharmaceuticalsrdquo Journal of Labelled Compoundsand Radiopharmaceuticals vol 57 no 4 pp 239ndash243 2014
[89] I Velikyan U Rosenstrom S Estrada et al ldquoSynthesis andpreclinical evaluation of 68Ga-labeled collagelin analogs forimaging and quantification of fibrosisrdquo Nuclear Medicine andBiology vol 41 no 9 pp 728ndash736 2014
[90] M F Ferreira G Pereira J P Andre and etal C ldquoGa[NO2A-N-(120572-amino)propionate] chelates Synthesis and evaluation aspotential tracers for 68Ga PETrdquoDalton Transactions vol 43 no21 pp 8037ndash8047 2014
[91] J Notni J Simecek and H-J Wester ldquoPhosphinic acid func-tionalized polyazacycloalkane chelators for radiodiagnosticsand radiotherapeutics Unique characteristics and applicationsrdquoChemMedChem vol 9 no 6 pp 1107ndash1115 2014
[92] J Simecek O Zemek P Hermann J Notni and H J WesterldquoTailored gallium( III) chelator NOPO synthesis characteriza-tion bioconjugation and application in preclinical Ga-68-PETimagingrdquoMolecular Pharmaceutics 2013
[93] D Parker B P Waldron and D S Yufit ldquoCrystallographicand solution NMR structural analyses of four hexacoordinatedgallium(iii) complexes based on ligands derived from 6-amino-perhydro-14-diazepinerdquo Dalton Transactions vol 42 no 22pp 8001ndash8008 2013
[94] B P Waldron D Parker C Burchardt D S Yufit M ZimnyandF Roesch ldquoStructure and stability of hexadentate complexesof ligands based on AAZTA for efficient PET labelling withgallium-68rdquo Chemical Communications vol 49 no 6 pp 579ndash581 2013
[95] D Parker and B PWaldron ldquoConformational analysis and syn-thetic approaches to polydentate perhydro-diazepine ligandsfor the complexation of gallium(iii)rdquo Organic amp BiomolecularChemistry vol 11 no 17 pp 2827ndash2838 2013
[96] I Velikyan H Maecke and B Langstrom ldquoConvenient prepa-ration of 68Ga-based PET-radiopharmaceuticals at room tem-peraturerdquo Bioconjugate Chemistry vol 19 no 2 pp 569ndash5732008
[97] J Erchegyi R Cescato B Waser J E Rivier and J C ReubildquoN-Imidazolebenzyl-histidine substitution in somatostatin andin its octapeptide analogue modulates receptor selectivity andfunctionrdquo Journal of Medicinal Chemistry vol 54 no 17 pp5981ndash5987 2011
[98] R Saha N Saha R S Donofrio and L L Bestervelt ldquoMicrobialsiderophores Amini reviewrdquo Journal of Basic Microbiology vol53 no 4 pp 303ndash317 2013
[99] V Nikolova S Angelova N Markova and T Dudev ldquoGalliumas a Therapeutic Agent A Thermodynamic Evaluation of theCompetition between Ga3+ and Fe3+ Ions in MetalloproteinsrdquoThe Journal of Physical Chemistry B vol 120 no 9 pp 2241ndash2248 2016
[100] C R Chitambar ldquoGallium and its competing roles with ironin biological systemsrdquo Biochimica et Biophysica Acta (BBA) -Molecular Cell Research vol 1863 no 8 pp 2044ndash2053 2016
[101] J A Lessa M A Soares and R G dos Santos ldquoGallium(III)complexes with 2-acetylpyridine-derived thiosemicarbazonesantimicrobial and cytotoxic effects and investigation on theinteractions with tubulinrdquo BioMetals vol 26 pp 151ndash165 2013
Contrast Media amp Molecular Imaging 19
[102] M van Oosten M Hahn L M A Crane et al ldquoTargetedimaging of bacterial infections Advances hurdles and hopesrdquoFEMS Microbiology Reviews vol 39 no 6 pp 892ndash916 2015
[103] M Vorster AMaes C V DWiele andM Sathekge ldquoGallium-68 PET A Powerful Generator-based Alternative to Infectionand Inflammation Imagingrdquo Seminars in Nuclear Medicine vol46 no 5 pp 436ndash447 2016
[104] M Kircher and C Lapa ldquoNovel Noninvasive Nuclear MedicineImaging Techniques for Cardiac Inflammationrdquo Current Car-diovascular Imaging Reports vol 10 no 2 article no 6 2017
[105] D AHammoud ldquoMolecular imaging of inflammation Currentstatusrdquo Journal of Nuclear Medicine vol 57 no 8 pp 1161ndash11652016
[106] D R Brenner D Scherer K Muir et al ldquoA review of the appli-cation of inflammatory biomarkers in epidemiologic cancerresearchrdquo Cancer Epidemiology Biomarkers amp Prevention vol23 no 9 pp 1729ndash1751 2014
[107] M D Turner B Nedjai T Hurst and D J PenningtonldquoCytokines and chemokines at the crossroads of cell signallingand inflammatory diseaserdquo Biochimica et Biophysica Acta (BBA)- Molecular Cell Research vol 1843 no 11 pp 2563ndash2582 2014
[108] L Werner H Guzner-Gur and I Dotan ldquoInvolvement ofCXCR4CXCR7CXCL12 interactions in inflammatory boweldiseaserdquoTheranostics vol 3 no 1 pp 40ndash46 2013
[109] S Jalkanen and M Salmi ldquoVAP-1 and CD73 endothelial cellsurface enzymes in leukocyte extravasationrdquo ArteriosclerosisThrombosis and Vascular Biology vol 28 no 1 pp 18ndash26 2008
[110] G Malviya F Galli I Sonni and A Signore ldquoImaging T-lymphocytes in inflammatory diseases A nuclear medicineapproachrdquo The Quarterly Journal of Nuclear Medicine andMolecular Imaging vol 58 no 3 pp 237ndash257 2014
[111] S Gratz H J RennenO C BoermanW J Oyen and P Burmaldquo(99m)Tc-interleukin-8 for imaging acute osteomyelitisrdquo Jour-nal of Nuclear Medicine vol 42 no 8 pp 1257ndash1264 2001
[112] S Gratz H J Rennen O C Boerman W J Oyen andF H Corstens ldquoRapid imaging of experimental colitis with(99m)Tc-interleukin-8 in rabbitsrdquo Journal of Nuclear Medicnevol 42 no 6 pp 917ndash923 2001
[113] C Alkim H Alkim A R Koksal S Boga and I SenldquoAngiogenesis in inflammatory bowel diseaserdquo InternationalJournal of Inflammation vol 2015 Article ID 970890 2015
[114] I S Alam T H Witney G Tomasi et al ldquoRadiolabeled RGDtracer kinetics annotates differential 120572v1205733 integrin expressionlinked to cell intrinsic and vessel expressionrdquoMolecular Imagingand Biology vol 16 no 4 pp 558ndash566 2014
[115] J Notni K Pohle and H-J Wester ldquoBe spoilt for choice withradiolabelled RGD peptides Preclinical evaluation of 68Ga-TRAP(RGD)3rdquoNuclear Medicine and Biology vol 40 no 1 pp33ndash41 2013
[116] J Oxboel M Brandt-Larsen C Schjoeth-Eskesen et al ldquoCom-parison of two new angiogenesis PET tracers 68Ga-NODAGA-E[c(RGDyK)]2 and 64Cu-NODAGA-E[c(RGDyK)]2 in vivoimaging studies in human xenograft tumorsrdquo Nuclear Medicineand Biology vol 41 no 3 pp 259ndash267 2014
[117] J Simecek J Notni T G Kapp H Kessler and H-J WesterldquoBenefits of NOPO as chelator in gallium-68 peptides exempli-fied by preclinical characterization of 68Ga-NOPO-c(RGDfK)rdquoMolecular Pharmaceutics vol 11 no 5 pp 1687ndash1695 2014
[118] M Trajkovic-Arsic P Mohajerani A Sarantopoulos et alldquoMultimodal molecular imaging of integrin avb3 for in vivodetection of pancreatic cancerrdquo Journal of NuclearMedicine vol55 no 3 pp 446ndash451 2014
[119] H Cai and P S Conti ldquoRGD-based PET tracers for imagingreceptor integrin 120572 v1205733 expressionrdquo Journal of Labelled Com-pounds and Radiopharmaceuticals vol 56 no 5 pp 264ndash2792013
[120] I Dijkgraaf S Y A Terry W J Mcbride et al ldquoImagingintegrin alpha-v-beta-3 expression in tumors with an 18F-labeled dimeric RGD peptiderdquo Contrast Media amp MolecularImaging vol 8 no 3 pp 238ndash245 2013
[121] P A Knetsch M Petrik C Rangger et al ldquo[68Ga]NS3-RGD and [68Ga] Oxo-DO3A-RGD for imaging 120572v1205733 integrinexpression Synthesis evaluation and comparisonrdquo NuclearMedicine and Biology vol 40 no 1 pp 65ndash72 2013
[122] Z Liu and F Wang ldquoDevelopment of RGD-based radiotracersfor tumor imaging and therapy Translating from bench tobedsiderdquo Current Molecular Medicine vol 13 no 10 pp 1487ndash1505 2013
[123] H Choi J H Phi J C Paeng et al ldquoImaging of integrin 120572v1205733expression using 68Ga-RGD positron emission tomography inpediatric cerebral infarctrdquoMolecular Imaging vol 12 no 4 pp213ndash217 2013
[124] H-J Yoon K W Kang I K Chun et al ldquoCorrelation of breastcancer subtypes based on estrogen receptor progesteronereceptor and HER2 with functional imaging parameters from68Ga-RGD PETCT and 18F-FDG PETCTrdquo European Journalof Nuclear Medicine and Molecular Imaging vol 41 no 8 pp1534ndash1543 2014
[125] R P Baum H R Kulkarni D Muller et al ldquoFirst-in-human study demonstrating tumor-angiogenesis by PETCTimaging with 68Ga-NODAGA-THERANOST a high-affinitypeptidomimetic for 120572v1205733 integrin receptor targetingrdquo CancerBiotherapy andRadiopharmaceuticals vol 30 no 4 pp 152ndash1592015
[126] R Haubner A Finkenstedt A Stegmayr et alldquo[68Ga]NODAGA-RGD ndash Metabolic stability biodistributionand dosimetry data from patients with hepatocellularcarcinoma and liver cirrhosisrdquo European Journal of NuclearMedicine and Molecular Imaging vol 43 no 11 pp 2005ndash20132016
[127] V Lopez-Rodrıguez C Galindo-Sarco F O Garcıa-Perez GFerro-Flores O Arrieta and M A Avila-Rodrıguez ldquoPET-based human dosimetry of the dimeric 120572v1205733 integrin ligand68Ga-DOTA-E-[c(RGDfK)]2 a potential tracer for imagingtumor angiogenesisrdquo Journal of Nuclear Medicine vol 57 no 3pp 404ndash409 2016
[128] M V Backer Z Levashova V Patel et al ldquoMolecular imagingof VEGF receptors in angiogenic vasculature with single-chainVEGF-based probesrdquo Nature Medicine vol 13 no 4 pp 504ndash509 2007
[129] MV Backer Z Levashova R Levenson F G Blankenberg andJ M Backer ldquoCysteine-containing fusion tag for site-specificconjugation of therapeutic and imaging agents to targetingproteinsrdquoMethods in Molecular Biology (Clifton NJ) vol 494pp 275ndash294 2008
[130] M Eder A V Krivoshein M Backer J M Backer UHaberkorn and M Eisenhut ldquoScVEGF-PEG-HBED-CC andscVEGF-PEG-NOTA conjugates comparison of easy-to-labelrecombinant proteins for [68Ga]PET imaging of VEGF recep-tors in angiogenic vasculaturerdquo Nuclear Medicine and Biologyvol 37 no 4 pp 405ndash412 2010
[131] E Blom I Velikyan A Monazzam P Razifar et al ldquoSynthe-sis and characterization of scVEGF-PEG-[ 68Ga]NOTA andscVEGF-PEG-[ 68Ga]DOTA PET tracersrdquo Journal of Labelled
20 Contrast Media amp Molecular Imaging
Compounds and Radiopharmaceuticals vol 54 no 11 pp 685ndash692 2011
[132] S Gratz M Behe and O C Boerman ldquo 99119898Tc-E-selectinbinding peptide for imaging acute osteomyelitis in a novel ratmodelrdquo Nuclear Medicine Communications vol 22 no 9 pp1003ndash1013 2001
[133] S B Jensen M Kakela L Joslashdal et al ldquoExploring the radiosyn-thesis and in vitro characteristics of [68Ga]Ga-DOTA-Siglec-9rdquoJournal of Labelled Compounds and Radiopharmaceuticals vol60 no 9 pp 439ndash449 2017
[134] B A Teicher and S P Fricker ldquoCXCL12 (SDF-1)CXCR4pathway in cancerrdquo Clinical Cancer Research vol 16 no 11 pp2927ndash2931 2010
[135] O Jacobson I D Weiss D O Kiesewetter J M Farber andX Chen ldquoPET of tumor CXCR4 expression with 4-18F-T140rdquoJournal of Nuclear Medicine vol 51 no 11 pp 1796ndash1804 2010
[136] A Aghanejad A R Jalilian Y Fazaeli et al ldquoSynthesis andevaluation of [67Ga]-AMD3100 A novel imaging agent fortargeting the chemokine receptorCXCR4rdquo Scientia Pharmaceu-tica vol 82 no 1 pp 29ndash42 2014
[137] O Jacobson I D Weiss L P Szajek et al ldquoPET imaging ofCXCR4 using copper-64 labeled peptide antagonistrdquoTheranos-tics vol 1 pp 251ndash262 2011
[138] O Jacobson I D Weiss L P Szajek et al ldquoImprovement ofCXCR4 tracer specificity for PET imagingrdquo Journal of Con-trolled Release vol 157 no 2 pp 216ndash223 2012
[139] H J Wester U Keller M Schottelius et al ldquoDisclosing theCXCR4 expression in lymphoproliferative diseases by targetedmolecular imagingrdquo Theranostics vol 5 no 6 pp 618ndash6302015
[140] E Gourni O Demmer M Schottelius et al ldquoPET of CXCR4expression by a 68Ga-labeled highly specific targeted contrastagentrdquo Journal of NuclearMedicine vol 52 no 11 pp 1803ndash18102011
[141] O Demmer I Dijkgraaf U Schumacher et al ldquoDesignsynthesis and functionalization of dimeric peptides targetingchemokine receptor CXCR4rdquo Journal of Medicinal Chemistryvol 54 no 21 pp 7648ndash7662 2011
[142] O Demmer E Gourni U Schumacher H Kessler and H-JWester ldquoPET Imaging of CXCR4 Receptors in Cancer by a NewOptimized Ligandrdquo ChemMedChem vol 6 no 10 pp 1789ndash1791 2011
[143] U Hennrich L Seyler M Schafer et al ldquoSynthesis and invitro evaluation of 68Ga-DOTA-4-FBn-TN14003 a novel tracerfor the imaging of CXCR4 expressionrdquo Bioorganic amp MedicinalChemistry vol 20 no 4 pp 1502ndash1510 2012
[144] G P C George E Stevens O Aberg et al ldquoPreclinical evalua-tion of a CXCR4-specific 68Ga-labelled TN14003 derivative forcancer PET imagingrdquo Bioorganic amp Medicinal Chemistry vol22 no 2 pp 796ndash803 2014
[145] S Poty E Gourni P Desogere et al ldquoAMD3100 A VersatilePlatform for CXCR4 Targeting 68Ga-Based Radiopharmaceu-ticalsrdquo Bioconjugate Chemistry vol 27 no 3 pp 752ndash761 2016
[146] K Philipp-Abbrederis K Herrmann S Knop et al ldquoIn vivomolecular imaging of chemokine receptor CXCR4 expressionin patients with advancedmultiple myelomardquo EMBOMolecularMedicine vol 7 no 4 pp 477ndash487 2015
[147] Z Wang M Zhang L Wang et al ldquoProspective study of 68Ga-NOTA-NFB Radiation dosimetry in healthy volunteers andfirst application in glioma patientsrdquo Theranostics vol 5 no 8pp 882ndash889 2015
[148] I M Jackson P J Scott and S Thompson ldquoClinical Applica-tions of Radiolabeled Peptides for PETrdquo Seminars in NuclearMedicine vol 47 no 5 pp 493ndash523 2017
[149] C Lapa T Reiter R A Werner et al ldquo[68Ga]Pentixafor-PETCT for Imaging of Chemokine Receptor 4 Expression afterMyocardial Infarctionrdquo JACC Cardiovascular Imaging vol 8no 12 pp 1466ndash1468 2015
[150] C Rischpler S G Nekolla H Kossmann et al ldquoUpregu-lated myocardial CXCR4-expression after myocardial infarc-tion assessed by simultaneous GA-68 pentixafor PETMRIrdquoJournal of Nuclear Cardiology vol 23 no 1 pp 131ndash133 2016
[151] F Hyafil J Pelisek I Laitinen et al ldquoImaging the CytokineReceptorCXCR4 in atherosclerotic plaqueswith the radiotracer68Ga-Pentixafor for PETrdquo Journal of Nuclear Medicine vol 58no 3 pp 499ndash506 2017
[152] Y Yi ldquoFolate receptor-targeted diagnostics and therapeutics forinflammatory diseasesrdquo ImmuneNetwork vol 16 no 6 pp 337ndash343 2016
[153] C M Paulos M J Turk G J Breur and P S Low ldquoFolatereceptor-mediated targeting of therapeutic and imaging agentsto activated macrophages in rheumatoid arthritisrdquo AdvancedDrug Delivery Reviews vol 56 no 8 pp 1205ndash1217 2004
[154] W Han R Zaynagetdinov F E Yull et al ldquoMolecular imagingof folate receptor 120573-positive macrophages during acute lunginflammationrdquo American Journal of Respiratory Cell and Molec-ular Biology vol 53 no 1 pp 50ndash59 2015
[155] B Kuhle C Muller and T L Ross ldquoA Novel 68Ga-Labeledpteroic acid-based PET tracer for tumor imaging via the folatereceptorrdquo Recent Results in Cancer Research vol 194 pp 257ndash267 2013
[156] C Brand V A Longo M Groaning W A Weber and TReiner ldquoDevelopment of a New Folate-Derived Ga-68-BasedPET Imaging AgentrdquoMolecular Imaging and Biology vol 19 no5 pp 754ndash761 2017
[157] M Fani XWang G Nicolas et al ldquoDevelopment of new folate-based PET radiotracers Preclinical evaluation of 68Ga-DOTA-folate conjugatesrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 38 no 1 pp 108ndash119 2011
[158] C J Mathias M R Lewis D E Reichert et al ldquoPreparationof 66Ga- and 68Ga-labeled Ga(III)-deferoxamine-folate aspotential folate-receptor-targeted PET radiopharmaceuticalsrdquoNuclear Medicine and Biology vol 30 no 7 pp 725ndash731 2003
[159] S-M Kim N Choi S Hwang et al ldquoFolate receptor-specific positron emission tomography imaging with folic acid-conjugated tissue inhibitor of metalloproteinase-2rdquo Bulletin ofthe Korean Chemical Society vol 34 no 11 pp 3243ndash3248 2013
[160] M Fani M-L Tamma G P Nicolas et al ldquoIn vivo imagingof folate receptor positive tumor xenografts using novel 68Ga-NODAGA-folate conjugatesrdquo Molecular Pharmaceutics vol 9no 5 pp 1136ndash1145 2012
[161] C Muller and R Schibli ldquoProspects in folate receptor-targetedradionuclide therapyrdquo Frontiers in Oncology vol 3 Article IDArticle 249 2013
[162] A Jain A Mathur U Pandey et al ldquoSynthesis and evaluationof a 68Ga labeled folic acid derivative for targeting folatereceptorsrdquo Applied Radiation and Isotopes vol 116 pp 77ndash842016
[163] W Xia A R Hilgenbrink E L Matteson M B Lockwood J-X Cheng and P S Low ldquoA functional folate receptor is inducedduring macrophage activation and can be used to target drugsto activated macrophagesrdquo Blood vol 113 no 2 pp 438ndash4462009
Contrast Media amp Molecular Imaging 21
[164] E P Krenning W A P Breeman P P M Kooij et alldquoLocalisation of endocrine-related tumours with radioiodi-nated analogue of somatostatinrdquoThe Lancet vol 1 no 8632 pp242ndash244 1989
[165] E P Krenning D J KwekkeboomWH Bakker et al ldquoSomato-statin receptor scintigraphy with [111In-DTPA-d-Phe1]- and[123I-Tyr3]-octreotide the Rotterdam experience with morethan 1000 patientsrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 20 no 8 pp 716ndash731 1993
[166] A Stahl G Meisetschlager M Schottelius et al ldquo[123I]Mtr-TOCA a radioiodinated and carbohydrated analogue ofoctreotide Scintigraphic comparison with [111In]octreotiderdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 33 no 1 pp 45ndash52 2006
[167] R Lebtahi J le Cloirec C Houzard et al ldquoDetection of neu-roendocrine tumors 99mTc-P829 scintigraphy compared with111In-pentetreotide scintigraphyrdquo Journal of Nuclear Medicinevol 43 no 7 pp 889ndash895 2002
[168] C Decristoforo T Maina B Nock M Gabriel P Cordopatisand R Moncayo ldquo99mTc-demotate 1 First data in tumourpatients - Results of a pilotphase I studyrdquo European Journal ofNuclearMedicine andMolecular Imaging vol 30 no 9 pp 1211ndash1219 2003
[169] C Decristoforo S J Mather W Cholewinski E DonnemillerG Riccabona and R Moncayo ldquo(99m)Tc-EDDAHYNIC-TOC A new (99m)Tc-labelled radiopharmaceutical forimaging somatostatin receptor-positive tumours First clinicalresults and intra-patient comparison with 111In-labelledoctreotide derivativesrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 27 no 9 pp 1318ndash1325 2000
[170] A Hubalewska-Dydejczyk K Fross-Baron R Mikołajczak etal ldquo99mTc-EDDAHYNIC-octreotate scintigraphy an efficientmethod for the detection and staging of carcinoid tumoursResults of 3 yearsrsquo experiencerdquo European Journal of NuclearMedicine and Molecular Imaging vol 33 no 10 pp 1123ndash11332006
[171] M Bangard M Behe S Guhlke et al ldquoDetection of somato-statin receptor-positive tumours using the new 99mC-tricine-HYNIC-D-Phe1-Tyr3-octreotide First results in patients andcomparison with 111In-DTPA-D-Phe1-octreotiderdquo EuropeanJournal of Nuclear Medicine and Molecular Imaging vol 27 no6 pp 628ndash637 2000
[172] A Helisch G J Forster H Reber et al ldquoPre-therapeuticdosimetry and biodistribution of 86Y-DOTA- Phe1-Tyr3-octreotide versus 111In-pentetreotide in patients with advancedneuroendocrine tumoursrdquo European Journal of NuclearMedicine and Molecular Imaging vol 31 no 10 pp 1386ndash13922004
[173] M Henze J Schuhmacher P Hipp et al ldquoPET imaging ofsomatostatin receptors using [68GA]DOTA-D-Phe1-Tyr3-Octreotide First results in patients with meningiomasrdquo Journalof Nuclear Medicine vol 42 no 7 pp 1053ndash1056 2001
[174] I Kayani J B Bomanji A Groves et al ldquoFunctional imaging ofneuroendocrine tumors with combined PETCT using 68Ga-DOTATATE (Dota-DPhe1 Tyr3-octreotate) and 18F-FDGrdquoCancer vol 112 no 11 pp 2447ndash2455 2008
[175] A Al-Nahhas ldquoNuclear medicine imaging of neuroendocrinetumoursrdquo Clinical Medicine vol 12 no 4 pp 377ndash380 2012
[176] V Ambrosini S Nicolini P Caroli et al ldquoPETCT imaging indifferent types of lung cancer an overviewrdquo European Journal ofRadiology vol 81 no 5 pp 988ndash1001 2012
[177] V Ambrosini D Campana P Tomassetti and S Fanti ldquo68Ga-labelled peptides for diagnosis of gastroenteropancreatic NETrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 39 no 1 pp S52ndashS60 2012
[178] K E Oberg J-C Reubi D J Kwekkeboom and E P KrenningldquoRole of somatostatins in gastroenteropancreatic neuroen-docrine tumor development and therapyrdquoGastroenterology vol139 no 3 pp 753-753 2010
[179] K Oberg ldquoGallium-68 somatostatin receptor PETCT Is ittime to replace 111Indium DTPA octreotide for patients withneuroendocrine tumorsrdquo Endocrine Journal vol 42 no 1 pp3-4 2012
[180] R Srirajaskanthan I Kayani A M Quigley J Soh M ECaplin and J Bomanji ldquoThe role of 68Ga-DOTATATE PET inpatients with neuroendocrine tumors and negative or equivocalfindings on 111In-DTPA-octreotide scintigraphyrdquo Journal ofNuclear Medicine vol 51 no 6 pp 875ndash882 2010
[181] A Kroiss D Putzer and C Uprimny ldquoFunctional imag-ing in phaeochromocytoma and neuroblastoma with 68Ga-DOTA-Tyr3-octreotide positron emission tomography and123I-metaiodobenzylguanidinerdquo European Journal of NuclearMedicine and Molecular Imaging vol 38 no 5 pp 865ndash8732011
[182] M Naji C Zhao S J Welsh et al ldquo68Ga-DOTA-TATE PETvs 123I-MIBG in identifying malignant neural crest tumoursrdquoMolecular Imaging and Biology vol 13 no 4 pp 769ndash775 2011
[183] V Ambrosini P Tomassetti P Castellucci et al ldquoComparisonbetween 68Ga-DOTA-NOC and 18F-DOPA PET for the detec-tion of gastro-entero-pancreatic and lung neuro-endocrinetumoursrdquo European Journal of Nuclear Medicine and MolecularImaging vol 35 no 8 pp 1431ndash1438 2008
[184] D Putzer M Gabriel B Henninger et al ldquoBone metastasesin patients with neuroendocrine tumor 68Ga- DOTA-Tyr3-octreotide PET in comparison to CT and bone scintigraphyrdquoJournal of Nuclear Medicine vol 50 no 8 pp 1214ndash1221 2009
[185] L K Anzola-Fuentes M Chianelli F Galli et al ldquoSomatostatinreceptor scintigraphy in patients with rheumatoid arthritis andsecondary Sjogrenrsquos syndrome treated with Infliximab a pilotstudyrdquo EJNMMI Research vol 6 no 1 article no 49 2016
[186] T Nobashi Y Nakamoto T Kubo et al ldquoThe utility of PETCTwith 68Ga-DOTATOC in sarcoidosis comparison with 67Ga-scintigraphyrdquoAnnals ofNuclearMedicine vol 30 no 8 pp 544ndash552 2016
[187] C Boy T A Heusner T D Poeppel et al ldquo68Ga-DOTATOCPETCT and somatostatin receptor (sst1-sst5) expression innormal human tissue Correlation of sst2mRNAand SUVmaxrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 38 no 7 pp 1224ndash1236 2011
[188] P Rinne S Hellberg M Kiugel et al ldquoComparison of Somato-statin Receptor 2-Targeting PET Tracers in the Detection ofMouse Atherosclerotic Plaquesrdquo Molecular Imaging and Biol-ogy vol 18 no 1 pp 99ndash108 2016
[189] M Asti E Ferrari S Croci et al ldquoSynthesis and characteri-zation of 68Ga-labeled curcumin and curcuminoid complexesas potential radiotracers for imaging of cancer and alzheimersdiseaserdquo Inorganic Chemistry vol 53 no 10 pp 4922ndash49332014
[190] A Signore I Santino and A W J M Glaudemans ldquoIn vivoimaging of microorganismsrdquo Clinical and Translational Imag-ing vol 4 no 3 pp 161-162 2016
[191] S Auletta F Galli C Lauri D Martinelli I Santino andA Signore ldquoImaging bacteria with radiolabelled quinolones
22 Contrast Media amp Molecular Imaging
cephalosporins and siderophores for imaging infection a sys-tematic reviewrdquo Clinical and Translational Imaging vol 4 no 4pp 229ndash252 2016
[192] X Ning S Lee Z Wang et al ldquoMaltodextrin-based imagingprobes detect bacteria in vivo with high sensitivity and speci-ficityrdquo Nature Materials vol 10 no 8 pp 602ndash607 2011
[193] J Ady andY Fong ldquoImaging for infection Fromvisualization ofinflammation to visualization of microbesrdquo Surgical Infectionsvol 15 no 6 pp 700ndash707 2014
[194] J M Sierra D Rodriguez-Puig A Soriano J Mensa C Pieraand J Vila ldquoAccumulation of 99mTc-ciprofloxacin in Staphy-lococcus aureus and Pseudomonas aeruginosardquo AntimicrobialAgents and Chemotherapy vol 52 no 7 pp 2691-2692 2008
[195] D I Andersson and D Hughes ldquoMicrobiological effects ofsublethal levels of antibioticsrdquoNature ReviewsMicrobiology vol12 no 7 pp 465ndash478 2014
[196] N Dumarey D Blocklet T Appelboom L Tant and ASchoutens ldquoInfecton is not specific for bacterial osteo-articularinfective pathologyrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 29 no 4 pp 530ndash535 2002
[197] K E Britton D W Wareham S S Das et al ldquoImaging bacte-rial infection with 99mTc-ciprofloxacin (Infecton)rdquo Journal ofClinical Pathology vol 55 no 11 pp 817ndash823 2002
[198] G Ferro-Flores M A Avila-Rodrıguez and F O Garcıa-PerezldquoImaging of bacteria with radiolabeled ubiquicidin by SPECTand PET techniquesrdquo Clinical and Translational Imaging vol 4no 3 pp 175ndash182 2016
[199] P S Hiemstra M T van den Barselaar M Roest P H Nibber-ing and R van Furth ldquoUbiquicidin a novel murine microbi-cidal protein present in the cytosolic fraction of macrophagesrdquoJournal of Leukocyte Biology vol 66 no 3 pp 423ndash428 1999
[200] M S Akhtar A Qaisar J Irfanullah et al ldquoAntimicrobialpeptide 99mTc-ubiquicidin 29ndash41 as human infection-imagingagent clinical trialrdquo Journal of Nuclear Medicne vol 46 no 4pp 567ndash573 2005
[201] M Assadi K Vahdat I Nabipour et al ldquoDiagnostic value of99mTc-ubiquicidin scintigraphy for osteomyelitis and compar-isons with 99mTc-methylene diphosphonate scintigraphy andmagnetic resonance imagingrdquo Nuclear Medicine Communica-tions vol 32 no 8 pp 716ndash723 2011
[202] T Emery ldquoExchange of Iron by Gallium in SiderophoresrdquoBiochemistry vol 25 no 16 pp 4629ndash4633 1986
[203] M Petrik C Zhai H Haas and C Decristoforo ldquoSiderophoresfor molecular imaging applicationsrdquo Clinical and TranslationalImaging vol 5 no 1 pp 15ndash27 2017
[204] H J Flint E A BayerM T Rincon R Lamed and B AWhiteldquoPolysaccharide utilization by gut bacteria potential for newinsights from genomic analysisrdquo Nature Reviews Microbiologyvol 6 no 2 pp 121ndash131 2008
[205] GGowrishankarMNamavari E B Jouannot et al ldquoInvestiga-tion of 6-[18F]-fluoromaltose as a novel PET tracer for imagingbacterial infectionrdquo PLoS ONE vol 9 no 9 Article ID e1079512014
[206] N Gholipour M Akhlaghi A M Kheirabadi et al ldquoChelator-free radiolabeling of dextran with 68Ga for PET studiesrdquoJournal of Radioanalytical and Nuclear Chemistry vol 311 no3 pp 1811ndash1817 2017
[207] C Bettegowda C A Foss I Cheong et al ldquoImaging bac-terial infections with radiolabeled 1-(21015840-deoxy-21015840- fluoro-120573-D-arabinofuranosyl)-5-iodouracilrdquo Proceedings of the NationalAcadamy of Sciences of the United States of America vol 102 no4 pp 1145ndash1150 2005
[208] S A Soghomonyan M Doubrovin J Pike et al ldquoPositronemission tomography (PET) imaging of tumor-localizedSalmonella expressing HSV1-TKrdquo Cancer GeneTherapy vol 12no 1 pp 101ndash108 2005
[209] C Palestro K Nichols S Sheikh-Fayyaz S Dewey P Singhaland K Bhargava ldquoCan Gallium-68 PET differentiate acuteinterstitial nephritis from acute tubular necrosisrdquo Journal ofNuclear Medicne vol 57 Supplement 2 p 551 2016
[210] A J Morguet D L Munz V Ivancevic et al ldquoImmunoscintig-raphy using technetium-99m-labeled anti-NCA-95 antigranu-locyte antibodies as an adjunct to echocardiography in subacuteinfective endocarditisrdquo Journal of the American College ofCardiology vol 23 no 5 pp 1171ndash1178 1994
[211] C van der Laken O Boerman W Oyen et al ldquoIn Vivo Expres-sion of Interleukin-1 Receptors during Various ExperimentallyInduced Inflammatory Conditionsrdquo The Journal of InfectiousDiseases vol 177 no 5 pp 1398ndash1401 1998
[212] C J Van Der Laken O C Boerman W J G Oyen M T PVan De Ven J W M Van Der Meer and F H M CorstensldquoScintigraphic detection of infection and inflammation Newdevelopments with special emphasis on receptor interactionrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 25 no 5 pp 535ndash546 1998
[213] C J van der LakenOC BoermanW J GOyenM T P van deVen J W M van der Meer and F H M Corstens ldquoImaging ofinfection in rabbits with radioiodinated interleukin-1 (120572 and 120573)its receptor antagonist and a chemotactic peptide a comparativestudyrdquo European Journal of Nuclear Medicine and MolecularImaging vol 25 no 4 pp 347ndash352 1998
[214] C J Van Der Laken O C BoermanW J G Oyen M T P VanDe Ven F H M Corstens and J W M Ven Der Meer ldquoThekinetics of radiolabelled interleukin-8 in infection and sterileinflammationrdquo Nuclear Medicine Communications vol 19 no3 pp 271ndash282 1998
[215] E Lazzeri P Erba M Perri et al ldquoScintigraphic imaging ofvertebral osteomyelitis with 111in-biotinrdquoThe Spine Journal vol33 no 7 pp E198ndashE204 2008
[216] E Blom B Langstrom and I Velikyan ldquo68Ga-labeling of biotinanalogues and their characterizationrdquo Bioconjugate Chemistryvol 20 no 6 pp 1146ndash1151 2009
[217] O Eriksson F Carlsson E Blom et al ldquoPreclinical evaluationof a 68Ga-labeled biotin analogue for applications in islettransplantationrdquo Nuclear Medicine and Biology vol 39 no 3pp 415ndash421 2012
[218] E A Weinstein A A Ordonez V P DeMarco et alldquoImaging Enterobacteriaceae infection in vivo with 18F-fluoro-deoxysorbitol positron emission tomographyrdquo Science Transla-tional Medicine vol 6 no 259 p 259ra146 2014
[219] K M Nielsen M H Kyneb A K O Alstrup et alldquo68Ga-labeled phage-display selected peptides as tracers forpositron emission tomography imaging of Staphylococcusaureus biofilm-associated infections Selection radiolabellingand preliminary biological evaluationrdquo Nuclear Medicine andBiology vol 43 no 10 pp 593ndash605 2016
[220] T J Makinen P Lankinen T Poyhonen J Jalava H T Aroand A Roivainen ldquoComparison of 18F-FDG and 68Ga PETimaging in the assessment of experimental osteomyelitis due toStaphylococcus aureusrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 32 no 11 pp 1259ndash1268 2005
[221] JMU Silvola I LaitinenH J Sipila et al ldquoUptake of 68galliumin atherosclerotic plaques in LDLRminusminusApoB100100micerdquo EJN-MMI Research vol 1 no 1 pp 1ndash8 2011
Contrast Media amp Molecular Imaging 23
[222] T A Wynn ldquoCellular and molecular mechanisms of fibrosisrdquoThe Journal of Pathology vol 214 no 2 pp 199ndash210 2008
[223] T Derlin D Jonigk J Bauersachs and FM Bengel ldquoMolecularImaging of Chemokine Receptor CXCR4 in NonndashSmall CellLung Cancer Using 68Ga-Pentixafor PETCT ComparisonWith 18F-FDGrdquo Clinical Nuclear Medicine 2016
[224] I Velikyan U Rosenstrom T N Bulenga O Eriksson andG Antoni ldquoFeasibility of multiple examinations using68ga-labelled collagelin analogues Organ distribution in rat forextrapolation to human organ and whole-body radiationdosimetryrdquo Pharmaceuticals vol 9 no 2 article no 31 2016
[225] S Jadhav M Kakela J Makila et al ldquoSynthesis and in VivoPET Imaging of Hyaluronan Conjugates of OligonucleotidesrdquoBioconjugate Chemistry vol 27 no 2 pp 391ndash403 2016
[226] A Autio A Saraste N Kudomi et al ldquoAssessment of bloodflow with (68) Ga-DOTA PET in experimental inflammation avalidation study using (15) O-waterrdquo American Journal ofNuclear Medicine and Molecular Imaging vol 4 no 6 pp 571ndash579 2014
[227] G Davies A Rolle A Maurer et al ldquoTowards translationalimmunoPETMR imaging of invasive pulmonary aspergillosisthe Humanised Monoclonal Antibody JF5 detects in vivordquoTheranostics vol 7 no 14 pp 3398ndash3414 2017
[228] DGoodwin CMeares GDavid et al ldquoMonoclonal antibodiesas reversible equilibrium carriers of radiopharmaceuticalsrdquoInternational Journal of Radiation Applications and Instrumen-tation Part B Nuclear Medicine and Biology vol 13 no 4 pp383ndash391 1986
[229] D A Goodwin C F Mears M McTigue and G S DavidldquoMonoclonal antibody hapten radiopharmaceutical deliveryrdquoNuclear Medicine Communications vol 7 no 8 pp 569ndash5801986
[230] S E Halpern and R O Dillman ldquoProblems associated withradioimmunodetection and possibilities for future solutionsrdquo JBiol Response Mod vol 6 no 3 pp 235ndash262 1987
[231] H Hong J Sun and W Cai ldquoRadionuclide-based cancerimaging targeting the carcinoembryonic antigenrdquo BiomarkerInsights vol 3 pp 435ndash451 2008
[232] G J Forster E B Santos P M Smith-Jones P Zanzonico andS M Larson ldquoPretargeted radioimmunotherapy with a single-chain antibodystreptavidin construct and radiolabeledDOTA-biotin Strategies for reduction of the renal doserdquo Journal ofNuclear Medicine vol 47 no 1 pp 140ndash149 2006
[233] Z Yao M Zhang H Kobayashi et al ldquoImproved targeting ofradiolabeled streptavidin in tumors pretargeted with biotiny-lated monoclonal antibodies through an avidin chaserdquo Journalof Nuclear Medicine vol 36 no 5 pp 837ndash841 1995
[234] C-H Chang R M Sharkey E A Rossi et al ldquoMolecularAdvances in Pretargeting Radioimunotherapy with BispecificAntibodies 1 Supported in part by USPHS Grant R01-CA-84379from the NIH and Department of Energy Grant DE-FG01-00NE22941 (both to R M S)1rdquo Mol Cancer Ther vol 1 no 7pp 553ndash563 2002
[235] R M Sharkey E A Rossi W J McBride C-H Chang andD M Goldenberg ldquoRecombinant Bispecific Monoclonal Anti-bodies Prepared by theDock-and-Lock Strategy for PretargetedRadioimmunotherapyrdquo Seminars in Nuclear Medicine vol 40no 3 pp 190ndash203 2010
[236] R M Sharkey E A Rossi C-H Chang and D M Golden-berg ldquoImproved cancer therapy and molecular imaging withmultivalent multispecific antibodiesrdquo Cancer Biotherapy andRadiopharmaceuticals vol 25 no 1 pp 1ndash12 2010
[237] D M Goldenberg R M Sharkey G Paganelli J Barbet andJ Chatal ldquoAntibody pretargeting advances cancer radioim-munodetection and radioimmunotherapyrdquo Journal of ClinicalOncology vol 24 no 5 pp 823ndash834 2006
[238] O C Boerman F G van Schaijk W J G Oyen and FH M Corstens ldquoPretargeted radioimmunotherapy of cancerprogress step by steprdquo Journal of Nuclear Medicine vol 44 no3 pp 400ndash411 2003
[239] J Schuhmacher S Kaul G Klivenyi et al ldquoImmunoscintigra-phy with positron emission tomography Gallium-68 chelateimaging of breast cancer pretargeted with bispecific anti-MUC1anti-Ga chelate antibodiesrdquo Cancer Research vol 61 no9 pp 3712ndash3717 2001
[240] J Schuhmacher G Klivenyi S Kaul et al ldquoPretargeting ofhuman mammary carcinoma xenografts with bispecific anti-MUC1anti-Ga chelate antibodies and immunoscintigraphywith PETrdquo Nuclear Medicine and Biology vol 28 no 7 pp 821ndash828 2001
[241] C Somasundaram S Matzku J Schuhmacher and M ZollerldquoDevelopment of a bispecific monoclonal antibody against agallium-67 chelate and the human melanoma-associated anti-gen p97 for potential use in pretargeted immunoscintigraphyrdquoCancer Immunology Immunotherapy vol 36 no 5 pp 337ndash3451993
[242] E A Rossi D L Rossi R Stein D M Goldenberg and C-H Chang ldquoA bispecific antibody-IFN1205722b immunocytokine tar-geting CD20 and HLA-DR is highly toxic to human lymphomaandmultiplemyeloma cellsrdquoCancer Research vol 70 no 19 pp7600ndash7609 2010
[243] R M Sharkey H Karacay S Litwin et al ldquoImproved ther-apeutic results by pretargeted radioimmunotherapy of non-Hodgkinrsquos lymphoma with a new recombinant trivalent anti-CD20 bispecific antibodyrdquo Cancer Research vol 68 no 13 pp5282ndash5290 2008
[244] G L Griffiths C-H Chang W J McBride et al ldquoReagentsandmethods for PETusing bispecific antibody pretargeting and68Ga-radiolabeled bivalent hapten-peptide-chelate conjugatesrdquoJournal of Nuclear Medicine vol 45 no 1 pp 30ndash39 2004
[245] J Watine M Miedouge and B Friedberg ldquoCarcinoembryonicantigen as an independent prognostic factor of recurrence andsurvival in patients resected for colorectal liver metastases Asystematic reviewrdquo Diseases of the Colon amp Rectum vol 44 no12 pp 1791ndash1799 2001
[246] M J Goldstein and E P Mitchell ldquoCarcinoembryonic antigenin the staging and follow-up of patients with colorectal cancerrdquoCancer Investigation vol 23 no 4 pp 338ndash351 2005
[247] D V Gold D M Goldenberg H Karacay et al ldquoA novelbispecific trivalent antibody construct for targeting pancreaticcarcinomardquo Cancer Research vol 68 no 12 pp 4819ndash48262008
[248] J Schuhmacher G Klivenyi R Matys et al ldquoMultistep tumortargeting in nudemice using bispecific antibodies and a galliumchelate suitable for immunoscintigraphy with positron emis-sion tomographyrdquo Cancer Research vol 55 no 1 pp 115ndash1231995
[249] G Klivenyi J Schuhmacher E Patzelt et al ldquoGallium-68chelate imaging of human colon carcinoma xenografts pre-targeted with bispecific anti-CD44(V6)anti-gallium chelateantibodiesrdquo Journal ofNuclearMedicine vol 39 no 10 pp 1769ndash1776 1998
[250] M Zoller J Schuhmacher J Reed W Maier-Borst and SMatzku ldquoEstablishment and characterization of monoclonal
24 Contrast Media amp Molecular Imaging
antibodies against an octahedral gallium chelate suitable forimmunoscintigraphy with PETrdquo Journal of Nuclear Medicinevol 33 no 7 pp 1366ndash1372 1992
[251] R M Sharkey T M Cardillo E A Rossi et al ldquoSignal ampli-fication in molecular imaging by pretargeting a multivalentbispecific antibodyrdquo Nature Medicine vol 11 no 11 pp 1250ndash1255 2005
[252] D M Goldenberg and R M Sharkey ldquoNovel radiolabeledantibody conjugatesrdquo Oncogene vol 26 no 25 pp 3734ndash37442007
[253] D M Goldenberg E A Rossi R M Sharkey W J McBrideand C-H Chang ldquoMultifunctional antibodies by the dock-and-lock method for improved cancer imaging and therapy bypretargetingrdquo Journal of NuclearMedicine vol 49 no 1 pp 158ndash163 2008
[254] R Schoffelen R M Sharkey D M Goldenberg et al ldquoPre-targeted immuno-positron emission tomography imaging ofcarcinoembryonic antigen-expressing tumors with a bispecificantibody and a68Ga- And18F-labeled hapten peptide in micewith human tumor xenograftsrdquoMolecular Cancer Therapeuticsvol 9 no 4 pp 1019ndash1027 2010
[255] E S Bos W H Kuijpers M Meesters-Winters et al ldquoIn vitroevaluation of DNA-DNA hybridization as a two-step approachin radioimmunotherapy of cancerrdquoCancer Research vol 54 no13 pp 3479ndash3486 1994
[256] G Paganelli M Bartolomei M Ferrari et al ldquoPre-TargetedLocoregional Radioimmunotherapy withrdquo Cancer biotherapyand radiopharmaceuticals vol 16 no 3 pp 227ndash235 2001
[257] A Forero P L Weiden J M Vose et al ldquoPhase 1 trial of a novelanti-CD20 fusion protein in pretargeted radioimmunotherapyfor B-cell non-Hodgkin lymphomardquo Blood vol 104 no 1 pp227ndash236 2004
[258] DM Goldenberg C-H Chang E A RossiW J McBride andR M Sharkey ldquoPretargeted molecular imaging and radioim-munotherapyrdquoTheranostics vol 2 no 5 pp 523ndash540 2012
[259] H Karacay R M Sharkey W J McBride E A Rossi C-HChang and D M Goldenberg ldquoOptimization of hapten-peptide labeling for pretargeted immunoPET of bispecificantibody using generator-produced 68Gardquo Journal of NuclearMedicine vol 52 no 4 pp 555ndash559 2011
[260] J R Oh and B C Ahn ldquoFalse-positive uptake on radioiodinewhole-body scintigraphy physiologic and pathologic variantsunrelated to thyroid cancerrdquo American Journal of NuclearMedicine and Molecular Imaging vol 2 no 2 pp 141ndash150 2012
[261] E Frampas C Rousseau C Bodet-Milin J Barbet J-F Chataland F Kraeber-Bodere ldquoImprovement of radioimmunotherapyusing pretargetingrdquo Frontiers in Oncology vol 3 Article ID00159 2013
[262] C S McKay and M G Finn ldquoClick chemistry in complexmixtures Bioorthogonal bioconjugationrdquo Chemistry amp Biologyvol 21 no 9 pp 1075ndash1101 2014
[263] B L Oliveira Z Guo and G J Bernardes ldquoInverse electrondemand DielsndashAlder reactions in chemical biologyrdquo ChemicalSociety Reviews vol 46 no 16 pp 4895ndash4950 2017
[264] B Nichols Z Qin J Yang D R Vera and N K Devaraj ldquo68Gachelating bioorthogonal tetrazine polymers for the multisteplabeling of cancer biomarkersrdquo Chemical Communications vol50 no 40 pp 5215ndash5217 2014
[265] R Rossin P R Verkerk S M van den Bosch et al ldquoInvivo chemistry for pretargeted tumor imaging in live micerdquoAngewandte Chemie International Edition vol 49 no 19 pp3375ndash3378 2010
[266] B M Zeglis K K Sevak T Reiner et al ldquoA pretargetedPET imaging strategy based on bioorthogonal diels-alder clickchemistryrdquo Journal of Nuclear Medicine vol 54 no 8 pp 1389ndash1396 2013
[267] J L Houghton R Membreno D Abdel-Atti et al ldquoEstablish-ment of the invivo efficacy of pretargeted radioimmunotherapyutilizing inverse electron demand diels-alder click chemistryrdquoMolecular Cancer Therapeutics vol 16 no 1 pp 124ndash133 2017
[268] J Funkhouser ldquoReinventing pharma the theranostic revolu-tionrdquo Current Drug Discovery pp 17ndash19 2002
[269] J Sorensen I Velikyan A Wennborg et al ldquoMeasuring HER2-expression in metastatic breast cancer using 68Ga-ABY025PETCTrdquo European Journal of Nuclear Medicine and MolecularImaging vol 41 pp S226ndashS226 2014
[270] I Velikyan A Wennborg J Feldwisch et al ldquoGMP compliantpreparation of a 68Gallium-labeled Affibody analogue forbreast cancer patient examination first-in-manrdquoEur JNuclMedMol Imaging vol 41 pp S228ndashS229 2014
[271] K Oberg ldquoMolecular imaging radiotherapy Theranostics forpersonalized patient management of neuroendocrine tumors(NETs)rdquoTheranostics vol 2 no 5 pp 448ndash458 2012
[272] I Velikyan AWennborg J FeldwischH Lindman J Carlssonand J Sorensen ldquoGood manufacturing practice production of [(68) Ga]Ga-ABY-025 for HER2 specific breast cancer imagingrdquoAmerican Journal of Nuclear Medicine and Molecular Imagingvol 6 no 2 pp 135ndash153 2016
[273] M Sandstrom K Lindskog I Velikyan et al ldquoBiodistributionand radiation dosimetry of the anti-HER2 Affibody molecule68Ga-ABY-025 in breast cancer patientsrdquo Journal of NuclearMedicine vol 57 no 6 pp 867ndash871 2016
[274] D Sandberg V Tolmachev I Velikyan et al ldquoIntra-imagereferencing for simplified assessment of HER2-expression inbreast cancer metastases using the Affibody molecule ABY-025with PET and SPECTrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 44 no 8 pp 1337ndash1346 2017
[275] H ZhangM AMoroz I Serganova et al ldquoImaging expressionof the human somatostatin receptor subtype-2 reporter genewith 68Ga-DOTATOCrdquo Journal ofNuclearMedicine vol 52 no1 pp 123ndash131 2011
[276] M Naji and A Al-Nahhas ldquo68Ga-labelled peptides in themanagement of neuroectodermal tumoursrdquo European Journalof Nuclear Medicine and Molecular Imaging vol 39 no 1 ppS61ndashS67 2012
[277] I Velikyan ldquoThe diversity of 68Ga-Based imaging agentsrdquoRecent Results in Cancer Research vol 194 pp 101ndash131 2013
[278] K Ferreira H-Y Hu V Fetz et al ldquoMultivalent siderophore-dotam conjugates as theranostics for imaging and treatment ofbacterial infectionsrdquo Angewandte Chemie International Editionvol 56 no 28 pp 8272ndash8276 2017
Computational and Mathematical Methods in Medicine
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Submit your manuscripts atwwwhindawicom
8 Contrast Media amp Molecular Imaging
NH ONHONH
OOO
HOHN O
HN
NN
N N
HO
O
N
N
O
O
N
N
O
O
O
Ga+
minus
（3
(a)
2
15
1
05
0
(b)
Figure 2 Accumulation of [68Ga]Ga-DOTA-folate (a) in the site of inflammation of rat inflammatory pawmodel induced by subcutaneouslyinjected Complete Freundrsquos Adjuvant (b) Adapted from [61]
4
2
0
Figure 3 Intense atherosclerotic inflammation (white arrows) was detected by [68Ga]Ga-DOTA-TATE in a patient with acute coronarysyndrome Adapted from [65]
uptake was detected in a nonarthritis patientrsquos hands and feet[163]
57 Targeting Somatostatin Receptors Somatostatin receptor(SSTR) ligand analogues have found an extensive appli-cation in diagnosis and radiotherapy of neuroendocrinetumours The elevated expression of SSTRs is known also insmall cell lung cancer breast cancer renal cell carcinomaprostate cancer and malignant lymphoma A number ofsomatostatin ligand analogues labelled with gamma- andpositron-emitting radionuclides were used clinically foroncological cases [85 164ndash174] 68Ga-labelled somatostatinanalogues demonstrated superior performance in terms ofhigher specificity and sensitivity detection rate shorterexamination time and quantification possibility and havebecome a golden standard for the detection of neuroen-docrine tumours (NETs) taking over that title from [111In]-pentetreotide (OctreoScan) and demonstrating specificityand sensitivity of over 90 [27 175ndash180] 68Ga-labelledagents for the imaging of NETs demonstrated advantages
also over other radionuclides and tracers such as [18F]FDG[174] 123I-metaiodobenzylguanidine ([123I]MIBG) [181 182][18F]DOPA [183] [99mTc]-dicarboxy propane diphosphonate[184] and [18F]NaF
SSTR are also overexpressed on activated macrophagesand T-lymphocytes 68Ga-labelled analogues were used ininflammation related diseases such as idiopathic pulmonaryfibrosis [62] Gravesrsquo and Hashimotorsquos diseases [63] coro-nary artery plaque imaging and characterization [64] andatherosclerotic inflammation with excellent macrophagespecificity (Figure 3) [65] Promising diagnostic potential ofa 99mTc-labelled analogue was demonstrated in patients withrheumatoid arthritis and secondary Sjogrenrsquos syndrome andthe method was suggested for the assistance in anti-TNFalpha antibody treatment planning [185] [68Ga]Ga-DOTA-TOCPET-CT was found superior to 67Ga-CitrateSPECT indetection of sarcoidosis lesions [186] A clinical study demon-strated correlation between uptake of [68Ga]Ga-DOTA-TOCand SST2 mRNA expression and recorded the information ina database [187] providing tools for accurate quantification
Contrast Media amp Molecular Imaging 9
and evaluation of disease progression and treatment responsein cancerous and inflammatory diseases involving SSTRsPreclinical study using atherosclerotic mice demonstratedsuperior targeting properties of [68Ga]Ga-DOTA-NOC ascompared to [18F]FDR-NOC [188] overall confirming thepotential of SSTR targeting for atherosclerotic plaque imag-ing
58 Imaging Neuroinflammation Despite difficulty ofdesigning 68Ga-labelled molecules capable of blood-brainbarrier penetration several agents were suggested for theimaging of neuroinflammation in particular A120573 plaquesdeposited on blood vessels [67ndash69] Bivalent styrylpyridineslabelled with 68Ga demonstrated high specificity and affinityfor A120573 plaques using postmortem Alzheimerrsquos disease (AD)brain sections [67] Benzofuran derivative comprising 68Gashowed promising results in terms of binding specificityand affinity investigated in vitro in sections of Tg2576mice [68] Although the synthesis of a 68Ga-labelledPittsburgh compound analogue was successful the in vitrobinding to amyloid deposits was limited [69] The commondisadvantage of these agents is poor blood-brain barrierpenetration nevertheless the exploration of more successfulanalogues continues Curcumin functions as an antioxidantantimicrobial anti-inflammatory and anticancer agentDiacetyl-curcumin and bis(dehydroxy)curcumin labelledwith 68Ga demonstrated in vitro binding to 120573-amyloid fibrilsand lung cancer cells [189] Potential application of the agentscould include diagnostic imaging of Alzheimerrsquos disease andvarious cancers
6 Imaging Infection
Infection imaging can be indirect utilizing targets involvedin the immune response namely inflammation as presentedin the inflammation targets section above or direct utilizingpathogen related targets The direct imaging is especiallycrucial in cases where inflammatory response is absent Thedifference in biochemistry and structure between bacterialand human cells might exclude physiological uptake byhuman tissuemaking it easier tomeet the favorable character-istics of an imaging agent However discrimination betweenthe various infectious microorganisms pathogenic bacteriaand microbiota targeting specific bacteria type as well asdifficulty of accessing bacteria aggregated in a biofilm makesthe task very challenging [190 191] The specific targetingof infection would require accumulation of the radioactivesignal in the pathogen The radiolabelled targeting agentsfor infection can be roughly divided into several groupsantibiotics based antimicrobial protein and peptide basedsiderophore and other metabolisable compound based andantigen-specific antibodies and antibody fragments (Table 3)
61 Radiolabelled Antibiotics Antimicrobials act on the pro-cesses that are specific to microbes for example bacteria andfungi and thus corresponding imaging agents might distin-guish infection from inflammation [191] They might requireinternalization or may bind to the cell surface dependent on
their biological action mechanism [191ndash193] The possibilityof antibiotic resistance development exists also in the case ofimaging agents even though the amount of such agents wouldbe subnanomolar [194 195] Another complication is possiblenonspecific uptake of antibiotics based agents by leucocytes[196] Considerable number of various antibiotic analogueshave been labelled with 99mTc 111In 131I 11C and 18F[102] and evaluated preclinically and clinically with 99mTc-ciprofloxacin becoming a commercial product (Infecton) [21197 198] However the further improvement of specificityis desirable [191] Antibiotics are accessible and cheap andthey demonstrate high sensitivity [102 191] making thedevelopment of 68Ga-labelled analogues very attractive giventhe earlier mentioned advantages that 68Ga as a radionu-clide in combination with PET provides Two 68Ga-labelledanalogues based on ciprofloxacin demonstrated potential fordiscrimination between bacterial infection and inflammationin rats infected with Staphylococcus aureus [70]
62 Radiolabelled Antimicrobial Proteins and Peptides Anti-microbial proteins and peptides for example serprocidinscathelicidins and defensins produced by the cells of immunesystem target microbial membrane lipids and impose micro-bicidal effect [35 43] They present a large group of poten-tial candidates for microbial imaging including bacteriafungi parasites and viruses Antimicrobial peptides havedemonstrated higher specificity for infection than antibioticanalogues They accumulate at infection but not sterileinflammation sites The most thoroughly studied antimicro-bial peptide ubiquicidin UBI [29ndash41] labelled with 99mTc[199] demonstrated promising results in human clinical trials[200 201] It has the potential for quantification of viableinfecting microorganisms and consequently for monitoringthe efficacy of antimicrobial therapy in patients
Fragments of an antimicrobial peptide ubiquicidin con-jugated to NOTA and labelled with 68Ga [68Ga]Ga-NOTA-UBI29-41 and [68Ga]Ga-NOTA-UBI30-41 demonstratedpossibility for the distinction between infection and inflam-mation in a rabbit model [71 72] Antimicrobial peptidefragments GF-17 and RAWVAWR-NH2 of respectivelyhuman cathelicidin LL-37 andhuman lysozyme active againstE coli and S aureus were labelled with 68Ga and theirbiodistribution in normal rats demonstrated fast clearancefrom liver [75] Antimicrobial depsipeptide based agent[68Ga]Ga-DOTA-TBIA101 targeting bacterial lipopolysac-charides detected muscular E coli-infection in mice (Fig-ure 4) [73] The agent was also studied in healthy rabbitsand various disease model rabbits such as sterile inflam-mation Staphylococcus aureus infection andMycobacteriumtuberculosis [74] The clearance of [68Ga]Ga-DOTA-TBIA101from blood and normal tissue was fast and enhanced uptakein sterile inflammation and Mycobacterium tuberculosis siteswas observed The improvement of the bacterial selectivitywill require modification of the agent structure
63 Radiolabelled Siderophores Bacteria and fungi producevarious siderophores for harvesting iron which is essentialfor their survival and growth [34 98 191] Siderophores
10 Contrast Media amp Molecular Imaging
(a)
(b)
(c) (d)
(e)
Figure 4 Left panel presents maximum intensity projection images of [68Ga]Ga-DOTA-TBIA101 distribution in a healthy mouse (a) and amouse with muscular infection site (MIS) in the right hind muscle tissue (white arrows) Right panel presents coronal (c) sagittal (d) andaxial (e) images with uptake in theMIS (white arrow) and absence of the uptake in the contralateralmuscle tissue Ki and Bl stand respectivelyfor kidney and bladder Reproduced from [73]
can also play a critical role in the development of biofilmsby microbes They are low molecular weight compoundsspecifically chelating Fe(III) and Ga(III) can form stablecomplexes with them mimicking Fe(III) [202 203]
Desferri-triacetylfusarinine C (TAFC) and desferri-ferricrocin (FC) labelled with 68Ga were used for theimaging of invasive pulmonary aspergillosis (IPA) caused byAspergillus fumigatus [15] [68Ga]Ga-TAFC demonstratedsuperior characteristics in terms of specific target bindingmetabolic stability and fast blood clearance in a rat modelof A fumigatus infection Seven analogues were developedin another study with TAFC and ferrioxamine E (FOXE)showing favorable binding clearance elimination andstability characteristics [16] as well as lung uptake inrat of invasive aspergillosis model wherein the uptakeextent was correlated with disease severity [17] [68Ga]Ga-triacetylfusarinine C and [68Ga]Ga-ferrioxamine E wereinvestigated in rat model of A fumigatus and demonstratedrapid uptake in the lungs (Figure 5) [76]
64 Radiolabelled Metabolisable Agents Mammalian micro-biota consumes (poly)saccharides in particular maltose andmaltodextrins [204] The transport mechanism is specific
to bacteria and is absent in mammalian cells making itpossible to utilize these (poly)saccharides for imaging agentdevelopment Maltodextrin functionalized with a fluorescentdye was internalized through the bacteria-specific maltodex-trin transport pathway and discriminated between activebacteria and inflammation in vivo [192] Maltose labelledwith 18F localized specifically bacterial infection in mice[205] Potential to label polysaccharides directly with 68Gamight be utilized extensively
As mentioned above the chemical properties of Ga(III)provide the potential for direct labelling of polysaccharidesDextran was labelled directly and resulting complex demon-strated sufficient stability in human serum however thefeasibility of the bacterial imaging was not demonstrated[206]
Trapping of nucleosides that are substrates of thymidinekinase occurring within bacteria was explored using 18Fand 125I labelled analogues of uracil [207] Promising resultswere obtained in seven bacterial species in mice Anotherstudy in the context of therapeutic bacteria developmentdemonstrated possibility of detecting Salmonella vectorswithin tumours using 18F-labelled uracil [208] However
Contrast Media amp Molecular Imaging 11
N
O
N
ON
HN
O
O
O
OO O
NH
O
O
O
O
NH
O
OGa
（3
（3
（3
（3
（3
（3
（2
(a) (b) (c)
Figure 5 Molecular structure of [68Ga]Ga-triacetylfusarinine C (a) used for the in vivo imaging of a rat with Aspergillus fumigatus infection(b) and negative control of noninfected rat (c) White arrows point at the infected (b) and normal (c) lungs Adapted from [76]
the development of 68Ga-labelled nucleosides that wouldmaintain their biological activity is challenging and fewexamples known from the literature confirm that [4 6]
7 68Ga-Citrate
As mentioned above 68GaPET provides a number of advan-tages over 67GaSPECT and following publications demon-strate it in clinical and preclinical studies [68Ga]Ga-citratedemonstrated high diagnostic accuracy of 90of osteomyeli-tis and diskitis in clinical studies (Figure 6) [18 19] Thisstudy demonstrates that [68Ga]Ga-citrate can be employedfor monitoring the response to treatment [68Ga]Ga-citratewas used clinically to follow-up surgical intervention inpatients with acute osteomyelitis and intra-abdominal infec-tion [77] The agent was also used to successfully visualizelungmalignancy and tuberculosis in patients however in caseof high prevalence of granulomatous diseases the distinctionbetween malignant and benign lung lesions was unclear [7879] Another clinical study conducted head-to-head compar-ison of [68Ga]Ga-citrate (Figure 7) and [18F]FDG in patientswith Staphylococcus aureus bacteremia [80] The detectionrate of osteomyelitis was similar and further investigationof [68Ga]Ga-citrate applicability in cases of osteomyelitisinduced by other pathogens as well as for monitoring healingprocess is warranted
Comparative study of [68Ga]Ga-citrate and [67Ga]Ga-citrate was performed in healthy and infection model rats[77] The performance of [68Ga]Ga-citrate was found supe-rior in terms of image contrast in the lower abdomen and
extremities Potential of [68Ga]Ga-citrate for the differentia-tion of acute interstitial nephritis from acute tubular necrosiswas studied in rat model of the disease and it was demon-strated that the kidney uptake correlated with the extentof mononuclear cell infiltration accompanying inflammation[209] 68Ga-labelled Apo-transferrin demonstrated bacterialinfection detection capacity in rat model with Staphylococcusaureus wherein the infection site was visualized 1 h afteradministration of the agent [14]
71 Radiolabelled Antibodies and Antibody FragmentsHuman immunoglobulin (HIG) binds to bacteria but alsoaccumulates at the sites of fungal and viral infection aswell as sterile inflammation due to binding to leukocytesThe improved specificity for bacteria was achieved for thefragments of HIG It is feasible to develop specific antibodiesto various antigens present on the bacterial cell surface [102]Monoclonal antibodies labelled with 99mTc were used forinfection imaging via granulocytes targeting NCA-95 [210]Various cytokines of interleukin family (IL-1 IL-8) labelledwith 123I or 99mTc demonstrated accumulation in the sitesof infection in various animal models [111 112 211ndash214]Registered antigranulocyte radiopharmaceuticals suchas LeuTech Scintimun and Leukoscan are based on99mTc-labelled antibodies This experience can be translatedto 68Ga however either the size of the antibodies mustbe reduced or pretargeting techniques must be appliedin order to overcome the discrepancy between the shortphysical half-life of 68Ga and slow pharmacokinetics ofantibodies
12 Contrast Media amp Molecular Imaging
(a) (b) (c) (d)
Figure 6 [68Ga]Ga-citrate PETCT examination of a patient affected by acute osteomyelitis before (left panel) and after (right panel) surgicalcurettage showing uptake in the transaxial (a c) and 3D reconstruction images (b d red area) Absence of the uptake after the therapyconfirms complete response to the treatment Adapted from [19]
Figure 7 Vertebral osteomyelitis (spondylodiscitis red arrow-heads) and abscesses in the iliopsoas and paravertebral area (redarrows) were detected by [68Ga]Ga-citrate in a patient admittedto the hospital with back pain and general symptoms The PETacquisition was performed 88min after administration of 245MBqof [68Ga]Ga-citrate Adapted from [80]
72 Radiolabelled Biotin Biotin is a growth factor utilizedin many bacteria An 111In-labelled analogue of biotin wassuccessfully utilized for diagnosis of vertebral infections ina clinical study [215] It would be rational to explore therelevance of 68Ga-labelled analogues given the advantagesof 68Ga over 111In and promising [68Ga]Ga-DOTA-Biotinanalogues [216 217] developed for monitoring survival oftransplanted avidin-coated islets
8 Miscellaneous
Stable Ga(III) complex with thiosemicarbazones demon-strated antimicrobial effect against P aeruginosa and Calbicans due to most probably both displacement of essentialFe(III) with Ga(III) and thiosemicarbazones [101] Substitu-tion of the stable Ga(III) by radioactive 68Ga might result ina specific infection imaging agent
Selective imaging of Enterobacteriaceae using 2-[18F]-fluorodeoxysorbitol (18F-FDS)was demonstrated in amurine
myositis model [218] The uptake of 18F-FDS was correlatedwith bacterial burden moreover the agent differentiatedinfection from sterile inflammation Given the potential of68Ga for the labelling of small biologically active molecules[4] it might be plausible to develop a respective analoguewith added value of the advantages that 68Ga offers includingsimpler production chemistry lowered radiation dose repet-itive examination and accessibility at clinical centers withoutcyclotrons and remote from [18F]-FDG distribution sites Asmentioned above the poor access to bacteria aggregated ina biofilm might make the imaging task challenging Severalpeptide candidates with affinity for S aureus biofilm weredesigned and labelled with 68Ga [219] The resulting agentsdemonstrated binding in vitro however it was not possible toblock the binding with excess of the cold peptide
Ionic 68Ga was found superior to [18F]-FDG in infectiondetection in the rat model with diffuse osteomyelitis [220] Inanother study the uptake of ionic 68Ga was observed in theaortic plaques of atherosclerotic mice specifically at the sitesrich inmacrophages [221] However the slow blood clearanceof ionic 68Ga presents a limitation
Chronic inflammation is the major reason of fibro-sis [222] 68Ga-labelled SST analogue ([68Ga]Ga-DOTA-NOC) demonstrated uptake in pathogenic areas in patientsaffected by idiopathic pulmonary fibrosis with potentialfor monitoring response to treatment and drug develop-ment [62] Another clinical study using [68Ga]Ga-pentixaforalso showed potential of the agent for monitoring dis-ease activity and response to treatment in idiopathic pul-monary fibrosis [223] Peptide based agents CNO2A-PEG2-c[CPGRVMHGLHLGDDEGPC] and [68Ga]Ga-NODAGA-PEG2-c[CPGRVMHGLHLGDDEGPC] for the imaging andquantification of fibrosis by PET were developed and char-acterized preclinically showing fast clearance from normal
Contrast Media amp Molecular Imaging 13
tissue and blood and binding specificity [89] Dosimetrycalculations demonstrated possibility of six examinations peryear in humans assuring disease monitoring in longitudinalstudies and routine clinical setup [224]
Several hyaluronan conjugates of oligonucleotides target-ing CD44 positive cells were developed and tested in healthyrats sham-operated rats and rats with myocardial infarction[225]The uptake of the agents was higher for the latter groupand varied dependent on the difference in the oligonucleotidestructure
TLR2 and TLR4 expression levels in neutrophils werefound higher in individuals with bacterial and viral infectionsthan those in control samples There is a possibility that IL-4IL-8 IL-10 IL-12 and TNF-a might serve as biomarkers forinfections and that IL-2 IL-8 or IL-10 is potentially able todistinguish between bacterial and viral infections [22]
Mannosylated human serum albumin labelled with 68Gavia NOTA chelator moiety ([68Ga]Ga-NOTA-MSA) wastested in a rat model of myocarditis targetingmannose recep-tors expressed onmacrophages infiltratingmyocardium [66]The uptake in the diseased myocardium was considerablyhigher than that of the normal one and it was precludedby administration of excess of nonlabelled MSA indicatingbinding specificity The tracer build-up was also observed inthe organs of macrophage accumulation
[68Ga]Ga-DOTA was investigated for the quantificationof increased blood flow which is one of the key events ininflammation [226] The uptake kinetics of [68Ga]Ga-DOTAin the site of inflammation in rats with induced inflamma-tion correlated well with that of 15O-water suggesting highrelevance [68Ga]Ga-DOTA
9 Pretargeted Imaging
The half-life of 68Ga is shorter than that of 64Cu 67Ga 99mTc89Zr 111In and 123124125I and thus in contrast to the latterit is not compatible with slow pharmacokinetics of largemolecules such as antibodies and glycoproteins The rangeof antigen-specific antibodies relevant to inflammation andinfection is broad and a number of 99mTc-labelled antibodieswere used clinically [20 21 227] The respective range of68Ga-based agents could be similarThe solution to overcomethe incompatibility of half-life time frames could be eitherthe reduction of the antibody size or the application of thepretargeting concept
The history of the pretargeting concept spans threedecades predominantly in the field of oncology [228ndash230]It was developed to improve image contrast and dosimetryin immunoimaging and radioimmunotherapy when usingradiolabelled antibody ligands with slow pharmacokinetics[231] The arsenal of antibodies is vast and diverse encourag-ing extensive investment into development of techniques thatwould allow their exploration to the fullest Pretargeting con-siders at least two major steps wherein a functionalized anti-body is first administered for target localization and clearancefrom blood and normal tissue and thereafter a radiolabelledsmall molecule capable of binding to the functionalized
antibody due to high affinity or covalent interaction is admin-istered The key properties of the radiolabelled molecules arefast pharmacokinetic and clearance Several techniques havebeen developed for the realization of pretargeting conceptincluding avidinstreptavidin-biotin systems [216 217 232233] bispecific antibodies (bsmAb) with haptens [232 234ndash254] antibody-oligonucleotide conjugates with complemen-tary oligonucleotides [255] biorthogonal systems allowingcovalent chemical reactions in vivo (Figure 8)
The high affinity of biotin to avidin and streptavidinproteins was utilized clinically and preclinically in pretar-geting approach for the imaging and therapy of pancreaticadenocarcinoma [232] glioblastoma [256] and lymphoma[257] However this pretargeting technique may requirethree steps in order to eliminate the excess of antibody-(strept)avidin conjugate circulating in the blood and notbound to the target by adding clearing agent Anotherapplication of the technique was monitoring transplantationof islets of Langerhans in the treatment for type 1 diabetesmellitus wherein the cells or cellmimetics were conjugated to(strept)avidin prior to the transplantation [216 217] Severalanalogues of biotin comprising DOTA chelate moiety forlabelling with 68Ga and ethylene glycol linker of variouslength demonstrated the influence of the latter on the affinitytowards avidin
Particular example of hapten molecules is the ones com-prising histamine-succinyl-glycine (HSG) motif and chelatemoiety [251ndash253 258] for the complexationwith 68Ga Severalanalogues were developed for the imaging of carcinoem-bryonic antigen (CEA) pretargeted with anti-CEA bsmAb[254 259 260] and two clinical studies of medullary thyroidcarcinoma and breast carcinoma positive for CEA using68Ga-labelled hapten molecules and bsmAb were initiated[261]
Bioorthogonal reactions are fast regioselective requiringsmall reagent concentration and occurring under mild con-ditions often in aqueous solution and temperature below 37∘C[262 263] Amongst various biorthogonal reaction types thecycloaddition of tetrazines and various dienophiles referredto as inverse-electron-demandDiels-Alder (IEDDA) reactionis themost successful in the context of pretargeting Antibod-ies functionalized with trans-cyclooctene (TCO) and a radi-olabelled tetrazine that can interact in vivo based on IEDDAreaction were studied [264ndash267] In particular 68Ga-labelledtetrazine dextran demonstrated favorable pharmacokineticsin a healthy mouse [264] However the proof of concept is tobe performed in a xenografted animal Accumulation of anti-TAG72 [265] and anti-A33 [266] antibodies functionalizedwith TCO in mouse xenografts was visualized respectivelyby an 111In and 64Cu-labelled tetrazine analogues Anti-CA199 antibody-TCO in combination with 177Lu-labelledtetrazine demonstrated radiotherapeutic effect in pancreaticcancer murine model [267]
Thepretargeted imaging techniquesmay contribute to theexpansion of immuno-PET with 68Ga providing the intrinsicadvantages of 68Ga and PET As mentioned above mostof the developed radiolabelled counterparts of pretargetingtechniques have demonstrated promising results There are
14 Contrast Media amp Molecular Imaging
H
ON
NN
O
OO
OO
NH
NS
NH
ONH
O
HO
ONH
O
Ga
HN
NH
NH
O
OO
HNN
HN
NH
NH
O
OO
HNN
（2
(a)
NH
O
O
NH
N
NNGa
O O
O O
O
O
O
N N
NN
OO
（2
(b)
N
N
O
O
N
N
O
O
O
NH
O
O
ONH
NHS
O
H
HO
NH
+
minus
(c)
Figure 8 Schematic presentation of pretargeting techniques (a) bispecific antibodies engineered to specifically bind with radiolabelledhapten molecules (b) bioorthogonal click chemistry for fast and specific covalent binding between for example a trans-cyclooctenefunctionalized antibody and a radiolabelled tetrazine (c) interaction between antibody-(strept)avidin conjugate and radiolabelled biotinutilizing extremely high affinity of (strept)avidin and biotin
Contrast Media amp Molecular Imaging 15
a considerable number of potential antibody biomarkersthat could be considered for the imaging of infection andinflammation
10 Theranostics Potential
Theranostics [268] embraces realization of personalizedmedicine by conducting diagnosis on individual basis andproviding possibility of predicting the efficacy of a specifictreatment and following up the response to the treatmentenabling adjustment of the latter very early in the processIn the context of nuclear medicine wherein the radiophar-maceuticals targeted at biomarkers specific to a disease cancarry either diagnostic radionuclides or therapeutic ones theconcept can be denoted as radiotheranostics [28] The tar-geted molecular imaging such as PET can offer noninvasivediagnosis specific to the disease for example tumour-typespecific and provide accurate localization of the lesions Thestrongest advantage of PET is the potential for quantificationof the target for example receptor expression investigationof the uptake kinetics and estimation of the dosimetryThesecharacteristics of PET allow for individualized treatmentselection and planning monitoring of treatment responseand detection of recurrent diseaseThe individualized patientmanagement provides such advantages as optimization ofthe treatment regimen for the improved response and exclu-sion of futile treatments minimization of risks and toxicitywith overall outcome of reduced cost and patient distressThe importance of individualized patient management wasdemonstrated by clinical studies wherein the influence ofdose of the administered radiopharmaceutical targeted atreceptors overexpressed in cancer lesions on the diagnosticoutcome was investigated in the same patient [85 269270] 68Ga-labelled SST analogues [26ndash28 271] and Affibodymolecules [5 272ndash274] used respectively in NENs andbreast cancer patients are the most prominent examplesof (radio)theranostics involving 68GaPET wherein 68Ga-labelled analogues were used not only for localization of thelesions but also for staging patient stratification prognosistherapy selection and monitoring of the response to thetreatment of NETs and other cancer types [2ndash4 6 85 176275ndash277]
The methodology can be translated to inflammationand infection allowing for accurate and specific selection oftreatment regimen and for follow-up and evaluation of theresponse to therapy resulting in improved treatment efficacyand decreased cost and side effects The accommodation ofboth imaging function and antibiotic function in the samemolecule is a novel example of a theranostic agent [278]A series of siderophores conjugated with DOTA moiety forthe radiolabelling and with antibiotics for the treatmentof bacterial infection were investigated preclinically Theaccumulation of the intravenously administered ampicillinconjugate in the site of subcutaneously injected P aeruginosain mice was clearly and focally visualized within 06 h withretention for at least 24 h These results obtained usinganalogues carrying dye for optical imaging can be translatedto 68Ga-labelled counterparts for PET
11 Conclusions
The medical need for specific agents for noninvasive quan-titative and whole-body imaging of inflammation and infec-tion has not been met yet despite decades of research How-ever the prerequisites in terms of identification of potentialtargets design and synthesis of the respective ligands andimaging technologies are evolving very fast The potentialof accurate and quantitative lesion localization as well asmonitoring of the treatment response promises personalizedpatient management
The use of 68Ga in oncology is established proving thestrong potential of 68Ga for the promotion of PET technol-ogy for effective and efficient diagnostics and personalizedmedicineThe experience of oncological 68Ga-based agents isgetting translated to inflammation and infection Pretargetedimaging technology opens wide possibilities based on anti-body biomarkers
Conflicts of Interest
The author declares that there are no conflicts of interestregarding the publication of this article
References
[1] I Velikyan ldquoContinued rapid growth inGa applications update2013 to June 2014rdquo Journal of Labelled CompoundsampRadiophar-maceuticals pp 99ndash121 2015
[2] I Velikyan ldquo 68Ga-based radiopharmaceuticals Production andapplication relationshiprdquo Molecules vol 20 no 7 pp 12913ndash12943 2015
[3] M Fani P Peitl and I Velikyan ldquoCurrent status of radiophar-maceuticals for the theranostics of neuroendocrine neoplasmsrdquoPharmaceuticals vol 10 no 1 article no 30 2017
[4] I Velikyan ldquoPositron emitting [68Ga]Ga-based imaging agentsChemistry and diversityrdquoMedicinal Chemistry vol 7 no 5 pp345ndash379 2011
[5] J Sorensen I Velikyan D Sandberg et al ldquoMeasuringHER2-receptor expression in metastatic breast cancer using[68Ga]ABY-025 Affibody PETCTrdquo Theranostics vol 6 no 2pp 262ndash271 2016
[6] I Velikyan ldquoProspective of 68Ga-Radiopharmaceutical devel-opmentrdquoTheranostics vol 4 no 1 pp 47ndash80 2014
[7] P Lankinen T J Makinen T A Poyhonen et al ldquo68Ga-DOTAVAP-P1 PET imaging capable of demonstrating the phaseof inflammation in healing bones and the progress of infectionin osteomyelitic bonesrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 35 no 2 pp 352ndash364 2008
[8] T UjulaMHuttunen P Luoto et al ldquoMatrixmetalloproteinase9 targeting peptides Syntheses 68Ga-labeling and preliminaryevaluation in a rat melanoma xenograft modelrdquo BioconjugateChemistry vol 21 no 9 pp 1612ndash1621 2010
[9] A Autio T Ujula P Luoto S Salomaki S Jalkanen and ARoivainen ldquoPET imaging of inflammation and adenocarcinomaxenografts using vascular adhesion protein 1 targeting peptide68Ga-DOTAVAP-P1 Comparison with 18F-FDGrdquo EuropeanJournal of Nuclear Medicine and Molecular Imaging vol 37 no10 pp 1918ndash1925 2010
16 Contrast Media amp Molecular Imaging
[10] J Silvola A Autio P Luoto S Jalkanen andA Roivainen ldquoPre-liminary evaluation of novel 68Ga-DOTAVAP-PEG-P2 peptidetargeting vascular adhesion protein-1rdquo Clinical Physiology andFunctional Imaging vol 30 no 1 pp 75ndash78 2010
[11] T Ujula S Salomaki P Virsu et al ldquoSynthesis 68Ga labelingand preliminary evaluation of DOTA peptide binding vascularadhesion protein-1 a potential PET imaging agent for diagnos-ing osteomyelitisrdquo Nuclear Medicine and Biology vol 36 no 6pp 631ndash641 2009
[12] A Autio T Henttinen H J Sipila S Jalkanen and ARoivainen ldquoMini-PEG spacering of VAP-1-targeting 68Ga-DOTAVAP-P1 peptide improves PET imaging of inflamma-tionrdquo EJNMMI Research vol 1 no 1 pp 1ndash7 2011
[13] K Aalto A Autio E A Kiss et al ldquoSiglec-9 is a novel leukocyteligand for vascular adhesion protein-1 and can be used in PETimaging of inflammation and cancerrdquo Blood vol 118 no 13 pp3725ndash3733 2011
[14] V Kumar D K Boddeti S G Evans F Roesch and RHowman-Giles ldquoPotential use of 68Ga-apo-transferrin as a PETimaging agent for detecting Staphylococcus aureus infectionrdquoNuclear Medicine and Biology vol 38 no 3 pp 393ndash398 2011
[15] M Petrik H Haas G Dobrozemsky et al ldquo68Ga-siderophoresfor PET imaging of invasive pulmonary aspergillosis Proof ofprinciplerdquo Journal of Nuclear Medicine vol 51 no 4 pp 639ndash645 2010
[16] M Petrik H Haas M Schrettl A Helbok M Blatzer and CDecristoforo ldquoIn vitro and in vivo evaluation of selected 68Ga-siderophores for infection imagingrdquo Nuclear Medicine andBiology vol 39 no 3 pp 361ndash369 2012
[17] M Petrik GM Franssen H Haas et al ldquoPreclinical evaluationof two 68Ga-siderophores as potential radiopharmaceuticals forAspergillus fumigatus infection imagingrdquo European Journal ofNuclearMedicine andMolecular Imaging vol 39 no 7 pp 1175ndash1183 2012
[18] A Rizzello D Di Pierro F Lodi et al ldquoSynthesis and qualitycontrol of 68Ga citrate for routine clinical PETrdquo NuclearMedicine Communications vol 30 no 7 pp 542ndash545 2009
[19] C Nanni C Errani and L Boriani ldquo 68Ga-citrate PETCT forevaluating patients with infections of the bone preliminaryresultsrdquo Journal of Nuclear Medicine vol 51 no 12 pp 1932ndash1936 2010
[20] S S Das A V Hall D W Wareham and K E Britton ldquoInfec-tion imaging with radiopharmaceuticals in the 21st centuryrdquoBrazilian Archives of Biology and Technology vol 45 no spepp 25ndash37 2002
[21] A Signore and A W J M Glaudemans ldquoThe molecularimaging approach to image infections and inflammation bynuclear medicine techniquesrdquo Annals of Nuclear Medicine vol25 no 10 pp 681ndash700 2011
[22] T Yusa K Tateda A Ohara and S Miyazaki ldquoNew possiblebiomarkers for diagnosis of infections and diagnostic distinc-tion between bacterial and viral infections in childrenrdquo Journalof Infection and Chemotherapy vol 23 no 2 pp 96ndash100 2017
[23] A Signore A W J M Glaudemans O Gheysens C Lauriand O A Catalano ldquoNuclear Medicine Imaging in PediatricInfection or Chronic Inflammatory Diseasesrdquo Seminars inNuclear Medicine vol 47 no 3 pp 286ndash303 2017
[24] I Velikyan ldquoMolecular imaging and radiotherapyTheranosticsfor personalized patient managementrdquo Theranostics vol 2 no5 pp 424ndash426 2012
[25] F Rosch and R P Baum ldquoGenerator-based PET radiophar-maceuticals for molecular imaging of tumours On the way
to THERANOSTICSrdquo Dalton Transactions vol 40 no 23 pp6104ndash6111 2011
[26] R P Baum H R Kulkarni and C Carreras ldquoPeptides andreceptors in image-guided therapy Theranostics for neuroen-docrine neoplasmsrdquo Seminars in Nuclear Medicine vol 42 no3 pp 190ndash207 2012
[27] R P Baum and H R Kulkarni ldquoTheranostics From molecularimaging using Ga-68 labeled tracers and PETCT to per-sonalized radionuclide therapy - the bad berka experiencerdquoTheranostics vol 2 no 5 pp 437ndash447 2012
[28] I Velikyan ldquoRadionuclides for Imaging andTherapy in Oncol-ogyrdquo Cancer Theranostics pp 285ndash325 2014
[29] J Czernin andWAWeber ldquoIssues and controversies in nuclearmedicine Introductionrdquo Journal of Nuclear Medicine vol 52no Supplement 2 pp 1Sndash2S 2011
[30] S J Goldsmith and S Vallabhajosula ldquoClinically proven radio-pharmaceuticals for infection imaging mechanisms and appli-cationsrdquo Seminars in Nuclear Medicine vol 39 no 1 pp 2ndash102009
[31] M F Tsan ldquoMechanism of gallium-67 accumulation in inflam-matory lesionsrdquo Journal of Nuclear Medicine vol 26 no 1 pp88ndash92 1985
[32] S L Kipper ldquoRadiolabelled leukocyte imaging of the abdomenrdquoin Nuclear Medicine Annual J Freeman Ed pp 81ndash126 RavenPress New York NY USA 1995
[33] F Jamar J Buscombe A Chiti et al ldquoEANMSNMMI guidelinefor 18F-FDG use in inflammation and infectionrdquo Journal ofNuclear Medicine vol 54 no 4 pp 647ndash658 2013
[34] C J Palestro ldquoThe current role of gallium imaging in infectionrdquoSeminars in Nuclear Medicine vol 24 no 2 pp 128ndash141 1994
[35] M S Akhtar M B Imran M A Nadeem and A ShahidldquoAntimicrobial peptides as infection imaging agents better thanradiolabeled antibioticsrdquo International Journal of Peptides vol2012 Article ID 965238 19 pages 2012
[36] D Delbeke and G M Segall ldquoStatus of and trends in nuclearmedicine in the United Statesrdquo Journal of Nuclear Medicine vol52 no 2 2011
[37] S S Gambhir J Czernin J Schwimmer D H Silverman R EColeman and M E Phelps ldquoA tabulated summary of the FDGPET literaturerdquo Journal of Nuclear Medicine vol 42 pp 1Sndash93S2001
[38] M J Lindsay B A Siegel S R Tunis et al ldquoThe NationalOncologic PET Registry ExpandedMedicare coverage for PETunder coverage with evidence developmentrdquo American Journalof Roentgenology vol 188 no 4 pp 1109ndash1113 2007
[39] F Gemmel H Van Den Wyngaert C Love M M Welling PGemmel and C J Palestro ldquoProsthetic joint infectionsradionuclide state-of-the-art imagingrdquo European Journal ofNuclearMedicine andMolecular Imaging vol 39 no 5 pp 892ndash909 2012
[40] J Sorensen ldquoHow does the patient benefit from clinical PETrdquoTheranostics vol 2 no 5 pp 427ndash436 2012
[41] S L Rice C A Roney P Daumar and J S Lewis ldquoThe nextgeneration of positron emission tomography radiopharmaceu-ticals in oncologyrdquo Seminars in Nuclear Medicine vol 41 no 4pp 265ndash282 2011
[42] R LWahl JMHerman and E Ford ldquoThePromise and Pitfallsof Positron Emission Tomography and Single-Photon EmissionComputed Tomography Molecular Imaging-Guided RadiationTherapyrdquo Seminars in Radiation Oncology vol 21 no 2 pp 88ndash100 2011
Contrast Media amp Molecular Imaging 17
[43] A W J M Glaudemans R H J A Slart J M Van Dijl MVan Oosten and G M Van Dam ldquoMolecular imaging of infec-tious and inflammatory diseases A terra incognitardquo Journal ofNuclear Medicine vol 56 no 5 pp 659ndash661 2015
[44] X Li W Bauer I Israel et al ldquoTargeting p-selectin by gallium-68-labeled fucoidan positron emission tomography for nonin-vasive characterization of vulnerable plaques Correlation within vivo 176t mrirdquo Arteriosclerosis Thrombosis and VascularBiology vol 34 no 8 pp 1661ndash1667 2014
[45] S Eichendorff P Svendsen D Bender et al ldquoBiodistributionand PET Imaging of a Novel [68Ga]-Anti-CD163-AntibodyConjugate in Rats with Collagen-Induced Arthritis and inControlsrdquoMolecular Imaging and Biology vol 17 no 1 pp 87ndash93 2014
[46] Z Zhu Y Yin K Zheng et al ldquoEvaluation of synovial angiogen-esis in patients with rheumatoid arthritis using 68Ga-PRGD2PETCT A prospective proof-of-concept cohort studyrdquo Annalsof the Rheumatic Diseases vol 73 no 6 pp 1269ndash1272 2014
[47] J S Eo J C Paeng S Lee et al ldquoAngiogenesis imaging inmyocardial infarction using 68Ga-NOTA- RGD PET Charac-terization and application to therapeutic efficacy monitoring inratsrdquo Coronary Artery Disease vol 24 no 4 pp 303ndash311 2013
[48] J H Kim Y-H Kim Y J Kim et al ldquoQuantitative positronemission tomography imaging of angiogenesis in rats with fore-limb ischemia using 68Ga-NOTA-c(RGDyK)rdquo Angiogenesisvol 16 no 4 pp 837ndash846 2013
[49] I Laitinen J Notni K Pohle et al ldquoComparison of cyclicRGD peptides for 120572v1205733 integrin detection in a rat model ofmyocardial infarctionrdquo EJNMMI Research vol 3 no 1 pp 1ndash9 2013
[50] M Kiugel I Dijkgraaf V Kyto et al ldquoDimeric [68Ga]DOTA-RGD Peptide Targeting 120572 ltinfgtvltinfgt 120573 ltinfgt3ltinfgt Inte-grin Reveals Extracellular Matrix Alterations after MyocardialInfarctionrdquo Molecular Imaging and Biology vol 16 no 6 pp793ndash801 2014
[51] M Gronman M Tarkia T Kiviniemi et al ldquoImaging of 120572v1205733integrin expression in experimental myocardial ischemia with[68Ga]NODAGA-RGD positron emission tomographyrdquo Jour-nal of Translational Medicine vol 15 no 1 p 144 2017
[52] J Haukkala I Laitinen P Luoto et al ldquo68Ga-DOTA-RGDpep-tide Biodistribution and binding into atherosclerotic plaquesin micerdquo European Journal of Nuclear Medicine and MolecularImaging vol 36 no 12 pp 2058ndash2067 2009
[53] H Virtanen A Autio R Siitonen et al ldquo68Ga-DOTA-Siglec-9- a new imaging tool to detect synovitisrdquo Arthritis Research ampTherapy vol 17 no 1 article no 308 2015
[54] J Retamal J Sorensen M Lubberink et al ldquoFeasibility of(68) Ga-labeled Siglec-9 peptide for the imaging of acutelung inflammation a pilot study in a porcine model of acuterespiratory distress syndromerdquoAm JNuclMedMol Imaging vol6 no 1 pp 18ndash31 2016
[55] J M U Silvola H Virtanen R Siitonen et al ldquoLeukocytetrafficking-associated vascular adhesion protein 1 is expressedand functionally active in atherosclerotic plaquesrdquo ScientificReports vol 6 Article ID 35089 2016
[56] H Ahtinen J Kulkova L Lindholm et al ldquo68Ga-DOTA-Siglec-9 PETCT imaging of peri-implant tissue responses andstaphylococcal infectionsrdquo EJNMMI Research vol 4 no 1article no 45 pp 1ndash11 2014
[57] A Autio S Jalkanen and A Roivainen ldquoNuclear imaging ofinflammation Homing-associated molecules as targetsrdquo EJN-MMI Research vol 3 no 1 pp 1ndash7 2013
[58] J TThackeray T Derlin AHaghikia et al ldquoMolecular Imagingof the Chemokine Receptor CXCR4 after Acute MyocardialInfarctionrdquo JACC Cardiovascular Imaging vol 8 no 12 pp1417ndash1426 2015
[59] J S Schmid A Schirbel A K Buck S Kropf H-J Westerand C Lapa ldquoPentixafor-Positron Emission TomographyComputed Tomography Detects Chemokine Receptor CXCR4Expression after Ischemic Strokerdquo Circulation CardiovascularImaging vol 9 no 9 Article ID e005217 2016
[60] J Zhou G Hao H Weng et al ldquoIn vivo evaluation ofmedical device-associated inflammation using a macrophage-specific positron emission tomography (PET) imaging proberdquoBioorganic amp Medicinal Chemistry Letters vol 23 no 7 pp2044ndash2047 2013
[61] S A Kularatne M-J Belanger X Meng et al ldquoComparativeanalysis of folate derived PET imaging agents with [ 18F]-2-fluoro-2-deoxy-d-glucose using a rodent inflammatory pawmodelrdquo Molecular Pharmaceutics vol 10 no 8 pp 3103ndash31112013
[62] V Ambrosini M Zompatori F De Luca et al ldquo68Ga-DOTANOCPETCTAllows Somatostatin Receptor Imaging inIdiopathic Pulmonary Fibrosis Preliminary Resultsrdquo Journal ofNuclear Medicine vol 51 no 12 pp 1950ndash1955 2010
[63] T Lincke J Singer R Kluge O Sabri and R Paschke ldquoRela-tive quantification of indium-111 pentetreotide and gallium-68DOTATOC uptake in the thyroid gland and association withthyroid pathologiesrdquoThyroid vol 19 no 4 pp 381ndash389 2009
[64] A Rominger T Saam E Vogl et al ldquoIn vivo imaging ofmacrophage activity in the coronary arteries using 68Ga-DOTATATE PETCT correlation with coronary calcium bur-den and risk factorsrdquo Journal of Nuclear Medicine vol 51 no 2pp 193ndash197 2010
[65] J M Tarkin F R Joshi N R Evans et al ldquoDetection ofAtherosclerotic Inflammation by 68Ga-DOTATATE PET Com-pared to [18F]FDG PET Imagingrdquo Journal of the AmericanCollege of Cardiology vol 69 no 14 pp 1774ndash1791 2017
[66] S-P Lee H-J Im S Kang et al ldquoNoninvasive imaging ofmyocardial inflammation in myocarditis using 68Ga-taggedmannosylated human serum albumin positron emissiontomographyrdquoTheranostics vol 7 no 2 pp 413ndash424 2017
[67] Z Zha J Song S R Choi et al ldquo68Ga-Bivalent PolypegylatedStyrylpyridine Conjugates for Imaging A120573 Plaques in CerebralAmyloid Angiopathyrdquo Bioconjugate Chemistry vol 27 no 5 pp1314ndash1323 2016
[68] H Watanabe M Ono S Iikuni et al ldquoA 68Ga complex basedon benzofuran scaffold for the detection of 120573-amyloid plaquesrdquoBioorganic amp Medicinal Chemistry Letters vol 24 no 20 pp4834ndash4837 2014
[69] D Cressier M Dhilly T T Cao Pham et al ldquoGallium-68 Com-plexes Conjugated to Pittsburgh Compound B Radiolabelingand Biological EvaluationrdquoMolecular Imaging and Biology vol18 no 3 pp 334ndash343 2016
[70] D Satpati CArjun R KrishnamohanG Samuel and S Baner-jee ldquo68Ga-labeledCiprofloxacinConjugates as Radiotracers forTargeting Bacterial InfectionrdquoChemical Biology ampDrug Designvol 87 no 5 pp 680ndash686 2016
[71] T Ebenhan N Chadwick and M M Sathekge ldquoPeptidesynthesis characterization and 68Ga-radiolabeling of NOTA-conjugated ubiquicidin fragments for prospective infectionimaging with PETCTrdquo Nuclear Medicine and Biology vol 41no 5 pp 390ndash400 2014
18 Contrast Media amp Molecular Imaging
[72] T Ebenhan J R Zeevaart and J D Venter ldquoPreclinicalevaluation of 68Ga-labeled 1 4 7-triazacyclononane-1 4 7-triacetic acid-ubiquicidin as a radioligand for PET infectionimagingrdquo Journal of Nuclear Medicine vol 55 no 2 pp 308ndash314 2014
[73] B B Mokaleng T Ebenhan S Ramesh et al ldquoSynthesis 68Ga-radiolabeling and preliminary in vivo assessment of adepsipeptide-derived compound as a potential PETCTinfection imaging agentrdquo BioMed Research International vol2015 Article ID 284354 2015
[74] T Ebenhan B Mokaleng J Venter H Kruger J Zeevaart andM Sathekge ldquoPreclinical Assessment of a 68Ga-DOTA-Functionalized Depsipeptide as a Radiodiagnostic InfectionImaging AgentrdquoMolecules vol 22 no 9 p 1403 2017
[75] S Chopra B Singh A Koul A Mishra and H Wester ldquoSyn-thesis of DOTA conjugated GF-17 and RAWVAWR-NH2 andradiolabeling with 68Ga as a potential PET tracer for infectionimagingrdquo J Nucl Med vol 57 Supplement 2 p 1115 2016
[76] M Petrik HHaas P Laverman et al ldquo 68Ga-triacetylfusarinineC and 68Ga-ferrioxamine e for aspergillus infection imaginguptake specificity in various microorganismsrdquoMolecular Imag-ing and Biology vol 16 no 1 pp 102ndash108 2014
[77] V Kumar and D K Boddeti ldquo 68Ga-radiopharmaceuticals forPET imaging of infection and inflammationrdquo Recent Results inCancer Research vol 194 pp 189ndash219 2013
[78] M Vorster A Maes A Jacobs et al ldquoEvaluating the possiblerole of 68Ga-citrate PETCT in the characterization of indeter-minate lung lesionsrdquo Annals of Nuclear Medicine vol 28 no 6pp 523ndash530 2014
[79] M Vorster B Mokaleng M M Sathekge and T Ebenhan ldquoAmodified technique for efficient radiolabeling of 68Ga-citratefrom a SnO2-based 68Ge68Ga generator for better infectionimagingrdquoHellenic Journal of Nuclear Medicine vol 16 no 3 pp193ndash198 2013
[80] S Salomaeki J Kemppainen U Hohenthal et al ldquoHead-to-head comparison of 68Ga-Citrate and 18F-FDG PETCT fordetection of infectious foci in patients with staphylococcusaureus bacteraemiardquo Contrast Media amp Molecular Imaging vol2017 p 8 2017
[81] L Fass ldquoImaging and cancer a reviewrdquoMolecular Oncology vol2 no 2 pp 115ndash152 2008
[82] A Chopra L Shan W C Eckelman et al ldquoMolecular imagingand contrast agent database (MICAD) Evolution and progressrdquoMolecular Imaging and Biology vol 14 no 1 pp 4ndash13 2012
[83] A Sanchez-Crespo P Andreo and S A Larsson ldquoPositronflight in human tissues and its influence on PET image spatialresolutionrdquo European Journal of Nuclear Medicine and Molecu-lar Imaging vol 31 no 1 pp 44ndash51 2004
[84] H W A M De Jong L Perk G W M Visser R Boellaard GAM S Van Dongen and A A Lammertsma ldquoHigh resolutionPET imaging characteristics of68Ga 124i and89Zr comparedto18Frdquo in Proceedings of the Nuclear Science Symposium Con-ference Record 2005 IEEE pp 1624ndash1627 Puerto Rico October2005
[85] I Velikyan A Sundin B Eriksson et al ldquoIn vivo bindingof [68Ga]-DOTATOC to somatostatin receptors in neuroen-docrine tumours - impact of peptide massrdquo Nuclear Medicineand Biology vol 37 no 3 pp 265ndash275 2010
[86] U Eberlein and M Lassmann ldquoDosimetry of [68Ga]-labeledcompoundsrdquo Applied Radiation and Isotopes vol 76 pp 70ndash742013
[87] C PettinatoA SarnelliMDiDonna et al ldquo68Ga-DOTANOCBiodistribution and dosimetry in patients affected by neuroen-docrine tumorsrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 35 no 1 pp 72ndash79 2008
[88] B P Burke G S Clemente and S J Archibald ldquoRecentadvances in chelator design and labelling methodology for68Ga radiopharmaceuticalsrdquo Journal of Labelled Compoundsand Radiopharmaceuticals vol 57 no 4 pp 239ndash243 2014
[89] I Velikyan U Rosenstrom S Estrada et al ldquoSynthesis andpreclinical evaluation of 68Ga-labeled collagelin analogs forimaging and quantification of fibrosisrdquo Nuclear Medicine andBiology vol 41 no 9 pp 728ndash736 2014
[90] M F Ferreira G Pereira J P Andre and etal C ldquoGa[NO2A-N-(120572-amino)propionate] chelates Synthesis and evaluation aspotential tracers for 68Ga PETrdquoDalton Transactions vol 43 no21 pp 8037ndash8047 2014
[91] J Notni J Simecek and H-J Wester ldquoPhosphinic acid func-tionalized polyazacycloalkane chelators for radiodiagnosticsand radiotherapeutics Unique characteristics and applicationsrdquoChemMedChem vol 9 no 6 pp 1107ndash1115 2014
[92] J Simecek O Zemek P Hermann J Notni and H J WesterldquoTailored gallium( III) chelator NOPO synthesis characteriza-tion bioconjugation and application in preclinical Ga-68-PETimagingrdquoMolecular Pharmaceutics 2013
[93] D Parker B P Waldron and D S Yufit ldquoCrystallographicand solution NMR structural analyses of four hexacoordinatedgallium(iii) complexes based on ligands derived from 6-amino-perhydro-14-diazepinerdquo Dalton Transactions vol 42 no 22pp 8001ndash8008 2013
[94] B P Waldron D Parker C Burchardt D S Yufit M ZimnyandF Roesch ldquoStructure and stability of hexadentate complexesof ligands based on AAZTA for efficient PET labelling withgallium-68rdquo Chemical Communications vol 49 no 6 pp 579ndash581 2013
[95] D Parker and B PWaldron ldquoConformational analysis and syn-thetic approaches to polydentate perhydro-diazepine ligandsfor the complexation of gallium(iii)rdquo Organic amp BiomolecularChemistry vol 11 no 17 pp 2827ndash2838 2013
[96] I Velikyan H Maecke and B Langstrom ldquoConvenient prepa-ration of 68Ga-based PET-radiopharmaceuticals at room tem-peraturerdquo Bioconjugate Chemistry vol 19 no 2 pp 569ndash5732008
[97] J Erchegyi R Cescato B Waser J E Rivier and J C ReubildquoN-Imidazolebenzyl-histidine substitution in somatostatin andin its octapeptide analogue modulates receptor selectivity andfunctionrdquo Journal of Medicinal Chemistry vol 54 no 17 pp5981ndash5987 2011
[98] R Saha N Saha R S Donofrio and L L Bestervelt ldquoMicrobialsiderophores Amini reviewrdquo Journal of Basic Microbiology vol53 no 4 pp 303ndash317 2013
[99] V Nikolova S Angelova N Markova and T Dudev ldquoGalliumas a Therapeutic Agent A Thermodynamic Evaluation of theCompetition between Ga3+ and Fe3+ Ions in MetalloproteinsrdquoThe Journal of Physical Chemistry B vol 120 no 9 pp 2241ndash2248 2016
[100] C R Chitambar ldquoGallium and its competing roles with ironin biological systemsrdquo Biochimica et Biophysica Acta (BBA) -Molecular Cell Research vol 1863 no 8 pp 2044ndash2053 2016
[101] J A Lessa M A Soares and R G dos Santos ldquoGallium(III)complexes with 2-acetylpyridine-derived thiosemicarbazonesantimicrobial and cytotoxic effects and investigation on theinteractions with tubulinrdquo BioMetals vol 26 pp 151ndash165 2013
Contrast Media amp Molecular Imaging 19
[102] M van Oosten M Hahn L M A Crane et al ldquoTargetedimaging of bacterial infections Advances hurdles and hopesrdquoFEMS Microbiology Reviews vol 39 no 6 pp 892ndash916 2015
[103] M Vorster AMaes C V DWiele andM Sathekge ldquoGallium-68 PET A Powerful Generator-based Alternative to Infectionand Inflammation Imagingrdquo Seminars in Nuclear Medicine vol46 no 5 pp 436ndash447 2016
[104] M Kircher and C Lapa ldquoNovel Noninvasive Nuclear MedicineImaging Techniques for Cardiac Inflammationrdquo Current Car-diovascular Imaging Reports vol 10 no 2 article no 6 2017
[105] D AHammoud ldquoMolecular imaging of inflammation Currentstatusrdquo Journal of Nuclear Medicine vol 57 no 8 pp 1161ndash11652016
[106] D R Brenner D Scherer K Muir et al ldquoA review of the appli-cation of inflammatory biomarkers in epidemiologic cancerresearchrdquo Cancer Epidemiology Biomarkers amp Prevention vol23 no 9 pp 1729ndash1751 2014
[107] M D Turner B Nedjai T Hurst and D J PenningtonldquoCytokines and chemokines at the crossroads of cell signallingand inflammatory diseaserdquo Biochimica et Biophysica Acta (BBA)- Molecular Cell Research vol 1843 no 11 pp 2563ndash2582 2014
[108] L Werner H Guzner-Gur and I Dotan ldquoInvolvement ofCXCR4CXCR7CXCL12 interactions in inflammatory boweldiseaserdquoTheranostics vol 3 no 1 pp 40ndash46 2013
[109] S Jalkanen and M Salmi ldquoVAP-1 and CD73 endothelial cellsurface enzymes in leukocyte extravasationrdquo ArteriosclerosisThrombosis and Vascular Biology vol 28 no 1 pp 18ndash26 2008
[110] G Malviya F Galli I Sonni and A Signore ldquoImaging T-lymphocytes in inflammatory diseases A nuclear medicineapproachrdquo The Quarterly Journal of Nuclear Medicine andMolecular Imaging vol 58 no 3 pp 237ndash257 2014
[111] S Gratz H J RennenO C BoermanW J Oyen and P Burmaldquo(99m)Tc-interleukin-8 for imaging acute osteomyelitisrdquo Jour-nal of Nuclear Medicine vol 42 no 8 pp 1257ndash1264 2001
[112] S Gratz H J Rennen O C Boerman W J Oyen andF H Corstens ldquoRapid imaging of experimental colitis with(99m)Tc-interleukin-8 in rabbitsrdquo Journal of Nuclear Medicnevol 42 no 6 pp 917ndash923 2001
[113] C Alkim H Alkim A R Koksal S Boga and I SenldquoAngiogenesis in inflammatory bowel diseaserdquo InternationalJournal of Inflammation vol 2015 Article ID 970890 2015
[114] I S Alam T H Witney G Tomasi et al ldquoRadiolabeled RGDtracer kinetics annotates differential 120572v1205733 integrin expressionlinked to cell intrinsic and vessel expressionrdquoMolecular Imagingand Biology vol 16 no 4 pp 558ndash566 2014
[115] J Notni K Pohle and H-J Wester ldquoBe spoilt for choice withradiolabelled RGD peptides Preclinical evaluation of 68Ga-TRAP(RGD)3rdquoNuclear Medicine and Biology vol 40 no 1 pp33ndash41 2013
[116] J Oxboel M Brandt-Larsen C Schjoeth-Eskesen et al ldquoCom-parison of two new angiogenesis PET tracers 68Ga-NODAGA-E[c(RGDyK)]2 and 64Cu-NODAGA-E[c(RGDyK)]2 in vivoimaging studies in human xenograft tumorsrdquo Nuclear Medicineand Biology vol 41 no 3 pp 259ndash267 2014
[117] J Simecek J Notni T G Kapp H Kessler and H-J WesterldquoBenefits of NOPO as chelator in gallium-68 peptides exempli-fied by preclinical characterization of 68Ga-NOPO-c(RGDfK)rdquoMolecular Pharmaceutics vol 11 no 5 pp 1687ndash1695 2014
[118] M Trajkovic-Arsic P Mohajerani A Sarantopoulos et alldquoMultimodal molecular imaging of integrin avb3 for in vivodetection of pancreatic cancerrdquo Journal of NuclearMedicine vol55 no 3 pp 446ndash451 2014
[119] H Cai and P S Conti ldquoRGD-based PET tracers for imagingreceptor integrin 120572 v1205733 expressionrdquo Journal of Labelled Com-pounds and Radiopharmaceuticals vol 56 no 5 pp 264ndash2792013
[120] I Dijkgraaf S Y A Terry W J Mcbride et al ldquoImagingintegrin alpha-v-beta-3 expression in tumors with an 18F-labeled dimeric RGD peptiderdquo Contrast Media amp MolecularImaging vol 8 no 3 pp 238ndash245 2013
[121] P A Knetsch M Petrik C Rangger et al ldquo[68Ga]NS3-RGD and [68Ga] Oxo-DO3A-RGD for imaging 120572v1205733 integrinexpression Synthesis evaluation and comparisonrdquo NuclearMedicine and Biology vol 40 no 1 pp 65ndash72 2013
[122] Z Liu and F Wang ldquoDevelopment of RGD-based radiotracersfor tumor imaging and therapy Translating from bench tobedsiderdquo Current Molecular Medicine vol 13 no 10 pp 1487ndash1505 2013
[123] H Choi J H Phi J C Paeng et al ldquoImaging of integrin 120572v1205733expression using 68Ga-RGD positron emission tomography inpediatric cerebral infarctrdquoMolecular Imaging vol 12 no 4 pp213ndash217 2013
[124] H-J Yoon K W Kang I K Chun et al ldquoCorrelation of breastcancer subtypes based on estrogen receptor progesteronereceptor and HER2 with functional imaging parameters from68Ga-RGD PETCT and 18F-FDG PETCTrdquo European Journalof Nuclear Medicine and Molecular Imaging vol 41 no 8 pp1534ndash1543 2014
[125] R P Baum H R Kulkarni D Muller et al ldquoFirst-in-human study demonstrating tumor-angiogenesis by PETCTimaging with 68Ga-NODAGA-THERANOST a high-affinitypeptidomimetic for 120572v1205733 integrin receptor targetingrdquo CancerBiotherapy andRadiopharmaceuticals vol 30 no 4 pp 152ndash1592015
[126] R Haubner A Finkenstedt A Stegmayr et alldquo[68Ga]NODAGA-RGD ndash Metabolic stability biodistributionand dosimetry data from patients with hepatocellularcarcinoma and liver cirrhosisrdquo European Journal of NuclearMedicine and Molecular Imaging vol 43 no 11 pp 2005ndash20132016
[127] V Lopez-Rodrıguez C Galindo-Sarco F O Garcıa-Perez GFerro-Flores O Arrieta and M A Avila-Rodrıguez ldquoPET-based human dosimetry of the dimeric 120572v1205733 integrin ligand68Ga-DOTA-E-[c(RGDfK)]2 a potential tracer for imagingtumor angiogenesisrdquo Journal of Nuclear Medicine vol 57 no 3pp 404ndash409 2016
[128] M V Backer Z Levashova V Patel et al ldquoMolecular imagingof VEGF receptors in angiogenic vasculature with single-chainVEGF-based probesrdquo Nature Medicine vol 13 no 4 pp 504ndash509 2007
[129] MV Backer Z Levashova R Levenson F G Blankenberg andJ M Backer ldquoCysteine-containing fusion tag for site-specificconjugation of therapeutic and imaging agents to targetingproteinsrdquoMethods in Molecular Biology (Clifton NJ) vol 494pp 275ndash294 2008
[130] M Eder A V Krivoshein M Backer J M Backer UHaberkorn and M Eisenhut ldquoScVEGF-PEG-HBED-CC andscVEGF-PEG-NOTA conjugates comparison of easy-to-labelrecombinant proteins for [68Ga]PET imaging of VEGF recep-tors in angiogenic vasculaturerdquo Nuclear Medicine and Biologyvol 37 no 4 pp 405ndash412 2010
[131] E Blom I Velikyan A Monazzam P Razifar et al ldquoSynthe-sis and characterization of scVEGF-PEG-[ 68Ga]NOTA andscVEGF-PEG-[ 68Ga]DOTA PET tracersrdquo Journal of Labelled
20 Contrast Media amp Molecular Imaging
Compounds and Radiopharmaceuticals vol 54 no 11 pp 685ndash692 2011
[132] S Gratz M Behe and O C Boerman ldquo 99119898Tc-E-selectinbinding peptide for imaging acute osteomyelitis in a novel ratmodelrdquo Nuclear Medicine Communications vol 22 no 9 pp1003ndash1013 2001
[133] S B Jensen M Kakela L Joslashdal et al ldquoExploring the radiosyn-thesis and in vitro characteristics of [68Ga]Ga-DOTA-Siglec-9rdquoJournal of Labelled Compounds and Radiopharmaceuticals vol60 no 9 pp 439ndash449 2017
[134] B A Teicher and S P Fricker ldquoCXCL12 (SDF-1)CXCR4pathway in cancerrdquo Clinical Cancer Research vol 16 no 11 pp2927ndash2931 2010
[135] O Jacobson I D Weiss D O Kiesewetter J M Farber andX Chen ldquoPET of tumor CXCR4 expression with 4-18F-T140rdquoJournal of Nuclear Medicine vol 51 no 11 pp 1796ndash1804 2010
[136] A Aghanejad A R Jalilian Y Fazaeli et al ldquoSynthesis andevaluation of [67Ga]-AMD3100 A novel imaging agent fortargeting the chemokine receptorCXCR4rdquo Scientia Pharmaceu-tica vol 82 no 1 pp 29ndash42 2014
[137] O Jacobson I D Weiss L P Szajek et al ldquoPET imaging ofCXCR4 using copper-64 labeled peptide antagonistrdquoTheranos-tics vol 1 pp 251ndash262 2011
[138] O Jacobson I D Weiss L P Szajek et al ldquoImprovement ofCXCR4 tracer specificity for PET imagingrdquo Journal of Con-trolled Release vol 157 no 2 pp 216ndash223 2012
[139] H J Wester U Keller M Schottelius et al ldquoDisclosing theCXCR4 expression in lymphoproliferative diseases by targetedmolecular imagingrdquo Theranostics vol 5 no 6 pp 618ndash6302015
[140] E Gourni O Demmer M Schottelius et al ldquoPET of CXCR4expression by a 68Ga-labeled highly specific targeted contrastagentrdquo Journal of NuclearMedicine vol 52 no 11 pp 1803ndash18102011
[141] O Demmer I Dijkgraaf U Schumacher et al ldquoDesignsynthesis and functionalization of dimeric peptides targetingchemokine receptor CXCR4rdquo Journal of Medicinal Chemistryvol 54 no 21 pp 7648ndash7662 2011
[142] O Demmer E Gourni U Schumacher H Kessler and H-JWester ldquoPET Imaging of CXCR4 Receptors in Cancer by a NewOptimized Ligandrdquo ChemMedChem vol 6 no 10 pp 1789ndash1791 2011
[143] U Hennrich L Seyler M Schafer et al ldquoSynthesis and invitro evaluation of 68Ga-DOTA-4-FBn-TN14003 a novel tracerfor the imaging of CXCR4 expressionrdquo Bioorganic amp MedicinalChemistry vol 20 no 4 pp 1502ndash1510 2012
[144] G P C George E Stevens O Aberg et al ldquoPreclinical evalua-tion of a CXCR4-specific 68Ga-labelled TN14003 derivative forcancer PET imagingrdquo Bioorganic amp Medicinal Chemistry vol22 no 2 pp 796ndash803 2014
[145] S Poty E Gourni P Desogere et al ldquoAMD3100 A VersatilePlatform for CXCR4 Targeting 68Ga-Based Radiopharmaceu-ticalsrdquo Bioconjugate Chemistry vol 27 no 3 pp 752ndash761 2016
[146] K Philipp-Abbrederis K Herrmann S Knop et al ldquoIn vivomolecular imaging of chemokine receptor CXCR4 expressionin patients with advancedmultiple myelomardquo EMBOMolecularMedicine vol 7 no 4 pp 477ndash487 2015
[147] Z Wang M Zhang L Wang et al ldquoProspective study of 68Ga-NOTA-NFB Radiation dosimetry in healthy volunteers andfirst application in glioma patientsrdquo Theranostics vol 5 no 8pp 882ndash889 2015
[148] I M Jackson P J Scott and S Thompson ldquoClinical Applica-tions of Radiolabeled Peptides for PETrdquo Seminars in NuclearMedicine vol 47 no 5 pp 493ndash523 2017
[149] C Lapa T Reiter R A Werner et al ldquo[68Ga]Pentixafor-PETCT for Imaging of Chemokine Receptor 4 Expression afterMyocardial Infarctionrdquo JACC Cardiovascular Imaging vol 8no 12 pp 1466ndash1468 2015
[150] C Rischpler S G Nekolla H Kossmann et al ldquoUpregu-lated myocardial CXCR4-expression after myocardial infarc-tion assessed by simultaneous GA-68 pentixafor PETMRIrdquoJournal of Nuclear Cardiology vol 23 no 1 pp 131ndash133 2016
[151] F Hyafil J Pelisek I Laitinen et al ldquoImaging the CytokineReceptorCXCR4 in atherosclerotic plaqueswith the radiotracer68Ga-Pentixafor for PETrdquo Journal of Nuclear Medicine vol 58no 3 pp 499ndash506 2017
[152] Y Yi ldquoFolate receptor-targeted diagnostics and therapeutics forinflammatory diseasesrdquo ImmuneNetwork vol 16 no 6 pp 337ndash343 2016
[153] C M Paulos M J Turk G J Breur and P S Low ldquoFolatereceptor-mediated targeting of therapeutic and imaging agentsto activated macrophages in rheumatoid arthritisrdquo AdvancedDrug Delivery Reviews vol 56 no 8 pp 1205ndash1217 2004
[154] W Han R Zaynagetdinov F E Yull et al ldquoMolecular imagingof folate receptor 120573-positive macrophages during acute lunginflammationrdquo American Journal of Respiratory Cell and Molec-ular Biology vol 53 no 1 pp 50ndash59 2015
[155] B Kuhle C Muller and T L Ross ldquoA Novel 68Ga-Labeledpteroic acid-based PET tracer for tumor imaging via the folatereceptorrdquo Recent Results in Cancer Research vol 194 pp 257ndash267 2013
[156] C Brand V A Longo M Groaning W A Weber and TReiner ldquoDevelopment of a New Folate-Derived Ga-68-BasedPET Imaging AgentrdquoMolecular Imaging and Biology vol 19 no5 pp 754ndash761 2017
[157] M Fani XWang G Nicolas et al ldquoDevelopment of new folate-based PET radiotracers Preclinical evaluation of 68Ga-DOTA-folate conjugatesrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 38 no 1 pp 108ndash119 2011
[158] C J Mathias M R Lewis D E Reichert et al ldquoPreparationof 66Ga- and 68Ga-labeled Ga(III)-deferoxamine-folate aspotential folate-receptor-targeted PET radiopharmaceuticalsrdquoNuclear Medicine and Biology vol 30 no 7 pp 725ndash731 2003
[159] S-M Kim N Choi S Hwang et al ldquoFolate receptor-specific positron emission tomography imaging with folic acid-conjugated tissue inhibitor of metalloproteinase-2rdquo Bulletin ofthe Korean Chemical Society vol 34 no 11 pp 3243ndash3248 2013
[160] M Fani M-L Tamma G P Nicolas et al ldquoIn vivo imagingof folate receptor positive tumor xenografts using novel 68Ga-NODAGA-folate conjugatesrdquo Molecular Pharmaceutics vol 9no 5 pp 1136ndash1145 2012
[161] C Muller and R Schibli ldquoProspects in folate receptor-targetedradionuclide therapyrdquo Frontiers in Oncology vol 3 Article IDArticle 249 2013
[162] A Jain A Mathur U Pandey et al ldquoSynthesis and evaluationof a 68Ga labeled folic acid derivative for targeting folatereceptorsrdquo Applied Radiation and Isotopes vol 116 pp 77ndash842016
[163] W Xia A R Hilgenbrink E L Matteson M B Lockwood J-X Cheng and P S Low ldquoA functional folate receptor is inducedduring macrophage activation and can be used to target drugsto activated macrophagesrdquo Blood vol 113 no 2 pp 438ndash4462009
Contrast Media amp Molecular Imaging 21
[164] E P Krenning W A P Breeman P P M Kooij et alldquoLocalisation of endocrine-related tumours with radioiodi-nated analogue of somatostatinrdquoThe Lancet vol 1 no 8632 pp242ndash244 1989
[165] E P Krenning D J KwekkeboomWH Bakker et al ldquoSomato-statin receptor scintigraphy with [111In-DTPA-d-Phe1]- and[123I-Tyr3]-octreotide the Rotterdam experience with morethan 1000 patientsrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 20 no 8 pp 716ndash731 1993
[166] A Stahl G Meisetschlager M Schottelius et al ldquo[123I]Mtr-TOCA a radioiodinated and carbohydrated analogue ofoctreotide Scintigraphic comparison with [111In]octreotiderdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 33 no 1 pp 45ndash52 2006
[167] R Lebtahi J le Cloirec C Houzard et al ldquoDetection of neu-roendocrine tumors 99mTc-P829 scintigraphy compared with111In-pentetreotide scintigraphyrdquo Journal of Nuclear Medicinevol 43 no 7 pp 889ndash895 2002
[168] C Decristoforo T Maina B Nock M Gabriel P Cordopatisand R Moncayo ldquo99mTc-demotate 1 First data in tumourpatients - Results of a pilotphase I studyrdquo European Journal ofNuclearMedicine andMolecular Imaging vol 30 no 9 pp 1211ndash1219 2003
[169] C Decristoforo S J Mather W Cholewinski E DonnemillerG Riccabona and R Moncayo ldquo(99m)Tc-EDDAHYNIC-TOC A new (99m)Tc-labelled radiopharmaceutical forimaging somatostatin receptor-positive tumours First clinicalresults and intra-patient comparison with 111In-labelledoctreotide derivativesrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 27 no 9 pp 1318ndash1325 2000
[170] A Hubalewska-Dydejczyk K Fross-Baron R Mikołajczak etal ldquo99mTc-EDDAHYNIC-octreotate scintigraphy an efficientmethod for the detection and staging of carcinoid tumoursResults of 3 yearsrsquo experiencerdquo European Journal of NuclearMedicine and Molecular Imaging vol 33 no 10 pp 1123ndash11332006
[171] M Bangard M Behe S Guhlke et al ldquoDetection of somato-statin receptor-positive tumours using the new 99mC-tricine-HYNIC-D-Phe1-Tyr3-octreotide First results in patients andcomparison with 111In-DTPA-D-Phe1-octreotiderdquo EuropeanJournal of Nuclear Medicine and Molecular Imaging vol 27 no6 pp 628ndash637 2000
[172] A Helisch G J Forster H Reber et al ldquoPre-therapeuticdosimetry and biodistribution of 86Y-DOTA- Phe1-Tyr3-octreotide versus 111In-pentetreotide in patients with advancedneuroendocrine tumoursrdquo European Journal of NuclearMedicine and Molecular Imaging vol 31 no 10 pp 1386ndash13922004
[173] M Henze J Schuhmacher P Hipp et al ldquoPET imaging ofsomatostatin receptors using [68GA]DOTA-D-Phe1-Tyr3-Octreotide First results in patients with meningiomasrdquo Journalof Nuclear Medicine vol 42 no 7 pp 1053ndash1056 2001
[174] I Kayani J B Bomanji A Groves et al ldquoFunctional imaging ofneuroendocrine tumors with combined PETCT using 68Ga-DOTATATE (Dota-DPhe1 Tyr3-octreotate) and 18F-FDGrdquoCancer vol 112 no 11 pp 2447ndash2455 2008
[175] A Al-Nahhas ldquoNuclear medicine imaging of neuroendocrinetumoursrdquo Clinical Medicine vol 12 no 4 pp 377ndash380 2012
[176] V Ambrosini S Nicolini P Caroli et al ldquoPETCT imaging indifferent types of lung cancer an overviewrdquo European Journal ofRadiology vol 81 no 5 pp 988ndash1001 2012
[177] V Ambrosini D Campana P Tomassetti and S Fanti ldquo68Ga-labelled peptides for diagnosis of gastroenteropancreatic NETrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 39 no 1 pp S52ndashS60 2012
[178] K E Oberg J-C Reubi D J Kwekkeboom and E P KrenningldquoRole of somatostatins in gastroenteropancreatic neuroen-docrine tumor development and therapyrdquoGastroenterology vol139 no 3 pp 753-753 2010
[179] K Oberg ldquoGallium-68 somatostatin receptor PETCT Is ittime to replace 111Indium DTPA octreotide for patients withneuroendocrine tumorsrdquo Endocrine Journal vol 42 no 1 pp3-4 2012
[180] R Srirajaskanthan I Kayani A M Quigley J Soh M ECaplin and J Bomanji ldquoThe role of 68Ga-DOTATATE PET inpatients with neuroendocrine tumors and negative or equivocalfindings on 111In-DTPA-octreotide scintigraphyrdquo Journal ofNuclear Medicine vol 51 no 6 pp 875ndash882 2010
[181] A Kroiss D Putzer and C Uprimny ldquoFunctional imag-ing in phaeochromocytoma and neuroblastoma with 68Ga-DOTA-Tyr3-octreotide positron emission tomography and123I-metaiodobenzylguanidinerdquo European Journal of NuclearMedicine and Molecular Imaging vol 38 no 5 pp 865ndash8732011
[182] M Naji C Zhao S J Welsh et al ldquo68Ga-DOTA-TATE PETvs 123I-MIBG in identifying malignant neural crest tumoursrdquoMolecular Imaging and Biology vol 13 no 4 pp 769ndash775 2011
[183] V Ambrosini P Tomassetti P Castellucci et al ldquoComparisonbetween 68Ga-DOTA-NOC and 18F-DOPA PET for the detec-tion of gastro-entero-pancreatic and lung neuro-endocrinetumoursrdquo European Journal of Nuclear Medicine and MolecularImaging vol 35 no 8 pp 1431ndash1438 2008
[184] D Putzer M Gabriel B Henninger et al ldquoBone metastasesin patients with neuroendocrine tumor 68Ga- DOTA-Tyr3-octreotide PET in comparison to CT and bone scintigraphyrdquoJournal of Nuclear Medicine vol 50 no 8 pp 1214ndash1221 2009
[185] L K Anzola-Fuentes M Chianelli F Galli et al ldquoSomatostatinreceptor scintigraphy in patients with rheumatoid arthritis andsecondary Sjogrenrsquos syndrome treated with Infliximab a pilotstudyrdquo EJNMMI Research vol 6 no 1 article no 49 2016
[186] T Nobashi Y Nakamoto T Kubo et al ldquoThe utility of PETCTwith 68Ga-DOTATOC in sarcoidosis comparison with 67Ga-scintigraphyrdquoAnnals ofNuclearMedicine vol 30 no 8 pp 544ndash552 2016
[187] C Boy T A Heusner T D Poeppel et al ldquo68Ga-DOTATOCPETCT and somatostatin receptor (sst1-sst5) expression innormal human tissue Correlation of sst2mRNAand SUVmaxrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 38 no 7 pp 1224ndash1236 2011
[188] P Rinne S Hellberg M Kiugel et al ldquoComparison of Somato-statin Receptor 2-Targeting PET Tracers in the Detection ofMouse Atherosclerotic Plaquesrdquo Molecular Imaging and Biol-ogy vol 18 no 1 pp 99ndash108 2016
[189] M Asti E Ferrari S Croci et al ldquoSynthesis and characteri-zation of 68Ga-labeled curcumin and curcuminoid complexesas potential radiotracers for imaging of cancer and alzheimersdiseaserdquo Inorganic Chemistry vol 53 no 10 pp 4922ndash49332014
[190] A Signore I Santino and A W J M Glaudemans ldquoIn vivoimaging of microorganismsrdquo Clinical and Translational Imag-ing vol 4 no 3 pp 161-162 2016
[191] S Auletta F Galli C Lauri D Martinelli I Santino andA Signore ldquoImaging bacteria with radiolabelled quinolones
22 Contrast Media amp Molecular Imaging
cephalosporins and siderophores for imaging infection a sys-tematic reviewrdquo Clinical and Translational Imaging vol 4 no 4pp 229ndash252 2016
[192] X Ning S Lee Z Wang et al ldquoMaltodextrin-based imagingprobes detect bacteria in vivo with high sensitivity and speci-ficityrdquo Nature Materials vol 10 no 8 pp 602ndash607 2011
[193] J Ady andY Fong ldquoImaging for infection Fromvisualization ofinflammation to visualization of microbesrdquo Surgical Infectionsvol 15 no 6 pp 700ndash707 2014
[194] J M Sierra D Rodriguez-Puig A Soriano J Mensa C Pieraand J Vila ldquoAccumulation of 99mTc-ciprofloxacin in Staphy-lococcus aureus and Pseudomonas aeruginosardquo AntimicrobialAgents and Chemotherapy vol 52 no 7 pp 2691-2692 2008
[195] D I Andersson and D Hughes ldquoMicrobiological effects ofsublethal levels of antibioticsrdquoNature ReviewsMicrobiology vol12 no 7 pp 465ndash478 2014
[196] N Dumarey D Blocklet T Appelboom L Tant and ASchoutens ldquoInfecton is not specific for bacterial osteo-articularinfective pathologyrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 29 no 4 pp 530ndash535 2002
[197] K E Britton D W Wareham S S Das et al ldquoImaging bacte-rial infection with 99mTc-ciprofloxacin (Infecton)rdquo Journal ofClinical Pathology vol 55 no 11 pp 817ndash823 2002
[198] G Ferro-Flores M A Avila-Rodrıguez and F O Garcıa-PerezldquoImaging of bacteria with radiolabeled ubiquicidin by SPECTand PET techniquesrdquo Clinical and Translational Imaging vol 4no 3 pp 175ndash182 2016
[199] P S Hiemstra M T van den Barselaar M Roest P H Nibber-ing and R van Furth ldquoUbiquicidin a novel murine microbi-cidal protein present in the cytosolic fraction of macrophagesrdquoJournal of Leukocyte Biology vol 66 no 3 pp 423ndash428 1999
[200] M S Akhtar A Qaisar J Irfanullah et al ldquoAntimicrobialpeptide 99mTc-ubiquicidin 29ndash41 as human infection-imagingagent clinical trialrdquo Journal of Nuclear Medicne vol 46 no 4pp 567ndash573 2005
[201] M Assadi K Vahdat I Nabipour et al ldquoDiagnostic value of99mTc-ubiquicidin scintigraphy for osteomyelitis and compar-isons with 99mTc-methylene diphosphonate scintigraphy andmagnetic resonance imagingrdquo Nuclear Medicine Communica-tions vol 32 no 8 pp 716ndash723 2011
[202] T Emery ldquoExchange of Iron by Gallium in SiderophoresrdquoBiochemistry vol 25 no 16 pp 4629ndash4633 1986
[203] M Petrik C Zhai H Haas and C Decristoforo ldquoSiderophoresfor molecular imaging applicationsrdquo Clinical and TranslationalImaging vol 5 no 1 pp 15ndash27 2017
[204] H J Flint E A BayerM T Rincon R Lamed and B AWhiteldquoPolysaccharide utilization by gut bacteria potential for newinsights from genomic analysisrdquo Nature Reviews Microbiologyvol 6 no 2 pp 121ndash131 2008
[205] GGowrishankarMNamavari E B Jouannot et al ldquoInvestiga-tion of 6-[18F]-fluoromaltose as a novel PET tracer for imagingbacterial infectionrdquo PLoS ONE vol 9 no 9 Article ID e1079512014
[206] N Gholipour M Akhlaghi A M Kheirabadi et al ldquoChelator-free radiolabeling of dextran with 68Ga for PET studiesrdquoJournal of Radioanalytical and Nuclear Chemistry vol 311 no3 pp 1811ndash1817 2017
[207] C Bettegowda C A Foss I Cheong et al ldquoImaging bac-terial infections with radiolabeled 1-(21015840-deoxy-21015840- fluoro-120573-D-arabinofuranosyl)-5-iodouracilrdquo Proceedings of the NationalAcadamy of Sciences of the United States of America vol 102 no4 pp 1145ndash1150 2005
[208] S A Soghomonyan M Doubrovin J Pike et al ldquoPositronemission tomography (PET) imaging of tumor-localizedSalmonella expressing HSV1-TKrdquo Cancer GeneTherapy vol 12no 1 pp 101ndash108 2005
[209] C Palestro K Nichols S Sheikh-Fayyaz S Dewey P Singhaland K Bhargava ldquoCan Gallium-68 PET differentiate acuteinterstitial nephritis from acute tubular necrosisrdquo Journal ofNuclear Medicne vol 57 Supplement 2 p 551 2016
[210] A J Morguet D L Munz V Ivancevic et al ldquoImmunoscintig-raphy using technetium-99m-labeled anti-NCA-95 antigranu-locyte antibodies as an adjunct to echocardiography in subacuteinfective endocarditisrdquo Journal of the American College ofCardiology vol 23 no 5 pp 1171ndash1178 1994
[211] C van der Laken O Boerman W Oyen et al ldquoIn Vivo Expres-sion of Interleukin-1 Receptors during Various ExperimentallyInduced Inflammatory Conditionsrdquo The Journal of InfectiousDiseases vol 177 no 5 pp 1398ndash1401 1998
[212] C J Van Der Laken O C Boerman W J G Oyen M T PVan De Ven J W M Van Der Meer and F H M CorstensldquoScintigraphic detection of infection and inflammation Newdevelopments with special emphasis on receptor interactionrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 25 no 5 pp 535ndash546 1998
[213] C J van der LakenOC BoermanW J GOyenM T P van deVen J W M van der Meer and F H M Corstens ldquoImaging ofinfection in rabbits with radioiodinated interleukin-1 (120572 and 120573)its receptor antagonist and a chemotactic peptide a comparativestudyrdquo European Journal of Nuclear Medicine and MolecularImaging vol 25 no 4 pp 347ndash352 1998
[214] C J Van Der Laken O C BoermanW J G Oyen M T P VanDe Ven F H M Corstens and J W M Ven Der Meer ldquoThekinetics of radiolabelled interleukin-8 in infection and sterileinflammationrdquo Nuclear Medicine Communications vol 19 no3 pp 271ndash282 1998
[215] E Lazzeri P Erba M Perri et al ldquoScintigraphic imaging ofvertebral osteomyelitis with 111in-biotinrdquoThe Spine Journal vol33 no 7 pp E198ndashE204 2008
[216] E Blom B Langstrom and I Velikyan ldquo68Ga-labeling of biotinanalogues and their characterizationrdquo Bioconjugate Chemistryvol 20 no 6 pp 1146ndash1151 2009
[217] O Eriksson F Carlsson E Blom et al ldquoPreclinical evaluationof a 68Ga-labeled biotin analogue for applications in islettransplantationrdquo Nuclear Medicine and Biology vol 39 no 3pp 415ndash421 2012
[218] E A Weinstein A A Ordonez V P DeMarco et alldquoImaging Enterobacteriaceae infection in vivo with 18F-fluoro-deoxysorbitol positron emission tomographyrdquo Science Transla-tional Medicine vol 6 no 259 p 259ra146 2014
[219] K M Nielsen M H Kyneb A K O Alstrup et alldquo68Ga-labeled phage-display selected peptides as tracers forpositron emission tomography imaging of Staphylococcusaureus biofilm-associated infections Selection radiolabellingand preliminary biological evaluationrdquo Nuclear Medicine andBiology vol 43 no 10 pp 593ndash605 2016
[220] T J Makinen P Lankinen T Poyhonen J Jalava H T Aroand A Roivainen ldquoComparison of 18F-FDG and 68Ga PETimaging in the assessment of experimental osteomyelitis due toStaphylococcus aureusrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 32 no 11 pp 1259ndash1268 2005
[221] JMU Silvola I LaitinenH J Sipila et al ldquoUptake of 68galliumin atherosclerotic plaques in LDLRminusminusApoB100100micerdquo EJN-MMI Research vol 1 no 1 pp 1ndash8 2011
Contrast Media amp Molecular Imaging 23
[222] T A Wynn ldquoCellular and molecular mechanisms of fibrosisrdquoThe Journal of Pathology vol 214 no 2 pp 199ndash210 2008
[223] T Derlin D Jonigk J Bauersachs and FM Bengel ldquoMolecularImaging of Chemokine Receptor CXCR4 in NonndashSmall CellLung Cancer Using 68Ga-Pentixafor PETCT ComparisonWith 18F-FDGrdquo Clinical Nuclear Medicine 2016
[224] I Velikyan U Rosenstrom T N Bulenga O Eriksson andG Antoni ldquoFeasibility of multiple examinations using68ga-labelled collagelin analogues Organ distribution in rat forextrapolation to human organ and whole-body radiationdosimetryrdquo Pharmaceuticals vol 9 no 2 article no 31 2016
[225] S Jadhav M Kakela J Makila et al ldquoSynthesis and in VivoPET Imaging of Hyaluronan Conjugates of OligonucleotidesrdquoBioconjugate Chemistry vol 27 no 2 pp 391ndash403 2016
[226] A Autio A Saraste N Kudomi et al ldquoAssessment of bloodflow with (68) Ga-DOTA PET in experimental inflammation avalidation study using (15) O-waterrdquo American Journal ofNuclear Medicine and Molecular Imaging vol 4 no 6 pp 571ndash579 2014
[227] G Davies A Rolle A Maurer et al ldquoTowards translationalimmunoPETMR imaging of invasive pulmonary aspergillosisthe Humanised Monoclonal Antibody JF5 detects in vivordquoTheranostics vol 7 no 14 pp 3398ndash3414 2017
[228] DGoodwin CMeares GDavid et al ldquoMonoclonal antibodiesas reversible equilibrium carriers of radiopharmaceuticalsrdquoInternational Journal of Radiation Applications and Instrumen-tation Part B Nuclear Medicine and Biology vol 13 no 4 pp383ndash391 1986
[229] D A Goodwin C F Mears M McTigue and G S DavidldquoMonoclonal antibody hapten radiopharmaceutical deliveryrdquoNuclear Medicine Communications vol 7 no 8 pp 569ndash5801986
[230] S E Halpern and R O Dillman ldquoProblems associated withradioimmunodetection and possibilities for future solutionsrdquo JBiol Response Mod vol 6 no 3 pp 235ndash262 1987
[231] H Hong J Sun and W Cai ldquoRadionuclide-based cancerimaging targeting the carcinoembryonic antigenrdquo BiomarkerInsights vol 3 pp 435ndash451 2008
[232] G J Forster E B Santos P M Smith-Jones P Zanzonico andS M Larson ldquoPretargeted radioimmunotherapy with a single-chain antibodystreptavidin construct and radiolabeledDOTA-biotin Strategies for reduction of the renal doserdquo Journal ofNuclear Medicine vol 47 no 1 pp 140ndash149 2006
[233] Z Yao M Zhang H Kobayashi et al ldquoImproved targeting ofradiolabeled streptavidin in tumors pretargeted with biotiny-lated monoclonal antibodies through an avidin chaserdquo Journalof Nuclear Medicine vol 36 no 5 pp 837ndash841 1995
[234] C-H Chang R M Sharkey E A Rossi et al ldquoMolecularAdvances in Pretargeting Radioimunotherapy with BispecificAntibodies 1 Supported in part by USPHS Grant R01-CA-84379from the NIH and Department of Energy Grant DE-FG01-00NE22941 (both to R M S)1rdquo Mol Cancer Ther vol 1 no 7pp 553ndash563 2002
[235] R M Sharkey E A Rossi W J McBride C-H Chang andD M Goldenberg ldquoRecombinant Bispecific Monoclonal Anti-bodies Prepared by theDock-and-Lock Strategy for PretargetedRadioimmunotherapyrdquo Seminars in Nuclear Medicine vol 40no 3 pp 190ndash203 2010
[236] R M Sharkey E A Rossi C-H Chang and D M Golden-berg ldquoImproved cancer therapy and molecular imaging withmultivalent multispecific antibodiesrdquo Cancer Biotherapy andRadiopharmaceuticals vol 25 no 1 pp 1ndash12 2010
[237] D M Goldenberg R M Sharkey G Paganelli J Barbet andJ Chatal ldquoAntibody pretargeting advances cancer radioim-munodetection and radioimmunotherapyrdquo Journal of ClinicalOncology vol 24 no 5 pp 823ndash834 2006
[238] O C Boerman F G van Schaijk W J G Oyen and FH M Corstens ldquoPretargeted radioimmunotherapy of cancerprogress step by steprdquo Journal of Nuclear Medicine vol 44 no3 pp 400ndash411 2003
[239] J Schuhmacher S Kaul G Klivenyi et al ldquoImmunoscintigra-phy with positron emission tomography Gallium-68 chelateimaging of breast cancer pretargeted with bispecific anti-MUC1anti-Ga chelate antibodiesrdquo Cancer Research vol 61 no9 pp 3712ndash3717 2001
[240] J Schuhmacher G Klivenyi S Kaul et al ldquoPretargeting ofhuman mammary carcinoma xenografts with bispecific anti-MUC1anti-Ga chelate antibodies and immunoscintigraphywith PETrdquo Nuclear Medicine and Biology vol 28 no 7 pp 821ndash828 2001
[241] C Somasundaram S Matzku J Schuhmacher and M ZollerldquoDevelopment of a bispecific monoclonal antibody against agallium-67 chelate and the human melanoma-associated anti-gen p97 for potential use in pretargeted immunoscintigraphyrdquoCancer Immunology Immunotherapy vol 36 no 5 pp 337ndash3451993
[242] E A Rossi D L Rossi R Stein D M Goldenberg and C-H Chang ldquoA bispecific antibody-IFN1205722b immunocytokine tar-geting CD20 and HLA-DR is highly toxic to human lymphomaandmultiplemyeloma cellsrdquoCancer Research vol 70 no 19 pp7600ndash7609 2010
[243] R M Sharkey H Karacay S Litwin et al ldquoImproved ther-apeutic results by pretargeted radioimmunotherapy of non-Hodgkinrsquos lymphoma with a new recombinant trivalent anti-CD20 bispecific antibodyrdquo Cancer Research vol 68 no 13 pp5282ndash5290 2008
[244] G L Griffiths C-H Chang W J McBride et al ldquoReagentsandmethods for PETusing bispecific antibody pretargeting and68Ga-radiolabeled bivalent hapten-peptide-chelate conjugatesrdquoJournal of Nuclear Medicine vol 45 no 1 pp 30ndash39 2004
[245] J Watine M Miedouge and B Friedberg ldquoCarcinoembryonicantigen as an independent prognostic factor of recurrence andsurvival in patients resected for colorectal liver metastases Asystematic reviewrdquo Diseases of the Colon amp Rectum vol 44 no12 pp 1791ndash1799 2001
[246] M J Goldstein and E P Mitchell ldquoCarcinoembryonic antigenin the staging and follow-up of patients with colorectal cancerrdquoCancer Investigation vol 23 no 4 pp 338ndash351 2005
[247] D V Gold D M Goldenberg H Karacay et al ldquoA novelbispecific trivalent antibody construct for targeting pancreaticcarcinomardquo Cancer Research vol 68 no 12 pp 4819ndash48262008
[248] J Schuhmacher G Klivenyi R Matys et al ldquoMultistep tumortargeting in nudemice using bispecific antibodies and a galliumchelate suitable for immunoscintigraphy with positron emis-sion tomographyrdquo Cancer Research vol 55 no 1 pp 115ndash1231995
[249] G Klivenyi J Schuhmacher E Patzelt et al ldquoGallium-68chelate imaging of human colon carcinoma xenografts pre-targeted with bispecific anti-CD44(V6)anti-gallium chelateantibodiesrdquo Journal ofNuclearMedicine vol 39 no 10 pp 1769ndash1776 1998
[250] M Zoller J Schuhmacher J Reed W Maier-Borst and SMatzku ldquoEstablishment and characterization of monoclonal
24 Contrast Media amp Molecular Imaging
antibodies against an octahedral gallium chelate suitable forimmunoscintigraphy with PETrdquo Journal of Nuclear Medicinevol 33 no 7 pp 1366ndash1372 1992
[251] R M Sharkey T M Cardillo E A Rossi et al ldquoSignal ampli-fication in molecular imaging by pretargeting a multivalentbispecific antibodyrdquo Nature Medicine vol 11 no 11 pp 1250ndash1255 2005
[252] D M Goldenberg and R M Sharkey ldquoNovel radiolabeledantibody conjugatesrdquo Oncogene vol 26 no 25 pp 3734ndash37442007
[253] D M Goldenberg E A Rossi R M Sharkey W J McBrideand C-H Chang ldquoMultifunctional antibodies by the dock-and-lock method for improved cancer imaging and therapy bypretargetingrdquo Journal of NuclearMedicine vol 49 no 1 pp 158ndash163 2008
[254] R Schoffelen R M Sharkey D M Goldenberg et al ldquoPre-targeted immuno-positron emission tomography imaging ofcarcinoembryonic antigen-expressing tumors with a bispecificantibody and a68Ga- And18F-labeled hapten peptide in micewith human tumor xenograftsrdquoMolecular Cancer Therapeuticsvol 9 no 4 pp 1019ndash1027 2010
[255] E S Bos W H Kuijpers M Meesters-Winters et al ldquoIn vitroevaluation of DNA-DNA hybridization as a two-step approachin radioimmunotherapy of cancerrdquoCancer Research vol 54 no13 pp 3479ndash3486 1994
[256] G Paganelli M Bartolomei M Ferrari et al ldquoPre-TargetedLocoregional Radioimmunotherapy withrdquo Cancer biotherapyand radiopharmaceuticals vol 16 no 3 pp 227ndash235 2001
[257] A Forero P L Weiden J M Vose et al ldquoPhase 1 trial of a novelanti-CD20 fusion protein in pretargeted radioimmunotherapyfor B-cell non-Hodgkin lymphomardquo Blood vol 104 no 1 pp227ndash236 2004
[258] DM Goldenberg C-H Chang E A RossiW J McBride andR M Sharkey ldquoPretargeted molecular imaging and radioim-munotherapyrdquoTheranostics vol 2 no 5 pp 523ndash540 2012
[259] H Karacay R M Sharkey W J McBride E A Rossi C-HChang and D M Goldenberg ldquoOptimization of hapten-peptide labeling for pretargeted immunoPET of bispecificantibody using generator-produced 68Gardquo Journal of NuclearMedicine vol 52 no 4 pp 555ndash559 2011
[260] J R Oh and B C Ahn ldquoFalse-positive uptake on radioiodinewhole-body scintigraphy physiologic and pathologic variantsunrelated to thyroid cancerrdquo American Journal of NuclearMedicine and Molecular Imaging vol 2 no 2 pp 141ndash150 2012
[261] E Frampas C Rousseau C Bodet-Milin J Barbet J-F Chataland F Kraeber-Bodere ldquoImprovement of radioimmunotherapyusing pretargetingrdquo Frontiers in Oncology vol 3 Article ID00159 2013
[262] C S McKay and M G Finn ldquoClick chemistry in complexmixtures Bioorthogonal bioconjugationrdquo Chemistry amp Biologyvol 21 no 9 pp 1075ndash1101 2014
[263] B L Oliveira Z Guo and G J Bernardes ldquoInverse electrondemand DielsndashAlder reactions in chemical biologyrdquo ChemicalSociety Reviews vol 46 no 16 pp 4895ndash4950 2017
[264] B Nichols Z Qin J Yang D R Vera and N K Devaraj ldquo68Gachelating bioorthogonal tetrazine polymers for the multisteplabeling of cancer biomarkersrdquo Chemical Communications vol50 no 40 pp 5215ndash5217 2014
[265] R Rossin P R Verkerk S M van den Bosch et al ldquoInvivo chemistry for pretargeted tumor imaging in live micerdquoAngewandte Chemie International Edition vol 49 no 19 pp3375ndash3378 2010
[266] B M Zeglis K K Sevak T Reiner et al ldquoA pretargetedPET imaging strategy based on bioorthogonal diels-alder clickchemistryrdquo Journal of Nuclear Medicine vol 54 no 8 pp 1389ndash1396 2013
[267] J L Houghton R Membreno D Abdel-Atti et al ldquoEstablish-ment of the invivo efficacy of pretargeted radioimmunotherapyutilizing inverse electron demand diels-alder click chemistryrdquoMolecular Cancer Therapeutics vol 16 no 1 pp 124ndash133 2017
[268] J Funkhouser ldquoReinventing pharma the theranostic revolu-tionrdquo Current Drug Discovery pp 17ndash19 2002
[269] J Sorensen I Velikyan A Wennborg et al ldquoMeasuring HER2-expression in metastatic breast cancer using 68Ga-ABY025PETCTrdquo European Journal of Nuclear Medicine and MolecularImaging vol 41 pp S226ndashS226 2014
[270] I Velikyan A Wennborg J Feldwisch et al ldquoGMP compliantpreparation of a 68Gallium-labeled Affibody analogue forbreast cancer patient examination first-in-manrdquoEur JNuclMedMol Imaging vol 41 pp S228ndashS229 2014
[271] K Oberg ldquoMolecular imaging radiotherapy Theranostics forpersonalized patient management of neuroendocrine tumors(NETs)rdquoTheranostics vol 2 no 5 pp 448ndash458 2012
[272] I Velikyan AWennborg J FeldwischH Lindman J Carlssonand J Sorensen ldquoGood manufacturing practice production of [(68) Ga]Ga-ABY-025 for HER2 specific breast cancer imagingrdquoAmerican Journal of Nuclear Medicine and Molecular Imagingvol 6 no 2 pp 135ndash153 2016
[273] M Sandstrom K Lindskog I Velikyan et al ldquoBiodistributionand radiation dosimetry of the anti-HER2 Affibody molecule68Ga-ABY-025 in breast cancer patientsrdquo Journal of NuclearMedicine vol 57 no 6 pp 867ndash871 2016
[274] D Sandberg V Tolmachev I Velikyan et al ldquoIntra-imagereferencing for simplified assessment of HER2-expression inbreast cancer metastases using the Affibody molecule ABY-025with PET and SPECTrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 44 no 8 pp 1337ndash1346 2017
[275] H ZhangM AMoroz I Serganova et al ldquoImaging expressionof the human somatostatin receptor subtype-2 reporter genewith 68Ga-DOTATOCrdquo Journal ofNuclearMedicine vol 52 no1 pp 123ndash131 2011
[276] M Naji and A Al-Nahhas ldquo68Ga-labelled peptides in themanagement of neuroectodermal tumoursrdquo European Journalof Nuclear Medicine and Molecular Imaging vol 39 no 1 ppS61ndashS67 2012
[277] I Velikyan ldquoThe diversity of 68Ga-Based imaging agentsrdquoRecent Results in Cancer Research vol 194 pp 101ndash131 2013
[278] K Ferreira H-Y Hu V Fetz et al ldquoMultivalent siderophore-dotam conjugates as theranostics for imaging and treatment ofbacterial infectionsrdquo Angewandte Chemie International Editionvol 56 no 28 pp 8272ndash8276 2017
Computational and Mathematical Methods in Medicine
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Volume 2018Hindawiwwwhindawicom
Submit your manuscripts atwwwhindawicom
Contrast Media amp Molecular Imaging 9
and evaluation of disease progression and treatment responsein cancerous and inflammatory diseases involving SSTRsPreclinical study using atherosclerotic mice demonstratedsuperior targeting properties of [68Ga]Ga-DOTA-NOC ascompared to [18F]FDR-NOC [188] overall confirming thepotential of SSTR targeting for atherosclerotic plaque imag-ing
58 Imaging Neuroinflammation Despite difficulty ofdesigning 68Ga-labelled molecules capable of blood-brainbarrier penetration several agents were suggested for theimaging of neuroinflammation in particular A120573 plaquesdeposited on blood vessels [67ndash69] Bivalent styrylpyridineslabelled with 68Ga demonstrated high specificity and affinityfor A120573 plaques using postmortem Alzheimerrsquos disease (AD)brain sections [67] Benzofuran derivative comprising 68Gashowed promising results in terms of binding specificityand affinity investigated in vitro in sections of Tg2576mice [68] Although the synthesis of a 68Ga-labelledPittsburgh compound analogue was successful the in vitrobinding to amyloid deposits was limited [69] The commondisadvantage of these agents is poor blood-brain barrierpenetration nevertheless the exploration of more successfulanalogues continues Curcumin functions as an antioxidantantimicrobial anti-inflammatory and anticancer agentDiacetyl-curcumin and bis(dehydroxy)curcumin labelledwith 68Ga demonstrated in vitro binding to 120573-amyloid fibrilsand lung cancer cells [189] Potential application of the agentscould include diagnostic imaging of Alzheimerrsquos disease andvarious cancers
6 Imaging Infection
Infection imaging can be indirect utilizing targets involvedin the immune response namely inflammation as presentedin the inflammation targets section above or direct utilizingpathogen related targets The direct imaging is especiallycrucial in cases where inflammatory response is absent Thedifference in biochemistry and structure between bacterialand human cells might exclude physiological uptake byhuman tissuemaking it easier tomeet the favorable character-istics of an imaging agent However discrimination betweenthe various infectious microorganisms pathogenic bacteriaand microbiota targeting specific bacteria type as well asdifficulty of accessing bacteria aggregated in a biofilm makesthe task very challenging [190 191] The specific targetingof infection would require accumulation of the radioactivesignal in the pathogen The radiolabelled targeting agentsfor infection can be roughly divided into several groupsantibiotics based antimicrobial protein and peptide basedsiderophore and other metabolisable compound based andantigen-specific antibodies and antibody fragments (Table 3)
61 Radiolabelled Antibiotics Antimicrobials act on the pro-cesses that are specific to microbes for example bacteria andfungi and thus corresponding imaging agents might distin-guish infection from inflammation [191] They might requireinternalization or may bind to the cell surface dependent on
their biological action mechanism [191ndash193] The possibilityof antibiotic resistance development exists also in the case ofimaging agents even though the amount of such agents wouldbe subnanomolar [194 195] Another complication is possiblenonspecific uptake of antibiotics based agents by leucocytes[196] Considerable number of various antibiotic analogueshave been labelled with 99mTc 111In 131I 11C and 18F[102] and evaluated preclinically and clinically with 99mTc-ciprofloxacin becoming a commercial product (Infecton) [21197 198] However the further improvement of specificityis desirable [191] Antibiotics are accessible and cheap andthey demonstrate high sensitivity [102 191] making thedevelopment of 68Ga-labelled analogues very attractive giventhe earlier mentioned advantages that 68Ga as a radionu-clide in combination with PET provides Two 68Ga-labelledanalogues based on ciprofloxacin demonstrated potential fordiscrimination between bacterial infection and inflammationin rats infected with Staphylococcus aureus [70]
62 Radiolabelled Antimicrobial Proteins and Peptides Anti-microbial proteins and peptides for example serprocidinscathelicidins and defensins produced by the cells of immunesystem target microbial membrane lipids and impose micro-bicidal effect [35 43] They present a large group of poten-tial candidates for microbial imaging including bacteriafungi parasites and viruses Antimicrobial peptides havedemonstrated higher specificity for infection than antibioticanalogues They accumulate at infection but not sterileinflammation sites The most thoroughly studied antimicro-bial peptide ubiquicidin UBI [29ndash41] labelled with 99mTc[199] demonstrated promising results in human clinical trials[200 201] It has the potential for quantification of viableinfecting microorganisms and consequently for monitoringthe efficacy of antimicrobial therapy in patients
Fragments of an antimicrobial peptide ubiquicidin con-jugated to NOTA and labelled with 68Ga [68Ga]Ga-NOTA-UBI29-41 and [68Ga]Ga-NOTA-UBI30-41 demonstratedpossibility for the distinction between infection and inflam-mation in a rabbit model [71 72] Antimicrobial peptidefragments GF-17 and RAWVAWR-NH2 of respectivelyhuman cathelicidin LL-37 andhuman lysozyme active againstE coli and S aureus were labelled with 68Ga and theirbiodistribution in normal rats demonstrated fast clearancefrom liver [75] Antimicrobial depsipeptide based agent[68Ga]Ga-DOTA-TBIA101 targeting bacterial lipopolysac-charides detected muscular E coli-infection in mice (Fig-ure 4) [73] The agent was also studied in healthy rabbitsand various disease model rabbits such as sterile inflam-mation Staphylococcus aureus infection andMycobacteriumtuberculosis [74] The clearance of [68Ga]Ga-DOTA-TBIA101from blood and normal tissue was fast and enhanced uptakein sterile inflammation and Mycobacterium tuberculosis siteswas observed The improvement of the bacterial selectivitywill require modification of the agent structure
63 Radiolabelled Siderophores Bacteria and fungi producevarious siderophores for harvesting iron which is essentialfor their survival and growth [34 98 191] Siderophores
10 Contrast Media amp Molecular Imaging
(a)
(b)
(c) (d)
(e)
Figure 4 Left panel presents maximum intensity projection images of [68Ga]Ga-DOTA-TBIA101 distribution in a healthy mouse (a) and amouse with muscular infection site (MIS) in the right hind muscle tissue (white arrows) Right panel presents coronal (c) sagittal (d) andaxial (e) images with uptake in theMIS (white arrow) and absence of the uptake in the contralateralmuscle tissue Ki and Bl stand respectivelyfor kidney and bladder Reproduced from [73]
can also play a critical role in the development of biofilmsby microbes They are low molecular weight compoundsspecifically chelating Fe(III) and Ga(III) can form stablecomplexes with them mimicking Fe(III) [202 203]
Desferri-triacetylfusarinine C (TAFC) and desferri-ferricrocin (FC) labelled with 68Ga were used for theimaging of invasive pulmonary aspergillosis (IPA) caused byAspergillus fumigatus [15] [68Ga]Ga-TAFC demonstratedsuperior characteristics in terms of specific target bindingmetabolic stability and fast blood clearance in a rat modelof A fumigatus infection Seven analogues were developedin another study with TAFC and ferrioxamine E (FOXE)showing favorable binding clearance elimination andstability characteristics [16] as well as lung uptake inrat of invasive aspergillosis model wherein the uptakeextent was correlated with disease severity [17] [68Ga]Ga-triacetylfusarinine C and [68Ga]Ga-ferrioxamine E wereinvestigated in rat model of A fumigatus and demonstratedrapid uptake in the lungs (Figure 5) [76]
64 Radiolabelled Metabolisable Agents Mammalian micro-biota consumes (poly)saccharides in particular maltose andmaltodextrins [204] The transport mechanism is specific
to bacteria and is absent in mammalian cells making itpossible to utilize these (poly)saccharides for imaging agentdevelopment Maltodextrin functionalized with a fluorescentdye was internalized through the bacteria-specific maltodex-trin transport pathway and discriminated between activebacteria and inflammation in vivo [192] Maltose labelledwith 18F localized specifically bacterial infection in mice[205] Potential to label polysaccharides directly with 68Gamight be utilized extensively
As mentioned above the chemical properties of Ga(III)provide the potential for direct labelling of polysaccharidesDextran was labelled directly and resulting complex demon-strated sufficient stability in human serum however thefeasibility of the bacterial imaging was not demonstrated[206]
Trapping of nucleosides that are substrates of thymidinekinase occurring within bacteria was explored using 18Fand 125I labelled analogues of uracil [207] Promising resultswere obtained in seven bacterial species in mice Anotherstudy in the context of therapeutic bacteria developmentdemonstrated possibility of detecting Salmonella vectorswithin tumours using 18F-labelled uracil [208] However
Contrast Media amp Molecular Imaging 11
N
O
N
ON
HN
O
O
O
OO O
NH
O
O
O
O
NH
O
OGa
（3
（3
（3
（3
（3
（3
（2
(a) (b) (c)
Figure 5 Molecular structure of [68Ga]Ga-triacetylfusarinine C (a) used for the in vivo imaging of a rat with Aspergillus fumigatus infection(b) and negative control of noninfected rat (c) White arrows point at the infected (b) and normal (c) lungs Adapted from [76]
the development of 68Ga-labelled nucleosides that wouldmaintain their biological activity is challenging and fewexamples known from the literature confirm that [4 6]
7 68Ga-Citrate
As mentioned above 68GaPET provides a number of advan-tages over 67GaSPECT and following publications demon-strate it in clinical and preclinical studies [68Ga]Ga-citratedemonstrated high diagnostic accuracy of 90of osteomyeli-tis and diskitis in clinical studies (Figure 6) [18 19] Thisstudy demonstrates that [68Ga]Ga-citrate can be employedfor monitoring the response to treatment [68Ga]Ga-citratewas used clinically to follow-up surgical intervention inpatients with acute osteomyelitis and intra-abdominal infec-tion [77] The agent was also used to successfully visualizelungmalignancy and tuberculosis in patients however in caseof high prevalence of granulomatous diseases the distinctionbetween malignant and benign lung lesions was unclear [7879] Another clinical study conducted head-to-head compar-ison of [68Ga]Ga-citrate (Figure 7) and [18F]FDG in patientswith Staphylococcus aureus bacteremia [80] The detectionrate of osteomyelitis was similar and further investigationof [68Ga]Ga-citrate applicability in cases of osteomyelitisinduced by other pathogens as well as for monitoring healingprocess is warranted
Comparative study of [68Ga]Ga-citrate and [67Ga]Ga-citrate was performed in healthy and infection model rats[77] The performance of [68Ga]Ga-citrate was found supe-rior in terms of image contrast in the lower abdomen and
extremities Potential of [68Ga]Ga-citrate for the differentia-tion of acute interstitial nephritis from acute tubular necrosiswas studied in rat model of the disease and it was demon-strated that the kidney uptake correlated with the extentof mononuclear cell infiltration accompanying inflammation[209] 68Ga-labelled Apo-transferrin demonstrated bacterialinfection detection capacity in rat model with Staphylococcusaureus wherein the infection site was visualized 1 h afteradministration of the agent [14]
71 Radiolabelled Antibodies and Antibody FragmentsHuman immunoglobulin (HIG) binds to bacteria but alsoaccumulates at the sites of fungal and viral infection aswell as sterile inflammation due to binding to leukocytesThe improved specificity for bacteria was achieved for thefragments of HIG It is feasible to develop specific antibodiesto various antigens present on the bacterial cell surface [102]Monoclonal antibodies labelled with 99mTc were used forinfection imaging via granulocytes targeting NCA-95 [210]Various cytokines of interleukin family (IL-1 IL-8) labelledwith 123I or 99mTc demonstrated accumulation in the sitesof infection in various animal models [111 112 211ndash214]Registered antigranulocyte radiopharmaceuticals suchas LeuTech Scintimun and Leukoscan are based on99mTc-labelled antibodies This experience can be translatedto 68Ga however either the size of the antibodies mustbe reduced or pretargeting techniques must be appliedin order to overcome the discrepancy between the shortphysical half-life of 68Ga and slow pharmacokinetics ofantibodies
12 Contrast Media amp Molecular Imaging
(a) (b) (c) (d)
Figure 6 [68Ga]Ga-citrate PETCT examination of a patient affected by acute osteomyelitis before (left panel) and after (right panel) surgicalcurettage showing uptake in the transaxial (a c) and 3D reconstruction images (b d red area) Absence of the uptake after the therapyconfirms complete response to the treatment Adapted from [19]
Figure 7 Vertebral osteomyelitis (spondylodiscitis red arrow-heads) and abscesses in the iliopsoas and paravertebral area (redarrows) were detected by [68Ga]Ga-citrate in a patient admittedto the hospital with back pain and general symptoms The PETacquisition was performed 88min after administration of 245MBqof [68Ga]Ga-citrate Adapted from [80]
72 Radiolabelled Biotin Biotin is a growth factor utilizedin many bacteria An 111In-labelled analogue of biotin wassuccessfully utilized for diagnosis of vertebral infections ina clinical study [215] It would be rational to explore therelevance of 68Ga-labelled analogues given the advantagesof 68Ga over 111In and promising [68Ga]Ga-DOTA-Biotinanalogues [216 217] developed for monitoring survival oftransplanted avidin-coated islets
8 Miscellaneous
Stable Ga(III) complex with thiosemicarbazones demon-strated antimicrobial effect against P aeruginosa and Calbicans due to most probably both displacement of essentialFe(III) with Ga(III) and thiosemicarbazones [101] Substitu-tion of the stable Ga(III) by radioactive 68Ga might result ina specific infection imaging agent
Selective imaging of Enterobacteriaceae using 2-[18F]-fluorodeoxysorbitol (18F-FDS)was demonstrated in amurine
myositis model [218] The uptake of 18F-FDS was correlatedwith bacterial burden moreover the agent differentiatedinfection from sterile inflammation Given the potential of68Ga for the labelling of small biologically active molecules[4] it might be plausible to develop a respective analoguewith added value of the advantages that 68Ga offers includingsimpler production chemistry lowered radiation dose repet-itive examination and accessibility at clinical centers withoutcyclotrons and remote from [18F]-FDG distribution sites Asmentioned above the poor access to bacteria aggregated ina biofilm might make the imaging task challenging Severalpeptide candidates with affinity for S aureus biofilm weredesigned and labelled with 68Ga [219] The resulting agentsdemonstrated binding in vitro however it was not possible toblock the binding with excess of the cold peptide
Ionic 68Ga was found superior to [18F]-FDG in infectiondetection in the rat model with diffuse osteomyelitis [220] Inanother study the uptake of ionic 68Ga was observed in theaortic plaques of atherosclerotic mice specifically at the sitesrich inmacrophages [221] However the slow blood clearanceof ionic 68Ga presents a limitation
Chronic inflammation is the major reason of fibro-sis [222] 68Ga-labelled SST analogue ([68Ga]Ga-DOTA-NOC) demonstrated uptake in pathogenic areas in patientsaffected by idiopathic pulmonary fibrosis with potentialfor monitoring response to treatment and drug develop-ment [62] Another clinical study using [68Ga]Ga-pentixaforalso showed potential of the agent for monitoring dis-ease activity and response to treatment in idiopathic pul-monary fibrosis [223] Peptide based agents CNO2A-PEG2-c[CPGRVMHGLHLGDDEGPC] and [68Ga]Ga-NODAGA-PEG2-c[CPGRVMHGLHLGDDEGPC] for the imaging andquantification of fibrosis by PET were developed and char-acterized preclinically showing fast clearance from normal
Contrast Media amp Molecular Imaging 13
tissue and blood and binding specificity [89] Dosimetrycalculations demonstrated possibility of six examinations peryear in humans assuring disease monitoring in longitudinalstudies and routine clinical setup [224]
Several hyaluronan conjugates of oligonucleotides target-ing CD44 positive cells were developed and tested in healthyrats sham-operated rats and rats with myocardial infarction[225]The uptake of the agents was higher for the latter groupand varied dependent on the difference in the oligonucleotidestructure
TLR2 and TLR4 expression levels in neutrophils werefound higher in individuals with bacterial and viral infectionsthan those in control samples There is a possibility that IL-4IL-8 IL-10 IL-12 and TNF-a might serve as biomarkers forinfections and that IL-2 IL-8 or IL-10 is potentially able todistinguish between bacterial and viral infections [22]
Mannosylated human serum albumin labelled with 68Gavia NOTA chelator moiety ([68Ga]Ga-NOTA-MSA) wastested in a rat model of myocarditis targetingmannose recep-tors expressed onmacrophages infiltratingmyocardium [66]The uptake in the diseased myocardium was considerablyhigher than that of the normal one and it was precludedby administration of excess of nonlabelled MSA indicatingbinding specificity The tracer build-up was also observed inthe organs of macrophage accumulation
[68Ga]Ga-DOTA was investigated for the quantificationof increased blood flow which is one of the key events ininflammation [226] The uptake kinetics of [68Ga]Ga-DOTAin the site of inflammation in rats with induced inflamma-tion correlated well with that of 15O-water suggesting highrelevance [68Ga]Ga-DOTA
9 Pretargeted Imaging
The half-life of 68Ga is shorter than that of 64Cu 67Ga 99mTc89Zr 111In and 123124125I and thus in contrast to the latterit is not compatible with slow pharmacokinetics of largemolecules such as antibodies and glycoproteins The rangeof antigen-specific antibodies relevant to inflammation andinfection is broad and a number of 99mTc-labelled antibodieswere used clinically [20 21 227] The respective range of68Ga-based agents could be similarThe solution to overcomethe incompatibility of half-life time frames could be eitherthe reduction of the antibody size or the application of thepretargeting concept
The history of the pretargeting concept spans threedecades predominantly in the field of oncology [228ndash230]It was developed to improve image contrast and dosimetryin immunoimaging and radioimmunotherapy when usingradiolabelled antibody ligands with slow pharmacokinetics[231] The arsenal of antibodies is vast and diverse encourag-ing extensive investment into development of techniques thatwould allow their exploration to the fullest Pretargeting con-siders at least two major steps wherein a functionalized anti-body is first administered for target localization and clearancefrom blood and normal tissue and thereafter a radiolabelledsmall molecule capable of binding to the functionalized
antibody due to high affinity or covalent interaction is admin-istered The key properties of the radiolabelled molecules arefast pharmacokinetic and clearance Several techniques havebeen developed for the realization of pretargeting conceptincluding avidinstreptavidin-biotin systems [216 217 232233] bispecific antibodies (bsmAb) with haptens [232 234ndash254] antibody-oligonucleotide conjugates with complemen-tary oligonucleotides [255] biorthogonal systems allowingcovalent chemical reactions in vivo (Figure 8)
The high affinity of biotin to avidin and streptavidinproteins was utilized clinically and preclinically in pretar-geting approach for the imaging and therapy of pancreaticadenocarcinoma [232] glioblastoma [256] and lymphoma[257] However this pretargeting technique may requirethree steps in order to eliminate the excess of antibody-(strept)avidin conjugate circulating in the blood and notbound to the target by adding clearing agent Anotherapplication of the technique was monitoring transplantationof islets of Langerhans in the treatment for type 1 diabetesmellitus wherein the cells or cellmimetics were conjugated to(strept)avidin prior to the transplantation [216 217] Severalanalogues of biotin comprising DOTA chelate moiety forlabelling with 68Ga and ethylene glycol linker of variouslength demonstrated the influence of the latter on the affinitytowards avidin
Particular example of hapten molecules is the ones com-prising histamine-succinyl-glycine (HSG) motif and chelatemoiety [251ndash253 258] for the complexationwith 68Ga Severalanalogues were developed for the imaging of carcinoem-bryonic antigen (CEA) pretargeted with anti-CEA bsmAb[254 259 260] and two clinical studies of medullary thyroidcarcinoma and breast carcinoma positive for CEA using68Ga-labelled hapten molecules and bsmAb were initiated[261]
Bioorthogonal reactions are fast regioselective requiringsmall reagent concentration and occurring under mild con-ditions often in aqueous solution and temperature below 37∘C[262 263] Amongst various biorthogonal reaction types thecycloaddition of tetrazines and various dienophiles referredto as inverse-electron-demandDiels-Alder (IEDDA) reactionis themost successful in the context of pretargeting Antibod-ies functionalized with trans-cyclooctene (TCO) and a radi-olabelled tetrazine that can interact in vivo based on IEDDAreaction were studied [264ndash267] In particular 68Ga-labelledtetrazine dextran demonstrated favorable pharmacokineticsin a healthy mouse [264] However the proof of concept is tobe performed in a xenografted animal Accumulation of anti-TAG72 [265] and anti-A33 [266] antibodies functionalizedwith TCO in mouse xenografts was visualized respectivelyby an 111In and 64Cu-labelled tetrazine analogues Anti-CA199 antibody-TCO in combination with 177Lu-labelledtetrazine demonstrated radiotherapeutic effect in pancreaticcancer murine model [267]
Thepretargeted imaging techniquesmay contribute to theexpansion of immuno-PET with 68Ga providing the intrinsicadvantages of 68Ga and PET As mentioned above mostof the developed radiolabelled counterparts of pretargetingtechniques have demonstrated promising results There are
14 Contrast Media amp Molecular Imaging
H
ON
NN
O
OO
OO
NH
NS
NH
ONH
O
HO
ONH
O
Ga
HN
NH
NH
O
OO
HNN
HN
NH
NH
O
OO
HNN
（2
(a)
NH
O
O
NH
N
NNGa
O O
O O
O
O
O
N N
NN
OO
（2
(b)
N
N
O
O
N
N
O
O
O
NH
O
O
ONH
NHS
O
H
HO
NH
+
minus
(c)
Figure 8 Schematic presentation of pretargeting techniques (a) bispecific antibodies engineered to specifically bind with radiolabelledhapten molecules (b) bioorthogonal click chemistry for fast and specific covalent binding between for example a trans-cyclooctenefunctionalized antibody and a radiolabelled tetrazine (c) interaction between antibody-(strept)avidin conjugate and radiolabelled biotinutilizing extremely high affinity of (strept)avidin and biotin
Contrast Media amp Molecular Imaging 15
a considerable number of potential antibody biomarkersthat could be considered for the imaging of infection andinflammation
10 Theranostics Potential
Theranostics [268] embraces realization of personalizedmedicine by conducting diagnosis on individual basis andproviding possibility of predicting the efficacy of a specifictreatment and following up the response to the treatmentenabling adjustment of the latter very early in the processIn the context of nuclear medicine wherein the radiophar-maceuticals targeted at biomarkers specific to a disease cancarry either diagnostic radionuclides or therapeutic ones theconcept can be denoted as radiotheranostics [28] The tar-geted molecular imaging such as PET can offer noninvasivediagnosis specific to the disease for example tumour-typespecific and provide accurate localization of the lesions Thestrongest advantage of PET is the potential for quantificationof the target for example receptor expression investigationof the uptake kinetics and estimation of the dosimetryThesecharacteristics of PET allow for individualized treatmentselection and planning monitoring of treatment responseand detection of recurrent diseaseThe individualized patientmanagement provides such advantages as optimization ofthe treatment regimen for the improved response and exclu-sion of futile treatments minimization of risks and toxicitywith overall outcome of reduced cost and patient distressThe importance of individualized patient management wasdemonstrated by clinical studies wherein the influence ofdose of the administered radiopharmaceutical targeted atreceptors overexpressed in cancer lesions on the diagnosticoutcome was investigated in the same patient [85 269270] 68Ga-labelled SST analogues [26ndash28 271] and Affibodymolecules [5 272ndash274] used respectively in NENs andbreast cancer patients are the most prominent examplesof (radio)theranostics involving 68GaPET wherein 68Ga-labelled analogues were used not only for localization of thelesions but also for staging patient stratification prognosistherapy selection and monitoring of the response to thetreatment of NETs and other cancer types [2ndash4 6 85 176275ndash277]
The methodology can be translated to inflammationand infection allowing for accurate and specific selection oftreatment regimen and for follow-up and evaluation of theresponse to therapy resulting in improved treatment efficacyand decreased cost and side effects The accommodation ofboth imaging function and antibiotic function in the samemolecule is a novel example of a theranostic agent [278]A series of siderophores conjugated with DOTA moiety forthe radiolabelling and with antibiotics for the treatmentof bacterial infection were investigated preclinically Theaccumulation of the intravenously administered ampicillinconjugate in the site of subcutaneously injected P aeruginosain mice was clearly and focally visualized within 06 h withretention for at least 24 h These results obtained usinganalogues carrying dye for optical imaging can be translatedto 68Ga-labelled counterparts for PET
11 Conclusions
The medical need for specific agents for noninvasive quan-titative and whole-body imaging of inflammation and infec-tion has not been met yet despite decades of research How-ever the prerequisites in terms of identification of potentialtargets design and synthesis of the respective ligands andimaging technologies are evolving very fast The potentialof accurate and quantitative lesion localization as well asmonitoring of the treatment response promises personalizedpatient management
The use of 68Ga in oncology is established proving thestrong potential of 68Ga for the promotion of PET technol-ogy for effective and efficient diagnostics and personalizedmedicineThe experience of oncological 68Ga-based agents isgetting translated to inflammation and infection Pretargetedimaging technology opens wide possibilities based on anti-body biomarkers
Conflicts of Interest
The author declares that there are no conflicts of interestregarding the publication of this article
References
[1] I Velikyan ldquoContinued rapid growth inGa applications update2013 to June 2014rdquo Journal of Labelled CompoundsampRadiophar-maceuticals pp 99ndash121 2015
[2] I Velikyan ldquo 68Ga-based radiopharmaceuticals Production andapplication relationshiprdquo Molecules vol 20 no 7 pp 12913ndash12943 2015
[3] M Fani P Peitl and I Velikyan ldquoCurrent status of radiophar-maceuticals for the theranostics of neuroendocrine neoplasmsrdquoPharmaceuticals vol 10 no 1 article no 30 2017
[4] I Velikyan ldquoPositron emitting [68Ga]Ga-based imaging agentsChemistry and diversityrdquoMedicinal Chemistry vol 7 no 5 pp345ndash379 2011
[5] J Sorensen I Velikyan D Sandberg et al ldquoMeasuringHER2-receptor expression in metastatic breast cancer using[68Ga]ABY-025 Affibody PETCTrdquo Theranostics vol 6 no 2pp 262ndash271 2016
[6] I Velikyan ldquoProspective of 68Ga-Radiopharmaceutical devel-opmentrdquoTheranostics vol 4 no 1 pp 47ndash80 2014
[7] P Lankinen T J Makinen T A Poyhonen et al ldquo68Ga-DOTAVAP-P1 PET imaging capable of demonstrating the phaseof inflammation in healing bones and the progress of infectionin osteomyelitic bonesrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 35 no 2 pp 352ndash364 2008
[8] T UjulaMHuttunen P Luoto et al ldquoMatrixmetalloproteinase9 targeting peptides Syntheses 68Ga-labeling and preliminaryevaluation in a rat melanoma xenograft modelrdquo BioconjugateChemistry vol 21 no 9 pp 1612ndash1621 2010
[9] A Autio T Ujula P Luoto S Salomaki S Jalkanen and ARoivainen ldquoPET imaging of inflammation and adenocarcinomaxenografts using vascular adhesion protein 1 targeting peptide68Ga-DOTAVAP-P1 Comparison with 18F-FDGrdquo EuropeanJournal of Nuclear Medicine and Molecular Imaging vol 37 no10 pp 1918ndash1925 2010
16 Contrast Media amp Molecular Imaging
[10] J Silvola A Autio P Luoto S Jalkanen andA Roivainen ldquoPre-liminary evaluation of novel 68Ga-DOTAVAP-PEG-P2 peptidetargeting vascular adhesion protein-1rdquo Clinical Physiology andFunctional Imaging vol 30 no 1 pp 75ndash78 2010
[11] T Ujula S Salomaki P Virsu et al ldquoSynthesis 68Ga labelingand preliminary evaluation of DOTA peptide binding vascularadhesion protein-1 a potential PET imaging agent for diagnos-ing osteomyelitisrdquo Nuclear Medicine and Biology vol 36 no 6pp 631ndash641 2009
[12] A Autio T Henttinen H J Sipila S Jalkanen and ARoivainen ldquoMini-PEG spacering of VAP-1-targeting 68Ga-DOTAVAP-P1 peptide improves PET imaging of inflamma-tionrdquo EJNMMI Research vol 1 no 1 pp 1ndash7 2011
[13] K Aalto A Autio E A Kiss et al ldquoSiglec-9 is a novel leukocyteligand for vascular adhesion protein-1 and can be used in PETimaging of inflammation and cancerrdquo Blood vol 118 no 13 pp3725ndash3733 2011
[14] V Kumar D K Boddeti S G Evans F Roesch and RHowman-Giles ldquoPotential use of 68Ga-apo-transferrin as a PETimaging agent for detecting Staphylococcus aureus infectionrdquoNuclear Medicine and Biology vol 38 no 3 pp 393ndash398 2011
[15] M Petrik H Haas G Dobrozemsky et al ldquo68Ga-siderophoresfor PET imaging of invasive pulmonary aspergillosis Proof ofprinciplerdquo Journal of Nuclear Medicine vol 51 no 4 pp 639ndash645 2010
[16] M Petrik H Haas M Schrettl A Helbok M Blatzer and CDecristoforo ldquoIn vitro and in vivo evaluation of selected 68Ga-siderophores for infection imagingrdquo Nuclear Medicine andBiology vol 39 no 3 pp 361ndash369 2012
[17] M Petrik GM Franssen H Haas et al ldquoPreclinical evaluationof two 68Ga-siderophores as potential radiopharmaceuticals forAspergillus fumigatus infection imagingrdquo European Journal ofNuclearMedicine andMolecular Imaging vol 39 no 7 pp 1175ndash1183 2012
[18] A Rizzello D Di Pierro F Lodi et al ldquoSynthesis and qualitycontrol of 68Ga citrate for routine clinical PETrdquo NuclearMedicine Communications vol 30 no 7 pp 542ndash545 2009
[19] C Nanni C Errani and L Boriani ldquo 68Ga-citrate PETCT forevaluating patients with infections of the bone preliminaryresultsrdquo Journal of Nuclear Medicine vol 51 no 12 pp 1932ndash1936 2010
[20] S S Das A V Hall D W Wareham and K E Britton ldquoInfec-tion imaging with radiopharmaceuticals in the 21st centuryrdquoBrazilian Archives of Biology and Technology vol 45 no spepp 25ndash37 2002
[21] A Signore and A W J M Glaudemans ldquoThe molecularimaging approach to image infections and inflammation bynuclear medicine techniquesrdquo Annals of Nuclear Medicine vol25 no 10 pp 681ndash700 2011
[22] T Yusa K Tateda A Ohara and S Miyazaki ldquoNew possiblebiomarkers for diagnosis of infections and diagnostic distinc-tion between bacterial and viral infections in childrenrdquo Journalof Infection and Chemotherapy vol 23 no 2 pp 96ndash100 2017
[23] A Signore A W J M Glaudemans O Gheysens C Lauriand O A Catalano ldquoNuclear Medicine Imaging in PediatricInfection or Chronic Inflammatory Diseasesrdquo Seminars inNuclear Medicine vol 47 no 3 pp 286ndash303 2017
[24] I Velikyan ldquoMolecular imaging and radiotherapyTheranosticsfor personalized patient managementrdquo Theranostics vol 2 no5 pp 424ndash426 2012
[25] F Rosch and R P Baum ldquoGenerator-based PET radiophar-maceuticals for molecular imaging of tumours On the way
to THERANOSTICSrdquo Dalton Transactions vol 40 no 23 pp6104ndash6111 2011
[26] R P Baum H R Kulkarni and C Carreras ldquoPeptides andreceptors in image-guided therapy Theranostics for neuroen-docrine neoplasmsrdquo Seminars in Nuclear Medicine vol 42 no3 pp 190ndash207 2012
[27] R P Baum and H R Kulkarni ldquoTheranostics From molecularimaging using Ga-68 labeled tracers and PETCT to per-sonalized radionuclide therapy - the bad berka experiencerdquoTheranostics vol 2 no 5 pp 437ndash447 2012
[28] I Velikyan ldquoRadionuclides for Imaging andTherapy in Oncol-ogyrdquo Cancer Theranostics pp 285ndash325 2014
[29] J Czernin andWAWeber ldquoIssues and controversies in nuclearmedicine Introductionrdquo Journal of Nuclear Medicine vol 52no Supplement 2 pp 1Sndash2S 2011
[30] S J Goldsmith and S Vallabhajosula ldquoClinically proven radio-pharmaceuticals for infection imaging mechanisms and appli-cationsrdquo Seminars in Nuclear Medicine vol 39 no 1 pp 2ndash102009
[31] M F Tsan ldquoMechanism of gallium-67 accumulation in inflam-matory lesionsrdquo Journal of Nuclear Medicine vol 26 no 1 pp88ndash92 1985
[32] S L Kipper ldquoRadiolabelled leukocyte imaging of the abdomenrdquoin Nuclear Medicine Annual J Freeman Ed pp 81ndash126 RavenPress New York NY USA 1995
[33] F Jamar J Buscombe A Chiti et al ldquoEANMSNMMI guidelinefor 18F-FDG use in inflammation and infectionrdquo Journal ofNuclear Medicine vol 54 no 4 pp 647ndash658 2013
[34] C J Palestro ldquoThe current role of gallium imaging in infectionrdquoSeminars in Nuclear Medicine vol 24 no 2 pp 128ndash141 1994
[35] M S Akhtar M B Imran M A Nadeem and A ShahidldquoAntimicrobial peptides as infection imaging agents better thanradiolabeled antibioticsrdquo International Journal of Peptides vol2012 Article ID 965238 19 pages 2012
[36] D Delbeke and G M Segall ldquoStatus of and trends in nuclearmedicine in the United Statesrdquo Journal of Nuclear Medicine vol52 no 2 2011
[37] S S Gambhir J Czernin J Schwimmer D H Silverman R EColeman and M E Phelps ldquoA tabulated summary of the FDGPET literaturerdquo Journal of Nuclear Medicine vol 42 pp 1Sndash93S2001
[38] M J Lindsay B A Siegel S R Tunis et al ldquoThe NationalOncologic PET Registry ExpandedMedicare coverage for PETunder coverage with evidence developmentrdquo American Journalof Roentgenology vol 188 no 4 pp 1109ndash1113 2007
[39] F Gemmel H Van Den Wyngaert C Love M M Welling PGemmel and C J Palestro ldquoProsthetic joint infectionsradionuclide state-of-the-art imagingrdquo European Journal ofNuclearMedicine andMolecular Imaging vol 39 no 5 pp 892ndash909 2012
[40] J Sorensen ldquoHow does the patient benefit from clinical PETrdquoTheranostics vol 2 no 5 pp 427ndash436 2012
[41] S L Rice C A Roney P Daumar and J S Lewis ldquoThe nextgeneration of positron emission tomography radiopharmaceu-ticals in oncologyrdquo Seminars in Nuclear Medicine vol 41 no 4pp 265ndash282 2011
[42] R LWahl JMHerman and E Ford ldquoThePromise and Pitfallsof Positron Emission Tomography and Single-Photon EmissionComputed Tomography Molecular Imaging-Guided RadiationTherapyrdquo Seminars in Radiation Oncology vol 21 no 2 pp 88ndash100 2011
Contrast Media amp Molecular Imaging 17
[43] A W J M Glaudemans R H J A Slart J M Van Dijl MVan Oosten and G M Van Dam ldquoMolecular imaging of infec-tious and inflammatory diseases A terra incognitardquo Journal ofNuclear Medicine vol 56 no 5 pp 659ndash661 2015
[44] X Li W Bauer I Israel et al ldquoTargeting p-selectin by gallium-68-labeled fucoidan positron emission tomography for nonin-vasive characterization of vulnerable plaques Correlation within vivo 176t mrirdquo Arteriosclerosis Thrombosis and VascularBiology vol 34 no 8 pp 1661ndash1667 2014
[45] S Eichendorff P Svendsen D Bender et al ldquoBiodistributionand PET Imaging of a Novel [68Ga]-Anti-CD163-AntibodyConjugate in Rats with Collagen-Induced Arthritis and inControlsrdquoMolecular Imaging and Biology vol 17 no 1 pp 87ndash93 2014
[46] Z Zhu Y Yin K Zheng et al ldquoEvaluation of synovial angiogen-esis in patients with rheumatoid arthritis using 68Ga-PRGD2PETCT A prospective proof-of-concept cohort studyrdquo Annalsof the Rheumatic Diseases vol 73 no 6 pp 1269ndash1272 2014
[47] J S Eo J C Paeng S Lee et al ldquoAngiogenesis imaging inmyocardial infarction using 68Ga-NOTA- RGD PET Charac-terization and application to therapeutic efficacy monitoring inratsrdquo Coronary Artery Disease vol 24 no 4 pp 303ndash311 2013
[48] J H Kim Y-H Kim Y J Kim et al ldquoQuantitative positronemission tomography imaging of angiogenesis in rats with fore-limb ischemia using 68Ga-NOTA-c(RGDyK)rdquo Angiogenesisvol 16 no 4 pp 837ndash846 2013
[49] I Laitinen J Notni K Pohle et al ldquoComparison of cyclicRGD peptides for 120572v1205733 integrin detection in a rat model ofmyocardial infarctionrdquo EJNMMI Research vol 3 no 1 pp 1ndash9 2013
[50] M Kiugel I Dijkgraaf V Kyto et al ldquoDimeric [68Ga]DOTA-RGD Peptide Targeting 120572 ltinfgtvltinfgt 120573 ltinfgt3ltinfgt Inte-grin Reveals Extracellular Matrix Alterations after MyocardialInfarctionrdquo Molecular Imaging and Biology vol 16 no 6 pp793ndash801 2014
[51] M Gronman M Tarkia T Kiviniemi et al ldquoImaging of 120572v1205733integrin expression in experimental myocardial ischemia with[68Ga]NODAGA-RGD positron emission tomographyrdquo Jour-nal of Translational Medicine vol 15 no 1 p 144 2017
[52] J Haukkala I Laitinen P Luoto et al ldquo68Ga-DOTA-RGDpep-tide Biodistribution and binding into atherosclerotic plaquesin micerdquo European Journal of Nuclear Medicine and MolecularImaging vol 36 no 12 pp 2058ndash2067 2009
[53] H Virtanen A Autio R Siitonen et al ldquo68Ga-DOTA-Siglec-9- a new imaging tool to detect synovitisrdquo Arthritis Research ampTherapy vol 17 no 1 article no 308 2015
[54] J Retamal J Sorensen M Lubberink et al ldquoFeasibility of(68) Ga-labeled Siglec-9 peptide for the imaging of acutelung inflammation a pilot study in a porcine model of acuterespiratory distress syndromerdquoAm JNuclMedMol Imaging vol6 no 1 pp 18ndash31 2016
[55] J M U Silvola H Virtanen R Siitonen et al ldquoLeukocytetrafficking-associated vascular adhesion protein 1 is expressedand functionally active in atherosclerotic plaquesrdquo ScientificReports vol 6 Article ID 35089 2016
[56] H Ahtinen J Kulkova L Lindholm et al ldquo68Ga-DOTA-Siglec-9 PETCT imaging of peri-implant tissue responses andstaphylococcal infectionsrdquo EJNMMI Research vol 4 no 1article no 45 pp 1ndash11 2014
[57] A Autio S Jalkanen and A Roivainen ldquoNuclear imaging ofinflammation Homing-associated molecules as targetsrdquo EJN-MMI Research vol 3 no 1 pp 1ndash7 2013
[58] J TThackeray T Derlin AHaghikia et al ldquoMolecular Imagingof the Chemokine Receptor CXCR4 after Acute MyocardialInfarctionrdquo JACC Cardiovascular Imaging vol 8 no 12 pp1417ndash1426 2015
[59] J S Schmid A Schirbel A K Buck S Kropf H-J Westerand C Lapa ldquoPentixafor-Positron Emission TomographyComputed Tomography Detects Chemokine Receptor CXCR4Expression after Ischemic Strokerdquo Circulation CardiovascularImaging vol 9 no 9 Article ID e005217 2016
[60] J Zhou G Hao H Weng et al ldquoIn vivo evaluation ofmedical device-associated inflammation using a macrophage-specific positron emission tomography (PET) imaging proberdquoBioorganic amp Medicinal Chemistry Letters vol 23 no 7 pp2044ndash2047 2013
[61] S A Kularatne M-J Belanger X Meng et al ldquoComparativeanalysis of folate derived PET imaging agents with [ 18F]-2-fluoro-2-deoxy-d-glucose using a rodent inflammatory pawmodelrdquo Molecular Pharmaceutics vol 10 no 8 pp 3103ndash31112013
[62] V Ambrosini M Zompatori F De Luca et al ldquo68Ga-DOTANOCPETCTAllows Somatostatin Receptor Imaging inIdiopathic Pulmonary Fibrosis Preliminary Resultsrdquo Journal ofNuclear Medicine vol 51 no 12 pp 1950ndash1955 2010
[63] T Lincke J Singer R Kluge O Sabri and R Paschke ldquoRela-tive quantification of indium-111 pentetreotide and gallium-68DOTATOC uptake in the thyroid gland and association withthyroid pathologiesrdquoThyroid vol 19 no 4 pp 381ndash389 2009
[64] A Rominger T Saam E Vogl et al ldquoIn vivo imaging ofmacrophage activity in the coronary arteries using 68Ga-DOTATATE PETCT correlation with coronary calcium bur-den and risk factorsrdquo Journal of Nuclear Medicine vol 51 no 2pp 193ndash197 2010
[65] J M Tarkin F R Joshi N R Evans et al ldquoDetection ofAtherosclerotic Inflammation by 68Ga-DOTATATE PET Com-pared to [18F]FDG PET Imagingrdquo Journal of the AmericanCollege of Cardiology vol 69 no 14 pp 1774ndash1791 2017
[66] S-P Lee H-J Im S Kang et al ldquoNoninvasive imaging ofmyocardial inflammation in myocarditis using 68Ga-taggedmannosylated human serum albumin positron emissiontomographyrdquoTheranostics vol 7 no 2 pp 413ndash424 2017
[67] Z Zha J Song S R Choi et al ldquo68Ga-Bivalent PolypegylatedStyrylpyridine Conjugates for Imaging A120573 Plaques in CerebralAmyloid Angiopathyrdquo Bioconjugate Chemistry vol 27 no 5 pp1314ndash1323 2016
[68] H Watanabe M Ono S Iikuni et al ldquoA 68Ga complex basedon benzofuran scaffold for the detection of 120573-amyloid plaquesrdquoBioorganic amp Medicinal Chemistry Letters vol 24 no 20 pp4834ndash4837 2014
[69] D Cressier M Dhilly T T Cao Pham et al ldquoGallium-68 Com-plexes Conjugated to Pittsburgh Compound B Radiolabelingand Biological EvaluationrdquoMolecular Imaging and Biology vol18 no 3 pp 334ndash343 2016
[70] D Satpati CArjun R KrishnamohanG Samuel and S Baner-jee ldquo68Ga-labeledCiprofloxacinConjugates as Radiotracers forTargeting Bacterial InfectionrdquoChemical Biology ampDrug Designvol 87 no 5 pp 680ndash686 2016
[71] T Ebenhan N Chadwick and M M Sathekge ldquoPeptidesynthesis characterization and 68Ga-radiolabeling of NOTA-conjugated ubiquicidin fragments for prospective infectionimaging with PETCTrdquo Nuclear Medicine and Biology vol 41no 5 pp 390ndash400 2014
18 Contrast Media amp Molecular Imaging
[72] T Ebenhan J R Zeevaart and J D Venter ldquoPreclinicalevaluation of 68Ga-labeled 1 4 7-triazacyclononane-1 4 7-triacetic acid-ubiquicidin as a radioligand for PET infectionimagingrdquo Journal of Nuclear Medicine vol 55 no 2 pp 308ndash314 2014
[73] B B Mokaleng T Ebenhan S Ramesh et al ldquoSynthesis 68Ga-radiolabeling and preliminary in vivo assessment of adepsipeptide-derived compound as a potential PETCTinfection imaging agentrdquo BioMed Research International vol2015 Article ID 284354 2015
[74] T Ebenhan B Mokaleng J Venter H Kruger J Zeevaart andM Sathekge ldquoPreclinical Assessment of a 68Ga-DOTA-Functionalized Depsipeptide as a Radiodiagnostic InfectionImaging AgentrdquoMolecules vol 22 no 9 p 1403 2017
[75] S Chopra B Singh A Koul A Mishra and H Wester ldquoSyn-thesis of DOTA conjugated GF-17 and RAWVAWR-NH2 andradiolabeling with 68Ga as a potential PET tracer for infectionimagingrdquo J Nucl Med vol 57 Supplement 2 p 1115 2016
[76] M Petrik HHaas P Laverman et al ldquo 68Ga-triacetylfusarinineC and 68Ga-ferrioxamine e for aspergillus infection imaginguptake specificity in various microorganismsrdquoMolecular Imag-ing and Biology vol 16 no 1 pp 102ndash108 2014
[77] V Kumar and D K Boddeti ldquo 68Ga-radiopharmaceuticals forPET imaging of infection and inflammationrdquo Recent Results inCancer Research vol 194 pp 189ndash219 2013
[78] M Vorster A Maes A Jacobs et al ldquoEvaluating the possiblerole of 68Ga-citrate PETCT in the characterization of indeter-minate lung lesionsrdquo Annals of Nuclear Medicine vol 28 no 6pp 523ndash530 2014
[79] M Vorster B Mokaleng M M Sathekge and T Ebenhan ldquoAmodified technique for efficient radiolabeling of 68Ga-citratefrom a SnO2-based 68Ge68Ga generator for better infectionimagingrdquoHellenic Journal of Nuclear Medicine vol 16 no 3 pp193ndash198 2013
[80] S Salomaeki J Kemppainen U Hohenthal et al ldquoHead-to-head comparison of 68Ga-Citrate and 18F-FDG PETCT fordetection of infectious foci in patients with staphylococcusaureus bacteraemiardquo Contrast Media amp Molecular Imaging vol2017 p 8 2017
[81] L Fass ldquoImaging and cancer a reviewrdquoMolecular Oncology vol2 no 2 pp 115ndash152 2008
[82] A Chopra L Shan W C Eckelman et al ldquoMolecular imagingand contrast agent database (MICAD) Evolution and progressrdquoMolecular Imaging and Biology vol 14 no 1 pp 4ndash13 2012
[83] A Sanchez-Crespo P Andreo and S A Larsson ldquoPositronflight in human tissues and its influence on PET image spatialresolutionrdquo European Journal of Nuclear Medicine and Molecu-lar Imaging vol 31 no 1 pp 44ndash51 2004
[84] H W A M De Jong L Perk G W M Visser R Boellaard GAM S Van Dongen and A A Lammertsma ldquoHigh resolutionPET imaging characteristics of68Ga 124i and89Zr comparedto18Frdquo in Proceedings of the Nuclear Science Symposium Con-ference Record 2005 IEEE pp 1624ndash1627 Puerto Rico October2005
[85] I Velikyan A Sundin B Eriksson et al ldquoIn vivo bindingof [68Ga]-DOTATOC to somatostatin receptors in neuroen-docrine tumours - impact of peptide massrdquo Nuclear Medicineand Biology vol 37 no 3 pp 265ndash275 2010
[86] U Eberlein and M Lassmann ldquoDosimetry of [68Ga]-labeledcompoundsrdquo Applied Radiation and Isotopes vol 76 pp 70ndash742013
[87] C PettinatoA SarnelliMDiDonna et al ldquo68Ga-DOTANOCBiodistribution and dosimetry in patients affected by neuroen-docrine tumorsrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 35 no 1 pp 72ndash79 2008
[88] B P Burke G S Clemente and S J Archibald ldquoRecentadvances in chelator design and labelling methodology for68Ga radiopharmaceuticalsrdquo Journal of Labelled Compoundsand Radiopharmaceuticals vol 57 no 4 pp 239ndash243 2014
[89] I Velikyan U Rosenstrom S Estrada et al ldquoSynthesis andpreclinical evaluation of 68Ga-labeled collagelin analogs forimaging and quantification of fibrosisrdquo Nuclear Medicine andBiology vol 41 no 9 pp 728ndash736 2014
[90] M F Ferreira G Pereira J P Andre and etal C ldquoGa[NO2A-N-(120572-amino)propionate] chelates Synthesis and evaluation aspotential tracers for 68Ga PETrdquoDalton Transactions vol 43 no21 pp 8037ndash8047 2014
[91] J Notni J Simecek and H-J Wester ldquoPhosphinic acid func-tionalized polyazacycloalkane chelators for radiodiagnosticsand radiotherapeutics Unique characteristics and applicationsrdquoChemMedChem vol 9 no 6 pp 1107ndash1115 2014
[92] J Simecek O Zemek P Hermann J Notni and H J WesterldquoTailored gallium( III) chelator NOPO synthesis characteriza-tion bioconjugation and application in preclinical Ga-68-PETimagingrdquoMolecular Pharmaceutics 2013
[93] D Parker B P Waldron and D S Yufit ldquoCrystallographicand solution NMR structural analyses of four hexacoordinatedgallium(iii) complexes based on ligands derived from 6-amino-perhydro-14-diazepinerdquo Dalton Transactions vol 42 no 22pp 8001ndash8008 2013
[94] B P Waldron D Parker C Burchardt D S Yufit M ZimnyandF Roesch ldquoStructure and stability of hexadentate complexesof ligands based on AAZTA for efficient PET labelling withgallium-68rdquo Chemical Communications vol 49 no 6 pp 579ndash581 2013
[95] D Parker and B PWaldron ldquoConformational analysis and syn-thetic approaches to polydentate perhydro-diazepine ligandsfor the complexation of gallium(iii)rdquo Organic amp BiomolecularChemistry vol 11 no 17 pp 2827ndash2838 2013
[96] I Velikyan H Maecke and B Langstrom ldquoConvenient prepa-ration of 68Ga-based PET-radiopharmaceuticals at room tem-peraturerdquo Bioconjugate Chemistry vol 19 no 2 pp 569ndash5732008
[97] J Erchegyi R Cescato B Waser J E Rivier and J C ReubildquoN-Imidazolebenzyl-histidine substitution in somatostatin andin its octapeptide analogue modulates receptor selectivity andfunctionrdquo Journal of Medicinal Chemistry vol 54 no 17 pp5981ndash5987 2011
[98] R Saha N Saha R S Donofrio and L L Bestervelt ldquoMicrobialsiderophores Amini reviewrdquo Journal of Basic Microbiology vol53 no 4 pp 303ndash317 2013
[99] V Nikolova S Angelova N Markova and T Dudev ldquoGalliumas a Therapeutic Agent A Thermodynamic Evaluation of theCompetition between Ga3+ and Fe3+ Ions in MetalloproteinsrdquoThe Journal of Physical Chemistry B vol 120 no 9 pp 2241ndash2248 2016
[100] C R Chitambar ldquoGallium and its competing roles with ironin biological systemsrdquo Biochimica et Biophysica Acta (BBA) -Molecular Cell Research vol 1863 no 8 pp 2044ndash2053 2016
[101] J A Lessa M A Soares and R G dos Santos ldquoGallium(III)complexes with 2-acetylpyridine-derived thiosemicarbazonesantimicrobial and cytotoxic effects and investigation on theinteractions with tubulinrdquo BioMetals vol 26 pp 151ndash165 2013
Contrast Media amp Molecular Imaging 19
[102] M van Oosten M Hahn L M A Crane et al ldquoTargetedimaging of bacterial infections Advances hurdles and hopesrdquoFEMS Microbiology Reviews vol 39 no 6 pp 892ndash916 2015
[103] M Vorster AMaes C V DWiele andM Sathekge ldquoGallium-68 PET A Powerful Generator-based Alternative to Infectionand Inflammation Imagingrdquo Seminars in Nuclear Medicine vol46 no 5 pp 436ndash447 2016
[104] M Kircher and C Lapa ldquoNovel Noninvasive Nuclear MedicineImaging Techniques for Cardiac Inflammationrdquo Current Car-diovascular Imaging Reports vol 10 no 2 article no 6 2017
[105] D AHammoud ldquoMolecular imaging of inflammation Currentstatusrdquo Journal of Nuclear Medicine vol 57 no 8 pp 1161ndash11652016
[106] D R Brenner D Scherer K Muir et al ldquoA review of the appli-cation of inflammatory biomarkers in epidemiologic cancerresearchrdquo Cancer Epidemiology Biomarkers amp Prevention vol23 no 9 pp 1729ndash1751 2014
[107] M D Turner B Nedjai T Hurst and D J PenningtonldquoCytokines and chemokines at the crossroads of cell signallingand inflammatory diseaserdquo Biochimica et Biophysica Acta (BBA)- Molecular Cell Research vol 1843 no 11 pp 2563ndash2582 2014
[108] L Werner H Guzner-Gur and I Dotan ldquoInvolvement ofCXCR4CXCR7CXCL12 interactions in inflammatory boweldiseaserdquoTheranostics vol 3 no 1 pp 40ndash46 2013
[109] S Jalkanen and M Salmi ldquoVAP-1 and CD73 endothelial cellsurface enzymes in leukocyte extravasationrdquo ArteriosclerosisThrombosis and Vascular Biology vol 28 no 1 pp 18ndash26 2008
[110] G Malviya F Galli I Sonni and A Signore ldquoImaging T-lymphocytes in inflammatory diseases A nuclear medicineapproachrdquo The Quarterly Journal of Nuclear Medicine andMolecular Imaging vol 58 no 3 pp 237ndash257 2014
[111] S Gratz H J RennenO C BoermanW J Oyen and P Burmaldquo(99m)Tc-interleukin-8 for imaging acute osteomyelitisrdquo Jour-nal of Nuclear Medicine vol 42 no 8 pp 1257ndash1264 2001
[112] S Gratz H J Rennen O C Boerman W J Oyen andF H Corstens ldquoRapid imaging of experimental colitis with(99m)Tc-interleukin-8 in rabbitsrdquo Journal of Nuclear Medicnevol 42 no 6 pp 917ndash923 2001
[113] C Alkim H Alkim A R Koksal S Boga and I SenldquoAngiogenesis in inflammatory bowel diseaserdquo InternationalJournal of Inflammation vol 2015 Article ID 970890 2015
[114] I S Alam T H Witney G Tomasi et al ldquoRadiolabeled RGDtracer kinetics annotates differential 120572v1205733 integrin expressionlinked to cell intrinsic and vessel expressionrdquoMolecular Imagingand Biology vol 16 no 4 pp 558ndash566 2014
[115] J Notni K Pohle and H-J Wester ldquoBe spoilt for choice withradiolabelled RGD peptides Preclinical evaluation of 68Ga-TRAP(RGD)3rdquoNuclear Medicine and Biology vol 40 no 1 pp33ndash41 2013
[116] J Oxboel M Brandt-Larsen C Schjoeth-Eskesen et al ldquoCom-parison of two new angiogenesis PET tracers 68Ga-NODAGA-E[c(RGDyK)]2 and 64Cu-NODAGA-E[c(RGDyK)]2 in vivoimaging studies in human xenograft tumorsrdquo Nuclear Medicineand Biology vol 41 no 3 pp 259ndash267 2014
[117] J Simecek J Notni T G Kapp H Kessler and H-J WesterldquoBenefits of NOPO as chelator in gallium-68 peptides exempli-fied by preclinical characterization of 68Ga-NOPO-c(RGDfK)rdquoMolecular Pharmaceutics vol 11 no 5 pp 1687ndash1695 2014
[118] M Trajkovic-Arsic P Mohajerani A Sarantopoulos et alldquoMultimodal molecular imaging of integrin avb3 for in vivodetection of pancreatic cancerrdquo Journal of NuclearMedicine vol55 no 3 pp 446ndash451 2014
[119] H Cai and P S Conti ldquoRGD-based PET tracers for imagingreceptor integrin 120572 v1205733 expressionrdquo Journal of Labelled Com-pounds and Radiopharmaceuticals vol 56 no 5 pp 264ndash2792013
[120] I Dijkgraaf S Y A Terry W J Mcbride et al ldquoImagingintegrin alpha-v-beta-3 expression in tumors with an 18F-labeled dimeric RGD peptiderdquo Contrast Media amp MolecularImaging vol 8 no 3 pp 238ndash245 2013
[121] P A Knetsch M Petrik C Rangger et al ldquo[68Ga]NS3-RGD and [68Ga] Oxo-DO3A-RGD for imaging 120572v1205733 integrinexpression Synthesis evaluation and comparisonrdquo NuclearMedicine and Biology vol 40 no 1 pp 65ndash72 2013
[122] Z Liu and F Wang ldquoDevelopment of RGD-based radiotracersfor tumor imaging and therapy Translating from bench tobedsiderdquo Current Molecular Medicine vol 13 no 10 pp 1487ndash1505 2013
[123] H Choi J H Phi J C Paeng et al ldquoImaging of integrin 120572v1205733expression using 68Ga-RGD positron emission tomography inpediatric cerebral infarctrdquoMolecular Imaging vol 12 no 4 pp213ndash217 2013
[124] H-J Yoon K W Kang I K Chun et al ldquoCorrelation of breastcancer subtypes based on estrogen receptor progesteronereceptor and HER2 with functional imaging parameters from68Ga-RGD PETCT and 18F-FDG PETCTrdquo European Journalof Nuclear Medicine and Molecular Imaging vol 41 no 8 pp1534ndash1543 2014
[125] R P Baum H R Kulkarni D Muller et al ldquoFirst-in-human study demonstrating tumor-angiogenesis by PETCTimaging with 68Ga-NODAGA-THERANOST a high-affinitypeptidomimetic for 120572v1205733 integrin receptor targetingrdquo CancerBiotherapy andRadiopharmaceuticals vol 30 no 4 pp 152ndash1592015
[126] R Haubner A Finkenstedt A Stegmayr et alldquo[68Ga]NODAGA-RGD ndash Metabolic stability biodistributionand dosimetry data from patients with hepatocellularcarcinoma and liver cirrhosisrdquo European Journal of NuclearMedicine and Molecular Imaging vol 43 no 11 pp 2005ndash20132016
[127] V Lopez-Rodrıguez C Galindo-Sarco F O Garcıa-Perez GFerro-Flores O Arrieta and M A Avila-Rodrıguez ldquoPET-based human dosimetry of the dimeric 120572v1205733 integrin ligand68Ga-DOTA-E-[c(RGDfK)]2 a potential tracer for imagingtumor angiogenesisrdquo Journal of Nuclear Medicine vol 57 no 3pp 404ndash409 2016
[128] M V Backer Z Levashova V Patel et al ldquoMolecular imagingof VEGF receptors in angiogenic vasculature with single-chainVEGF-based probesrdquo Nature Medicine vol 13 no 4 pp 504ndash509 2007
[129] MV Backer Z Levashova R Levenson F G Blankenberg andJ M Backer ldquoCysteine-containing fusion tag for site-specificconjugation of therapeutic and imaging agents to targetingproteinsrdquoMethods in Molecular Biology (Clifton NJ) vol 494pp 275ndash294 2008
[130] M Eder A V Krivoshein M Backer J M Backer UHaberkorn and M Eisenhut ldquoScVEGF-PEG-HBED-CC andscVEGF-PEG-NOTA conjugates comparison of easy-to-labelrecombinant proteins for [68Ga]PET imaging of VEGF recep-tors in angiogenic vasculaturerdquo Nuclear Medicine and Biologyvol 37 no 4 pp 405ndash412 2010
[131] E Blom I Velikyan A Monazzam P Razifar et al ldquoSynthe-sis and characterization of scVEGF-PEG-[ 68Ga]NOTA andscVEGF-PEG-[ 68Ga]DOTA PET tracersrdquo Journal of Labelled
20 Contrast Media amp Molecular Imaging
Compounds and Radiopharmaceuticals vol 54 no 11 pp 685ndash692 2011
[132] S Gratz M Behe and O C Boerman ldquo 99119898Tc-E-selectinbinding peptide for imaging acute osteomyelitis in a novel ratmodelrdquo Nuclear Medicine Communications vol 22 no 9 pp1003ndash1013 2001
[133] S B Jensen M Kakela L Joslashdal et al ldquoExploring the radiosyn-thesis and in vitro characteristics of [68Ga]Ga-DOTA-Siglec-9rdquoJournal of Labelled Compounds and Radiopharmaceuticals vol60 no 9 pp 439ndash449 2017
[134] B A Teicher and S P Fricker ldquoCXCL12 (SDF-1)CXCR4pathway in cancerrdquo Clinical Cancer Research vol 16 no 11 pp2927ndash2931 2010
[135] O Jacobson I D Weiss D O Kiesewetter J M Farber andX Chen ldquoPET of tumor CXCR4 expression with 4-18F-T140rdquoJournal of Nuclear Medicine vol 51 no 11 pp 1796ndash1804 2010
[136] A Aghanejad A R Jalilian Y Fazaeli et al ldquoSynthesis andevaluation of [67Ga]-AMD3100 A novel imaging agent fortargeting the chemokine receptorCXCR4rdquo Scientia Pharmaceu-tica vol 82 no 1 pp 29ndash42 2014
[137] O Jacobson I D Weiss L P Szajek et al ldquoPET imaging ofCXCR4 using copper-64 labeled peptide antagonistrdquoTheranos-tics vol 1 pp 251ndash262 2011
[138] O Jacobson I D Weiss L P Szajek et al ldquoImprovement ofCXCR4 tracer specificity for PET imagingrdquo Journal of Con-trolled Release vol 157 no 2 pp 216ndash223 2012
[139] H J Wester U Keller M Schottelius et al ldquoDisclosing theCXCR4 expression in lymphoproliferative diseases by targetedmolecular imagingrdquo Theranostics vol 5 no 6 pp 618ndash6302015
[140] E Gourni O Demmer M Schottelius et al ldquoPET of CXCR4expression by a 68Ga-labeled highly specific targeted contrastagentrdquo Journal of NuclearMedicine vol 52 no 11 pp 1803ndash18102011
[141] O Demmer I Dijkgraaf U Schumacher et al ldquoDesignsynthesis and functionalization of dimeric peptides targetingchemokine receptor CXCR4rdquo Journal of Medicinal Chemistryvol 54 no 21 pp 7648ndash7662 2011
[142] O Demmer E Gourni U Schumacher H Kessler and H-JWester ldquoPET Imaging of CXCR4 Receptors in Cancer by a NewOptimized Ligandrdquo ChemMedChem vol 6 no 10 pp 1789ndash1791 2011
[143] U Hennrich L Seyler M Schafer et al ldquoSynthesis and invitro evaluation of 68Ga-DOTA-4-FBn-TN14003 a novel tracerfor the imaging of CXCR4 expressionrdquo Bioorganic amp MedicinalChemistry vol 20 no 4 pp 1502ndash1510 2012
[144] G P C George E Stevens O Aberg et al ldquoPreclinical evalua-tion of a CXCR4-specific 68Ga-labelled TN14003 derivative forcancer PET imagingrdquo Bioorganic amp Medicinal Chemistry vol22 no 2 pp 796ndash803 2014
[145] S Poty E Gourni P Desogere et al ldquoAMD3100 A VersatilePlatform for CXCR4 Targeting 68Ga-Based Radiopharmaceu-ticalsrdquo Bioconjugate Chemistry vol 27 no 3 pp 752ndash761 2016
[146] K Philipp-Abbrederis K Herrmann S Knop et al ldquoIn vivomolecular imaging of chemokine receptor CXCR4 expressionin patients with advancedmultiple myelomardquo EMBOMolecularMedicine vol 7 no 4 pp 477ndash487 2015
[147] Z Wang M Zhang L Wang et al ldquoProspective study of 68Ga-NOTA-NFB Radiation dosimetry in healthy volunteers andfirst application in glioma patientsrdquo Theranostics vol 5 no 8pp 882ndash889 2015
[148] I M Jackson P J Scott and S Thompson ldquoClinical Applica-tions of Radiolabeled Peptides for PETrdquo Seminars in NuclearMedicine vol 47 no 5 pp 493ndash523 2017
[149] C Lapa T Reiter R A Werner et al ldquo[68Ga]Pentixafor-PETCT for Imaging of Chemokine Receptor 4 Expression afterMyocardial Infarctionrdquo JACC Cardiovascular Imaging vol 8no 12 pp 1466ndash1468 2015
[150] C Rischpler S G Nekolla H Kossmann et al ldquoUpregu-lated myocardial CXCR4-expression after myocardial infarc-tion assessed by simultaneous GA-68 pentixafor PETMRIrdquoJournal of Nuclear Cardiology vol 23 no 1 pp 131ndash133 2016
[151] F Hyafil J Pelisek I Laitinen et al ldquoImaging the CytokineReceptorCXCR4 in atherosclerotic plaqueswith the radiotracer68Ga-Pentixafor for PETrdquo Journal of Nuclear Medicine vol 58no 3 pp 499ndash506 2017
[152] Y Yi ldquoFolate receptor-targeted diagnostics and therapeutics forinflammatory diseasesrdquo ImmuneNetwork vol 16 no 6 pp 337ndash343 2016
[153] C M Paulos M J Turk G J Breur and P S Low ldquoFolatereceptor-mediated targeting of therapeutic and imaging agentsto activated macrophages in rheumatoid arthritisrdquo AdvancedDrug Delivery Reviews vol 56 no 8 pp 1205ndash1217 2004
[154] W Han R Zaynagetdinov F E Yull et al ldquoMolecular imagingof folate receptor 120573-positive macrophages during acute lunginflammationrdquo American Journal of Respiratory Cell and Molec-ular Biology vol 53 no 1 pp 50ndash59 2015
[155] B Kuhle C Muller and T L Ross ldquoA Novel 68Ga-Labeledpteroic acid-based PET tracer for tumor imaging via the folatereceptorrdquo Recent Results in Cancer Research vol 194 pp 257ndash267 2013
[156] C Brand V A Longo M Groaning W A Weber and TReiner ldquoDevelopment of a New Folate-Derived Ga-68-BasedPET Imaging AgentrdquoMolecular Imaging and Biology vol 19 no5 pp 754ndash761 2017
[157] M Fani XWang G Nicolas et al ldquoDevelopment of new folate-based PET radiotracers Preclinical evaluation of 68Ga-DOTA-folate conjugatesrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 38 no 1 pp 108ndash119 2011
[158] C J Mathias M R Lewis D E Reichert et al ldquoPreparationof 66Ga- and 68Ga-labeled Ga(III)-deferoxamine-folate aspotential folate-receptor-targeted PET radiopharmaceuticalsrdquoNuclear Medicine and Biology vol 30 no 7 pp 725ndash731 2003
[159] S-M Kim N Choi S Hwang et al ldquoFolate receptor-specific positron emission tomography imaging with folic acid-conjugated tissue inhibitor of metalloproteinase-2rdquo Bulletin ofthe Korean Chemical Society vol 34 no 11 pp 3243ndash3248 2013
[160] M Fani M-L Tamma G P Nicolas et al ldquoIn vivo imagingof folate receptor positive tumor xenografts using novel 68Ga-NODAGA-folate conjugatesrdquo Molecular Pharmaceutics vol 9no 5 pp 1136ndash1145 2012
[161] C Muller and R Schibli ldquoProspects in folate receptor-targetedradionuclide therapyrdquo Frontiers in Oncology vol 3 Article IDArticle 249 2013
[162] A Jain A Mathur U Pandey et al ldquoSynthesis and evaluationof a 68Ga labeled folic acid derivative for targeting folatereceptorsrdquo Applied Radiation and Isotopes vol 116 pp 77ndash842016
[163] W Xia A R Hilgenbrink E L Matteson M B Lockwood J-X Cheng and P S Low ldquoA functional folate receptor is inducedduring macrophage activation and can be used to target drugsto activated macrophagesrdquo Blood vol 113 no 2 pp 438ndash4462009
Contrast Media amp Molecular Imaging 21
[164] E P Krenning W A P Breeman P P M Kooij et alldquoLocalisation of endocrine-related tumours with radioiodi-nated analogue of somatostatinrdquoThe Lancet vol 1 no 8632 pp242ndash244 1989
[165] E P Krenning D J KwekkeboomWH Bakker et al ldquoSomato-statin receptor scintigraphy with [111In-DTPA-d-Phe1]- and[123I-Tyr3]-octreotide the Rotterdam experience with morethan 1000 patientsrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 20 no 8 pp 716ndash731 1993
[166] A Stahl G Meisetschlager M Schottelius et al ldquo[123I]Mtr-TOCA a radioiodinated and carbohydrated analogue ofoctreotide Scintigraphic comparison with [111In]octreotiderdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 33 no 1 pp 45ndash52 2006
[167] R Lebtahi J le Cloirec C Houzard et al ldquoDetection of neu-roendocrine tumors 99mTc-P829 scintigraphy compared with111In-pentetreotide scintigraphyrdquo Journal of Nuclear Medicinevol 43 no 7 pp 889ndash895 2002
[168] C Decristoforo T Maina B Nock M Gabriel P Cordopatisand R Moncayo ldquo99mTc-demotate 1 First data in tumourpatients - Results of a pilotphase I studyrdquo European Journal ofNuclearMedicine andMolecular Imaging vol 30 no 9 pp 1211ndash1219 2003
[169] C Decristoforo S J Mather W Cholewinski E DonnemillerG Riccabona and R Moncayo ldquo(99m)Tc-EDDAHYNIC-TOC A new (99m)Tc-labelled radiopharmaceutical forimaging somatostatin receptor-positive tumours First clinicalresults and intra-patient comparison with 111In-labelledoctreotide derivativesrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 27 no 9 pp 1318ndash1325 2000
[170] A Hubalewska-Dydejczyk K Fross-Baron R Mikołajczak etal ldquo99mTc-EDDAHYNIC-octreotate scintigraphy an efficientmethod for the detection and staging of carcinoid tumoursResults of 3 yearsrsquo experiencerdquo European Journal of NuclearMedicine and Molecular Imaging vol 33 no 10 pp 1123ndash11332006
[171] M Bangard M Behe S Guhlke et al ldquoDetection of somato-statin receptor-positive tumours using the new 99mC-tricine-HYNIC-D-Phe1-Tyr3-octreotide First results in patients andcomparison with 111In-DTPA-D-Phe1-octreotiderdquo EuropeanJournal of Nuclear Medicine and Molecular Imaging vol 27 no6 pp 628ndash637 2000
[172] A Helisch G J Forster H Reber et al ldquoPre-therapeuticdosimetry and biodistribution of 86Y-DOTA- Phe1-Tyr3-octreotide versus 111In-pentetreotide in patients with advancedneuroendocrine tumoursrdquo European Journal of NuclearMedicine and Molecular Imaging vol 31 no 10 pp 1386ndash13922004
[173] M Henze J Schuhmacher P Hipp et al ldquoPET imaging ofsomatostatin receptors using [68GA]DOTA-D-Phe1-Tyr3-Octreotide First results in patients with meningiomasrdquo Journalof Nuclear Medicine vol 42 no 7 pp 1053ndash1056 2001
[174] I Kayani J B Bomanji A Groves et al ldquoFunctional imaging ofneuroendocrine tumors with combined PETCT using 68Ga-DOTATATE (Dota-DPhe1 Tyr3-octreotate) and 18F-FDGrdquoCancer vol 112 no 11 pp 2447ndash2455 2008
[175] A Al-Nahhas ldquoNuclear medicine imaging of neuroendocrinetumoursrdquo Clinical Medicine vol 12 no 4 pp 377ndash380 2012
[176] V Ambrosini S Nicolini P Caroli et al ldquoPETCT imaging indifferent types of lung cancer an overviewrdquo European Journal ofRadiology vol 81 no 5 pp 988ndash1001 2012
[177] V Ambrosini D Campana P Tomassetti and S Fanti ldquo68Ga-labelled peptides for diagnosis of gastroenteropancreatic NETrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 39 no 1 pp S52ndashS60 2012
[178] K E Oberg J-C Reubi D J Kwekkeboom and E P KrenningldquoRole of somatostatins in gastroenteropancreatic neuroen-docrine tumor development and therapyrdquoGastroenterology vol139 no 3 pp 753-753 2010
[179] K Oberg ldquoGallium-68 somatostatin receptor PETCT Is ittime to replace 111Indium DTPA octreotide for patients withneuroendocrine tumorsrdquo Endocrine Journal vol 42 no 1 pp3-4 2012
[180] R Srirajaskanthan I Kayani A M Quigley J Soh M ECaplin and J Bomanji ldquoThe role of 68Ga-DOTATATE PET inpatients with neuroendocrine tumors and negative or equivocalfindings on 111In-DTPA-octreotide scintigraphyrdquo Journal ofNuclear Medicine vol 51 no 6 pp 875ndash882 2010
[181] A Kroiss D Putzer and C Uprimny ldquoFunctional imag-ing in phaeochromocytoma and neuroblastoma with 68Ga-DOTA-Tyr3-octreotide positron emission tomography and123I-metaiodobenzylguanidinerdquo European Journal of NuclearMedicine and Molecular Imaging vol 38 no 5 pp 865ndash8732011
[182] M Naji C Zhao S J Welsh et al ldquo68Ga-DOTA-TATE PETvs 123I-MIBG in identifying malignant neural crest tumoursrdquoMolecular Imaging and Biology vol 13 no 4 pp 769ndash775 2011
[183] V Ambrosini P Tomassetti P Castellucci et al ldquoComparisonbetween 68Ga-DOTA-NOC and 18F-DOPA PET for the detec-tion of gastro-entero-pancreatic and lung neuro-endocrinetumoursrdquo European Journal of Nuclear Medicine and MolecularImaging vol 35 no 8 pp 1431ndash1438 2008
[184] D Putzer M Gabriel B Henninger et al ldquoBone metastasesin patients with neuroendocrine tumor 68Ga- DOTA-Tyr3-octreotide PET in comparison to CT and bone scintigraphyrdquoJournal of Nuclear Medicine vol 50 no 8 pp 1214ndash1221 2009
[185] L K Anzola-Fuentes M Chianelli F Galli et al ldquoSomatostatinreceptor scintigraphy in patients with rheumatoid arthritis andsecondary Sjogrenrsquos syndrome treated with Infliximab a pilotstudyrdquo EJNMMI Research vol 6 no 1 article no 49 2016
[186] T Nobashi Y Nakamoto T Kubo et al ldquoThe utility of PETCTwith 68Ga-DOTATOC in sarcoidosis comparison with 67Ga-scintigraphyrdquoAnnals ofNuclearMedicine vol 30 no 8 pp 544ndash552 2016
[187] C Boy T A Heusner T D Poeppel et al ldquo68Ga-DOTATOCPETCT and somatostatin receptor (sst1-sst5) expression innormal human tissue Correlation of sst2mRNAand SUVmaxrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 38 no 7 pp 1224ndash1236 2011
[188] P Rinne S Hellberg M Kiugel et al ldquoComparison of Somato-statin Receptor 2-Targeting PET Tracers in the Detection ofMouse Atherosclerotic Plaquesrdquo Molecular Imaging and Biol-ogy vol 18 no 1 pp 99ndash108 2016
[189] M Asti E Ferrari S Croci et al ldquoSynthesis and characteri-zation of 68Ga-labeled curcumin and curcuminoid complexesas potential radiotracers for imaging of cancer and alzheimersdiseaserdquo Inorganic Chemistry vol 53 no 10 pp 4922ndash49332014
[190] A Signore I Santino and A W J M Glaudemans ldquoIn vivoimaging of microorganismsrdquo Clinical and Translational Imag-ing vol 4 no 3 pp 161-162 2016
[191] S Auletta F Galli C Lauri D Martinelli I Santino andA Signore ldquoImaging bacteria with radiolabelled quinolones
22 Contrast Media amp Molecular Imaging
cephalosporins and siderophores for imaging infection a sys-tematic reviewrdquo Clinical and Translational Imaging vol 4 no 4pp 229ndash252 2016
[192] X Ning S Lee Z Wang et al ldquoMaltodextrin-based imagingprobes detect bacteria in vivo with high sensitivity and speci-ficityrdquo Nature Materials vol 10 no 8 pp 602ndash607 2011
[193] J Ady andY Fong ldquoImaging for infection Fromvisualization ofinflammation to visualization of microbesrdquo Surgical Infectionsvol 15 no 6 pp 700ndash707 2014
[194] J M Sierra D Rodriguez-Puig A Soriano J Mensa C Pieraand J Vila ldquoAccumulation of 99mTc-ciprofloxacin in Staphy-lococcus aureus and Pseudomonas aeruginosardquo AntimicrobialAgents and Chemotherapy vol 52 no 7 pp 2691-2692 2008
[195] D I Andersson and D Hughes ldquoMicrobiological effects ofsublethal levels of antibioticsrdquoNature ReviewsMicrobiology vol12 no 7 pp 465ndash478 2014
[196] N Dumarey D Blocklet T Appelboom L Tant and ASchoutens ldquoInfecton is not specific for bacterial osteo-articularinfective pathologyrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 29 no 4 pp 530ndash535 2002
[197] K E Britton D W Wareham S S Das et al ldquoImaging bacte-rial infection with 99mTc-ciprofloxacin (Infecton)rdquo Journal ofClinical Pathology vol 55 no 11 pp 817ndash823 2002
[198] G Ferro-Flores M A Avila-Rodrıguez and F O Garcıa-PerezldquoImaging of bacteria with radiolabeled ubiquicidin by SPECTand PET techniquesrdquo Clinical and Translational Imaging vol 4no 3 pp 175ndash182 2016
[199] P S Hiemstra M T van den Barselaar M Roest P H Nibber-ing and R van Furth ldquoUbiquicidin a novel murine microbi-cidal protein present in the cytosolic fraction of macrophagesrdquoJournal of Leukocyte Biology vol 66 no 3 pp 423ndash428 1999
[200] M S Akhtar A Qaisar J Irfanullah et al ldquoAntimicrobialpeptide 99mTc-ubiquicidin 29ndash41 as human infection-imagingagent clinical trialrdquo Journal of Nuclear Medicne vol 46 no 4pp 567ndash573 2005
[201] M Assadi K Vahdat I Nabipour et al ldquoDiagnostic value of99mTc-ubiquicidin scintigraphy for osteomyelitis and compar-isons with 99mTc-methylene diphosphonate scintigraphy andmagnetic resonance imagingrdquo Nuclear Medicine Communica-tions vol 32 no 8 pp 716ndash723 2011
[202] T Emery ldquoExchange of Iron by Gallium in SiderophoresrdquoBiochemistry vol 25 no 16 pp 4629ndash4633 1986
[203] M Petrik C Zhai H Haas and C Decristoforo ldquoSiderophoresfor molecular imaging applicationsrdquo Clinical and TranslationalImaging vol 5 no 1 pp 15ndash27 2017
[204] H J Flint E A BayerM T Rincon R Lamed and B AWhiteldquoPolysaccharide utilization by gut bacteria potential for newinsights from genomic analysisrdquo Nature Reviews Microbiologyvol 6 no 2 pp 121ndash131 2008
[205] GGowrishankarMNamavari E B Jouannot et al ldquoInvestiga-tion of 6-[18F]-fluoromaltose as a novel PET tracer for imagingbacterial infectionrdquo PLoS ONE vol 9 no 9 Article ID e1079512014
[206] N Gholipour M Akhlaghi A M Kheirabadi et al ldquoChelator-free radiolabeling of dextran with 68Ga for PET studiesrdquoJournal of Radioanalytical and Nuclear Chemistry vol 311 no3 pp 1811ndash1817 2017
[207] C Bettegowda C A Foss I Cheong et al ldquoImaging bac-terial infections with radiolabeled 1-(21015840-deoxy-21015840- fluoro-120573-D-arabinofuranosyl)-5-iodouracilrdquo Proceedings of the NationalAcadamy of Sciences of the United States of America vol 102 no4 pp 1145ndash1150 2005
[208] S A Soghomonyan M Doubrovin J Pike et al ldquoPositronemission tomography (PET) imaging of tumor-localizedSalmonella expressing HSV1-TKrdquo Cancer GeneTherapy vol 12no 1 pp 101ndash108 2005
[209] C Palestro K Nichols S Sheikh-Fayyaz S Dewey P Singhaland K Bhargava ldquoCan Gallium-68 PET differentiate acuteinterstitial nephritis from acute tubular necrosisrdquo Journal ofNuclear Medicne vol 57 Supplement 2 p 551 2016
[210] A J Morguet D L Munz V Ivancevic et al ldquoImmunoscintig-raphy using technetium-99m-labeled anti-NCA-95 antigranu-locyte antibodies as an adjunct to echocardiography in subacuteinfective endocarditisrdquo Journal of the American College ofCardiology vol 23 no 5 pp 1171ndash1178 1994
[211] C van der Laken O Boerman W Oyen et al ldquoIn Vivo Expres-sion of Interleukin-1 Receptors during Various ExperimentallyInduced Inflammatory Conditionsrdquo The Journal of InfectiousDiseases vol 177 no 5 pp 1398ndash1401 1998
[212] C J Van Der Laken O C Boerman W J G Oyen M T PVan De Ven J W M Van Der Meer and F H M CorstensldquoScintigraphic detection of infection and inflammation Newdevelopments with special emphasis on receptor interactionrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 25 no 5 pp 535ndash546 1998
[213] C J van der LakenOC BoermanW J GOyenM T P van deVen J W M van der Meer and F H M Corstens ldquoImaging ofinfection in rabbits with radioiodinated interleukin-1 (120572 and 120573)its receptor antagonist and a chemotactic peptide a comparativestudyrdquo European Journal of Nuclear Medicine and MolecularImaging vol 25 no 4 pp 347ndash352 1998
[214] C J Van Der Laken O C BoermanW J G Oyen M T P VanDe Ven F H M Corstens and J W M Ven Der Meer ldquoThekinetics of radiolabelled interleukin-8 in infection and sterileinflammationrdquo Nuclear Medicine Communications vol 19 no3 pp 271ndash282 1998
[215] E Lazzeri P Erba M Perri et al ldquoScintigraphic imaging ofvertebral osteomyelitis with 111in-biotinrdquoThe Spine Journal vol33 no 7 pp E198ndashE204 2008
[216] E Blom B Langstrom and I Velikyan ldquo68Ga-labeling of biotinanalogues and their characterizationrdquo Bioconjugate Chemistryvol 20 no 6 pp 1146ndash1151 2009
[217] O Eriksson F Carlsson E Blom et al ldquoPreclinical evaluationof a 68Ga-labeled biotin analogue for applications in islettransplantationrdquo Nuclear Medicine and Biology vol 39 no 3pp 415ndash421 2012
[218] E A Weinstein A A Ordonez V P DeMarco et alldquoImaging Enterobacteriaceae infection in vivo with 18F-fluoro-deoxysorbitol positron emission tomographyrdquo Science Transla-tional Medicine vol 6 no 259 p 259ra146 2014
[219] K M Nielsen M H Kyneb A K O Alstrup et alldquo68Ga-labeled phage-display selected peptides as tracers forpositron emission tomography imaging of Staphylococcusaureus biofilm-associated infections Selection radiolabellingand preliminary biological evaluationrdquo Nuclear Medicine andBiology vol 43 no 10 pp 593ndash605 2016
[220] T J Makinen P Lankinen T Poyhonen J Jalava H T Aroand A Roivainen ldquoComparison of 18F-FDG and 68Ga PETimaging in the assessment of experimental osteomyelitis due toStaphylococcus aureusrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 32 no 11 pp 1259ndash1268 2005
[221] JMU Silvola I LaitinenH J Sipila et al ldquoUptake of 68galliumin atherosclerotic plaques in LDLRminusminusApoB100100micerdquo EJN-MMI Research vol 1 no 1 pp 1ndash8 2011
Contrast Media amp Molecular Imaging 23
[222] T A Wynn ldquoCellular and molecular mechanisms of fibrosisrdquoThe Journal of Pathology vol 214 no 2 pp 199ndash210 2008
[223] T Derlin D Jonigk J Bauersachs and FM Bengel ldquoMolecularImaging of Chemokine Receptor CXCR4 in NonndashSmall CellLung Cancer Using 68Ga-Pentixafor PETCT ComparisonWith 18F-FDGrdquo Clinical Nuclear Medicine 2016
[224] I Velikyan U Rosenstrom T N Bulenga O Eriksson andG Antoni ldquoFeasibility of multiple examinations using68ga-labelled collagelin analogues Organ distribution in rat forextrapolation to human organ and whole-body radiationdosimetryrdquo Pharmaceuticals vol 9 no 2 article no 31 2016
[225] S Jadhav M Kakela J Makila et al ldquoSynthesis and in VivoPET Imaging of Hyaluronan Conjugates of OligonucleotidesrdquoBioconjugate Chemistry vol 27 no 2 pp 391ndash403 2016
[226] A Autio A Saraste N Kudomi et al ldquoAssessment of bloodflow with (68) Ga-DOTA PET in experimental inflammation avalidation study using (15) O-waterrdquo American Journal ofNuclear Medicine and Molecular Imaging vol 4 no 6 pp 571ndash579 2014
[227] G Davies A Rolle A Maurer et al ldquoTowards translationalimmunoPETMR imaging of invasive pulmonary aspergillosisthe Humanised Monoclonal Antibody JF5 detects in vivordquoTheranostics vol 7 no 14 pp 3398ndash3414 2017
[228] DGoodwin CMeares GDavid et al ldquoMonoclonal antibodiesas reversible equilibrium carriers of radiopharmaceuticalsrdquoInternational Journal of Radiation Applications and Instrumen-tation Part B Nuclear Medicine and Biology vol 13 no 4 pp383ndash391 1986
[229] D A Goodwin C F Mears M McTigue and G S DavidldquoMonoclonal antibody hapten radiopharmaceutical deliveryrdquoNuclear Medicine Communications vol 7 no 8 pp 569ndash5801986
[230] S E Halpern and R O Dillman ldquoProblems associated withradioimmunodetection and possibilities for future solutionsrdquo JBiol Response Mod vol 6 no 3 pp 235ndash262 1987
[231] H Hong J Sun and W Cai ldquoRadionuclide-based cancerimaging targeting the carcinoembryonic antigenrdquo BiomarkerInsights vol 3 pp 435ndash451 2008
[232] G J Forster E B Santos P M Smith-Jones P Zanzonico andS M Larson ldquoPretargeted radioimmunotherapy with a single-chain antibodystreptavidin construct and radiolabeledDOTA-biotin Strategies for reduction of the renal doserdquo Journal ofNuclear Medicine vol 47 no 1 pp 140ndash149 2006
[233] Z Yao M Zhang H Kobayashi et al ldquoImproved targeting ofradiolabeled streptavidin in tumors pretargeted with biotiny-lated monoclonal antibodies through an avidin chaserdquo Journalof Nuclear Medicine vol 36 no 5 pp 837ndash841 1995
[234] C-H Chang R M Sharkey E A Rossi et al ldquoMolecularAdvances in Pretargeting Radioimunotherapy with BispecificAntibodies 1 Supported in part by USPHS Grant R01-CA-84379from the NIH and Department of Energy Grant DE-FG01-00NE22941 (both to R M S)1rdquo Mol Cancer Ther vol 1 no 7pp 553ndash563 2002
[235] R M Sharkey E A Rossi W J McBride C-H Chang andD M Goldenberg ldquoRecombinant Bispecific Monoclonal Anti-bodies Prepared by theDock-and-Lock Strategy for PretargetedRadioimmunotherapyrdquo Seminars in Nuclear Medicine vol 40no 3 pp 190ndash203 2010
[236] R M Sharkey E A Rossi C-H Chang and D M Golden-berg ldquoImproved cancer therapy and molecular imaging withmultivalent multispecific antibodiesrdquo Cancer Biotherapy andRadiopharmaceuticals vol 25 no 1 pp 1ndash12 2010
[237] D M Goldenberg R M Sharkey G Paganelli J Barbet andJ Chatal ldquoAntibody pretargeting advances cancer radioim-munodetection and radioimmunotherapyrdquo Journal of ClinicalOncology vol 24 no 5 pp 823ndash834 2006
[238] O C Boerman F G van Schaijk W J G Oyen and FH M Corstens ldquoPretargeted radioimmunotherapy of cancerprogress step by steprdquo Journal of Nuclear Medicine vol 44 no3 pp 400ndash411 2003
[239] J Schuhmacher S Kaul G Klivenyi et al ldquoImmunoscintigra-phy with positron emission tomography Gallium-68 chelateimaging of breast cancer pretargeted with bispecific anti-MUC1anti-Ga chelate antibodiesrdquo Cancer Research vol 61 no9 pp 3712ndash3717 2001
[240] J Schuhmacher G Klivenyi S Kaul et al ldquoPretargeting ofhuman mammary carcinoma xenografts with bispecific anti-MUC1anti-Ga chelate antibodies and immunoscintigraphywith PETrdquo Nuclear Medicine and Biology vol 28 no 7 pp 821ndash828 2001
[241] C Somasundaram S Matzku J Schuhmacher and M ZollerldquoDevelopment of a bispecific monoclonal antibody against agallium-67 chelate and the human melanoma-associated anti-gen p97 for potential use in pretargeted immunoscintigraphyrdquoCancer Immunology Immunotherapy vol 36 no 5 pp 337ndash3451993
[242] E A Rossi D L Rossi R Stein D M Goldenberg and C-H Chang ldquoA bispecific antibody-IFN1205722b immunocytokine tar-geting CD20 and HLA-DR is highly toxic to human lymphomaandmultiplemyeloma cellsrdquoCancer Research vol 70 no 19 pp7600ndash7609 2010
[243] R M Sharkey H Karacay S Litwin et al ldquoImproved ther-apeutic results by pretargeted radioimmunotherapy of non-Hodgkinrsquos lymphoma with a new recombinant trivalent anti-CD20 bispecific antibodyrdquo Cancer Research vol 68 no 13 pp5282ndash5290 2008
[244] G L Griffiths C-H Chang W J McBride et al ldquoReagentsandmethods for PETusing bispecific antibody pretargeting and68Ga-radiolabeled bivalent hapten-peptide-chelate conjugatesrdquoJournal of Nuclear Medicine vol 45 no 1 pp 30ndash39 2004
[245] J Watine M Miedouge and B Friedberg ldquoCarcinoembryonicantigen as an independent prognostic factor of recurrence andsurvival in patients resected for colorectal liver metastases Asystematic reviewrdquo Diseases of the Colon amp Rectum vol 44 no12 pp 1791ndash1799 2001
[246] M J Goldstein and E P Mitchell ldquoCarcinoembryonic antigenin the staging and follow-up of patients with colorectal cancerrdquoCancer Investigation vol 23 no 4 pp 338ndash351 2005
[247] D V Gold D M Goldenberg H Karacay et al ldquoA novelbispecific trivalent antibody construct for targeting pancreaticcarcinomardquo Cancer Research vol 68 no 12 pp 4819ndash48262008
[248] J Schuhmacher G Klivenyi R Matys et al ldquoMultistep tumortargeting in nudemice using bispecific antibodies and a galliumchelate suitable for immunoscintigraphy with positron emis-sion tomographyrdquo Cancer Research vol 55 no 1 pp 115ndash1231995
[249] G Klivenyi J Schuhmacher E Patzelt et al ldquoGallium-68chelate imaging of human colon carcinoma xenografts pre-targeted with bispecific anti-CD44(V6)anti-gallium chelateantibodiesrdquo Journal ofNuclearMedicine vol 39 no 10 pp 1769ndash1776 1998
[250] M Zoller J Schuhmacher J Reed W Maier-Borst and SMatzku ldquoEstablishment and characterization of monoclonal
24 Contrast Media amp Molecular Imaging
antibodies against an octahedral gallium chelate suitable forimmunoscintigraphy with PETrdquo Journal of Nuclear Medicinevol 33 no 7 pp 1366ndash1372 1992
[251] R M Sharkey T M Cardillo E A Rossi et al ldquoSignal ampli-fication in molecular imaging by pretargeting a multivalentbispecific antibodyrdquo Nature Medicine vol 11 no 11 pp 1250ndash1255 2005
[252] D M Goldenberg and R M Sharkey ldquoNovel radiolabeledantibody conjugatesrdquo Oncogene vol 26 no 25 pp 3734ndash37442007
[253] D M Goldenberg E A Rossi R M Sharkey W J McBrideand C-H Chang ldquoMultifunctional antibodies by the dock-and-lock method for improved cancer imaging and therapy bypretargetingrdquo Journal of NuclearMedicine vol 49 no 1 pp 158ndash163 2008
[254] R Schoffelen R M Sharkey D M Goldenberg et al ldquoPre-targeted immuno-positron emission tomography imaging ofcarcinoembryonic antigen-expressing tumors with a bispecificantibody and a68Ga- And18F-labeled hapten peptide in micewith human tumor xenograftsrdquoMolecular Cancer Therapeuticsvol 9 no 4 pp 1019ndash1027 2010
[255] E S Bos W H Kuijpers M Meesters-Winters et al ldquoIn vitroevaluation of DNA-DNA hybridization as a two-step approachin radioimmunotherapy of cancerrdquoCancer Research vol 54 no13 pp 3479ndash3486 1994
[256] G Paganelli M Bartolomei M Ferrari et al ldquoPre-TargetedLocoregional Radioimmunotherapy withrdquo Cancer biotherapyand radiopharmaceuticals vol 16 no 3 pp 227ndash235 2001
[257] A Forero P L Weiden J M Vose et al ldquoPhase 1 trial of a novelanti-CD20 fusion protein in pretargeted radioimmunotherapyfor B-cell non-Hodgkin lymphomardquo Blood vol 104 no 1 pp227ndash236 2004
[258] DM Goldenberg C-H Chang E A RossiW J McBride andR M Sharkey ldquoPretargeted molecular imaging and radioim-munotherapyrdquoTheranostics vol 2 no 5 pp 523ndash540 2012
[259] H Karacay R M Sharkey W J McBride E A Rossi C-HChang and D M Goldenberg ldquoOptimization of hapten-peptide labeling for pretargeted immunoPET of bispecificantibody using generator-produced 68Gardquo Journal of NuclearMedicine vol 52 no 4 pp 555ndash559 2011
[260] J R Oh and B C Ahn ldquoFalse-positive uptake on radioiodinewhole-body scintigraphy physiologic and pathologic variantsunrelated to thyroid cancerrdquo American Journal of NuclearMedicine and Molecular Imaging vol 2 no 2 pp 141ndash150 2012
[261] E Frampas C Rousseau C Bodet-Milin J Barbet J-F Chataland F Kraeber-Bodere ldquoImprovement of radioimmunotherapyusing pretargetingrdquo Frontiers in Oncology vol 3 Article ID00159 2013
[262] C S McKay and M G Finn ldquoClick chemistry in complexmixtures Bioorthogonal bioconjugationrdquo Chemistry amp Biologyvol 21 no 9 pp 1075ndash1101 2014
[263] B L Oliveira Z Guo and G J Bernardes ldquoInverse electrondemand DielsndashAlder reactions in chemical biologyrdquo ChemicalSociety Reviews vol 46 no 16 pp 4895ndash4950 2017
[264] B Nichols Z Qin J Yang D R Vera and N K Devaraj ldquo68Gachelating bioorthogonal tetrazine polymers for the multisteplabeling of cancer biomarkersrdquo Chemical Communications vol50 no 40 pp 5215ndash5217 2014
[265] R Rossin P R Verkerk S M van den Bosch et al ldquoInvivo chemistry for pretargeted tumor imaging in live micerdquoAngewandte Chemie International Edition vol 49 no 19 pp3375ndash3378 2010
[266] B M Zeglis K K Sevak T Reiner et al ldquoA pretargetedPET imaging strategy based on bioorthogonal diels-alder clickchemistryrdquo Journal of Nuclear Medicine vol 54 no 8 pp 1389ndash1396 2013
[267] J L Houghton R Membreno D Abdel-Atti et al ldquoEstablish-ment of the invivo efficacy of pretargeted radioimmunotherapyutilizing inverse electron demand diels-alder click chemistryrdquoMolecular Cancer Therapeutics vol 16 no 1 pp 124ndash133 2017
[268] J Funkhouser ldquoReinventing pharma the theranostic revolu-tionrdquo Current Drug Discovery pp 17ndash19 2002
[269] J Sorensen I Velikyan A Wennborg et al ldquoMeasuring HER2-expression in metastatic breast cancer using 68Ga-ABY025PETCTrdquo European Journal of Nuclear Medicine and MolecularImaging vol 41 pp S226ndashS226 2014
[270] I Velikyan A Wennborg J Feldwisch et al ldquoGMP compliantpreparation of a 68Gallium-labeled Affibody analogue forbreast cancer patient examination first-in-manrdquoEur JNuclMedMol Imaging vol 41 pp S228ndashS229 2014
[271] K Oberg ldquoMolecular imaging radiotherapy Theranostics forpersonalized patient management of neuroendocrine tumors(NETs)rdquoTheranostics vol 2 no 5 pp 448ndash458 2012
[272] I Velikyan AWennborg J FeldwischH Lindman J Carlssonand J Sorensen ldquoGood manufacturing practice production of [(68) Ga]Ga-ABY-025 for HER2 specific breast cancer imagingrdquoAmerican Journal of Nuclear Medicine and Molecular Imagingvol 6 no 2 pp 135ndash153 2016
[273] M Sandstrom K Lindskog I Velikyan et al ldquoBiodistributionand radiation dosimetry of the anti-HER2 Affibody molecule68Ga-ABY-025 in breast cancer patientsrdquo Journal of NuclearMedicine vol 57 no 6 pp 867ndash871 2016
[274] D Sandberg V Tolmachev I Velikyan et al ldquoIntra-imagereferencing for simplified assessment of HER2-expression inbreast cancer metastases using the Affibody molecule ABY-025with PET and SPECTrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 44 no 8 pp 1337ndash1346 2017
[275] H ZhangM AMoroz I Serganova et al ldquoImaging expressionof the human somatostatin receptor subtype-2 reporter genewith 68Ga-DOTATOCrdquo Journal ofNuclearMedicine vol 52 no1 pp 123ndash131 2011
[276] M Naji and A Al-Nahhas ldquo68Ga-labelled peptides in themanagement of neuroectodermal tumoursrdquo European Journalof Nuclear Medicine and Molecular Imaging vol 39 no 1 ppS61ndashS67 2012
[277] I Velikyan ldquoThe diversity of 68Ga-Based imaging agentsrdquoRecent Results in Cancer Research vol 194 pp 101ndash131 2013
[278] K Ferreira H-Y Hu V Fetz et al ldquoMultivalent siderophore-dotam conjugates as theranostics for imaging and treatment ofbacterial infectionsrdquo Angewandte Chemie International Editionvol 56 no 28 pp 8272ndash8276 2017
Computational and Mathematical Methods in Medicine
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Research and TreatmentAIDS
Hindawiwwwhindawicom Volume 2018
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Parkinsonrsquos Disease
Evidence-Based Complementary andAlternative Medicine
Volume 2018Hindawiwwwhindawicom
Submit your manuscripts atwwwhindawicom
10 Contrast Media amp Molecular Imaging
(a)
(b)
(c) (d)
(e)
Figure 4 Left panel presents maximum intensity projection images of [68Ga]Ga-DOTA-TBIA101 distribution in a healthy mouse (a) and amouse with muscular infection site (MIS) in the right hind muscle tissue (white arrows) Right panel presents coronal (c) sagittal (d) andaxial (e) images with uptake in theMIS (white arrow) and absence of the uptake in the contralateralmuscle tissue Ki and Bl stand respectivelyfor kidney and bladder Reproduced from [73]
can also play a critical role in the development of biofilmsby microbes They are low molecular weight compoundsspecifically chelating Fe(III) and Ga(III) can form stablecomplexes with them mimicking Fe(III) [202 203]
Desferri-triacetylfusarinine C (TAFC) and desferri-ferricrocin (FC) labelled with 68Ga were used for theimaging of invasive pulmonary aspergillosis (IPA) caused byAspergillus fumigatus [15] [68Ga]Ga-TAFC demonstratedsuperior characteristics in terms of specific target bindingmetabolic stability and fast blood clearance in a rat modelof A fumigatus infection Seven analogues were developedin another study with TAFC and ferrioxamine E (FOXE)showing favorable binding clearance elimination andstability characteristics [16] as well as lung uptake inrat of invasive aspergillosis model wherein the uptakeextent was correlated with disease severity [17] [68Ga]Ga-triacetylfusarinine C and [68Ga]Ga-ferrioxamine E wereinvestigated in rat model of A fumigatus and demonstratedrapid uptake in the lungs (Figure 5) [76]
64 Radiolabelled Metabolisable Agents Mammalian micro-biota consumes (poly)saccharides in particular maltose andmaltodextrins [204] The transport mechanism is specific
to bacteria and is absent in mammalian cells making itpossible to utilize these (poly)saccharides for imaging agentdevelopment Maltodextrin functionalized with a fluorescentdye was internalized through the bacteria-specific maltodex-trin transport pathway and discriminated between activebacteria and inflammation in vivo [192] Maltose labelledwith 18F localized specifically bacterial infection in mice[205] Potential to label polysaccharides directly with 68Gamight be utilized extensively
As mentioned above the chemical properties of Ga(III)provide the potential for direct labelling of polysaccharidesDextran was labelled directly and resulting complex demon-strated sufficient stability in human serum however thefeasibility of the bacterial imaging was not demonstrated[206]
Trapping of nucleosides that are substrates of thymidinekinase occurring within bacteria was explored using 18Fand 125I labelled analogues of uracil [207] Promising resultswere obtained in seven bacterial species in mice Anotherstudy in the context of therapeutic bacteria developmentdemonstrated possibility of detecting Salmonella vectorswithin tumours using 18F-labelled uracil [208] However
Contrast Media amp Molecular Imaging 11
N
O
N
ON
HN
O
O
O
OO O
NH
O
O
O
O
NH
O
OGa
（3
（3
（3
（3
（3
（3
（2
(a) (b) (c)
Figure 5 Molecular structure of [68Ga]Ga-triacetylfusarinine C (a) used for the in vivo imaging of a rat with Aspergillus fumigatus infection(b) and negative control of noninfected rat (c) White arrows point at the infected (b) and normal (c) lungs Adapted from [76]
the development of 68Ga-labelled nucleosides that wouldmaintain their biological activity is challenging and fewexamples known from the literature confirm that [4 6]
7 68Ga-Citrate
As mentioned above 68GaPET provides a number of advan-tages over 67GaSPECT and following publications demon-strate it in clinical and preclinical studies [68Ga]Ga-citratedemonstrated high diagnostic accuracy of 90of osteomyeli-tis and diskitis in clinical studies (Figure 6) [18 19] Thisstudy demonstrates that [68Ga]Ga-citrate can be employedfor monitoring the response to treatment [68Ga]Ga-citratewas used clinically to follow-up surgical intervention inpatients with acute osteomyelitis and intra-abdominal infec-tion [77] The agent was also used to successfully visualizelungmalignancy and tuberculosis in patients however in caseof high prevalence of granulomatous diseases the distinctionbetween malignant and benign lung lesions was unclear [7879] Another clinical study conducted head-to-head compar-ison of [68Ga]Ga-citrate (Figure 7) and [18F]FDG in patientswith Staphylococcus aureus bacteremia [80] The detectionrate of osteomyelitis was similar and further investigationof [68Ga]Ga-citrate applicability in cases of osteomyelitisinduced by other pathogens as well as for monitoring healingprocess is warranted
Comparative study of [68Ga]Ga-citrate and [67Ga]Ga-citrate was performed in healthy and infection model rats[77] The performance of [68Ga]Ga-citrate was found supe-rior in terms of image contrast in the lower abdomen and
extremities Potential of [68Ga]Ga-citrate for the differentia-tion of acute interstitial nephritis from acute tubular necrosiswas studied in rat model of the disease and it was demon-strated that the kidney uptake correlated with the extentof mononuclear cell infiltration accompanying inflammation[209] 68Ga-labelled Apo-transferrin demonstrated bacterialinfection detection capacity in rat model with Staphylococcusaureus wherein the infection site was visualized 1 h afteradministration of the agent [14]
71 Radiolabelled Antibodies and Antibody FragmentsHuman immunoglobulin (HIG) binds to bacteria but alsoaccumulates at the sites of fungal and viral infection aswell as sterile inflammation due to binding to leukocytesThe improved specificity for bacteria was achieved for thefragments of HIG It is feasible to develop specific antibodiesto various antigens present on the bacterial cell surface [102]Monoclonal antibodies labelled with 99mTc were used forinfection imaging via granulocytes targeting NCA-95 [210]Various cytokines of interleukin family (IL-1 IL-8) labelledwith 123I or 99mTc demonstrated accumulation in the sitesof infection in various animal models [111 112 211ndash214]Registered antigranulocyte radiopharmaceuticals suchas LeuTech Scintimun and Leukoscan are based on99mTc-labelled antibodies This experience can be translatedto 68Ga however either the size of the antibodies mustbe reduced or pretargeting techniques must be appliedin order to overcome the discrepancy between the shortphysical half-life of 68Ga and slow pharmacokinetics ofantibodies
12 Contrast Media amp Molecular Imaging
(a) (b) (c) (d)
Figure 6 [68Ga]Ga-citrate PETCT examination of a patient affected by acute osteomyelitis before (left panel) and after (right panel) surgicalcurettage showing uptake in the transaxial (a c) and 3D reconstruction images (b d red area) Absence of the uptake after the therapyconfirms complete response to the treatment Adapted from [19]
Figure 7 Vertebral osteomyelitis (spondylodiscitis red arrow-heads) and abscesses in the iliopsoas and paravertebral area (redarrows) were detected by [68Ga]Ga-citrate in a patient admittedto the hospital with back pain and general symptoms The PETacquisition was performed 88min after administration of 245MBqof [68Ga]Ga-citrate Adapted from [80]
72 Radiolabelled Biotin Biotin is a growth factor utilizedin many bacteria An 111In-labelled analogue of biotin wassuccessfully utilized for diagnosis of vertebral infections ina clinical study [215] It would be rational to explore therelevance of 68Ga-labelled analogues given the advantagesof 68Ga over 111In and promising [68Ga]Ga-DOTA-Biotinanalogues [216 217] developed for monitoring survival oftransplanted avidin-coated islets
8 Miscellaneous
Stable Ga(III) complex with thiosemicarbazones demon-strated antimicrobial effect against P aeruginosa and Calbicans due to most probably both displacement of essentialFe(III) with Ga(III) and thiosemicarbazones [101] Substitu-tion of the stable Ga(III) by radioactive 68Ga might result ina specific infection imaging agent
Selective imaging of Enterobacteriaceae using 2-[18F]-fluorodeoxysorbitol (18F-FDS)was demonstrated in amurine
myositis model [218] The uptake of 18F-FDS was correlatedwith bacterial burden moreover the agent differentiatedinfection from sterile inflammation Given the potential of68Ga for the labelling of small biologically active molecules[4] it might be plausible to develop a respective analoguewith added value of the advantages that 68Ga offers includingsimpler production chemistry lowered radiation dose repet-itive examination and accessibility at clinical centers withoutcyclotrons and remote from [18F]-FDG distribution sites Asmentioned above the poor access to bacteria aggregated ina biofilm might make the imaging task challenging Severalpeptide candidates with affinity for S aureus biofilm weredesigned and labelled with 68Ga [219] The resulting agentsdemonstrated binding in vitro however it was not possible toblock the binding with excess of the cold peptide
Ionic 68Ga was found superior to [18F]-FDG in infectiondetection in the rat model with diffuse osteomyelitis [220] Inanother study the uptake of ionic 68Ga was observed in theaortic plaques of atherosclerotic mice specifically at the sitesrich inmacrophages [221] However the slow blood clearanceof ionic 68Ga presents a limitation
Chronic inflammation is the major reason of fibro-sis [222] 68Ga-labelled SST analogue ([68Ga]Ga-DOTA-NOC) demonstrated uptake in pathogenic areas in patientsaffected by idiopathic pulmonary fibrosis with potentialfor monitoring response to treatment and drug develop-ment [62] Another clinical study using [68Ga]Ga-pentixaforalso showed potential of the agent for monitoring dis-ease activity and response to treatment in idiopathic pul-monary fibrosis [223] Peptide based agents CNO2A-PEG2-c[CPGRVMHGLHLGDDEGPC] and [68Ga]Ga-NODAGA-PEG2-c[CPGRVMHGLHLGDDEGPC] for the imaging andquantification of fibrosis by PET were developed and char-acterized preclinically showing fast clearance from normal
Contrast Media amp Molecular Imaging 13
tissue and blood and binding specificity [89] Dosimetrycalculations demonstrated possibility of six examinations peryear in humans assuring disease monitoring in longitudinalstudies and routine clinical setup [224]
Several hyaluronan conjugates of oligonucleotides target-ing CD44 positive cells were developed and tested in healthyrats sham-operated rats and rats with myocardial infarction[225]The uptake of the agents was higher for the latter groupand varied dependent on the difference in the oligonucleotidestructure
TLR2 and TLR4 expression levels in neutrophils werefound higher in individuals with bacterial and viral infectionsthan those in control samples There is a possibility that IL-4IL-8 IL-10 IL-12 and TNF-a might serve as biomarkers forinfections and that IL-2 IL-8 or IL-10 is potentially able todistinguish between bacterial and viral infections [22]
Mannosylated human serum albumin labelled with 68Gavia NOTA chelator moiety ([68Ga]Ga-NOTA-MSA) wastested in a rat model of myocarditis targetingmannose recep-tors expressed onmacrophages infiltratingmyocardium [66]The uptake in the diseased myocardium was considerablyhigher than that of the normal one and it was precludedby administration of excess of nonlabelled MSA indicatingbinding specificity The tracer build-up was also observed inthe organs of macrophage accumulation
[68Ga]Ga-DOTA was investigated for the quantificationof increased blood flow which is one of the key events ininflammation [226] The uptake kinetics of [68Ga]Ga-DOTAin the site of inflammation in rats with induced inflamma-tion correlated well with that of 15O-water suggesting highrelevance [68Ga]Ga-DOTA
9 Pretargeted Imaging
The half-life of 68Ga is shorter than that of 64Cu 67Ga 99mTc89Zr 111In and 123124125I and thus in contrast to the latterit is not compatible with slow pharmacokinetics of largemolecules such as antibodies and glycoproteins The rangeof antigen-specific antibodies relevant to inflammation andinfection is broad and a number of 99mTc-labelled antibodieswere used clinically [20 21 227] The respective range of68Ga-based agents could be similarThe solution to overcomethe incompatibility of half-life time frames could be eitherthe reduction of the antibody size or the application of thepretargeting concept
The history of the pretargeting concept spans threedecades predominantly in the field of oncology [228ndash230]It was developed to improve image contrast and dosimetryin immunoimaging and radioimmunotherapy when usingradiolabelled antibody ligands with slow pharmacokinetics[231] The arsenal of antibodies is vast and diverse encourag-ing extensive investment into development of techniques thatwould allow their exploration to the fullest Pretargeting con-siders at least two major steps wherein a functionalized anti-body is first administered for target localization and clearancefrom blood and normal tissue and thereafter a radiolabelledsmall molecule capable of binding to the functionalized
antibody due to high affinity or covalent interaction is admin-istered The key properties of the radiolabelled molecules arefast pharmacokinetic and clearance Several techniques havebeen developed for the realization of pretargeting conceptincluding avidinstreptavidin-biotin systems [216 217 232233] bispecific antibodies (bsmAb) with haptens [232 234ndash254] antibody-oligonucleotide conjugates with complemen-tary oligonucleotides [255] biorthogonal systems allowingcovalent chemical reactions in vivo (Figure 8)
The high affinity of biotin to avidin and streptavidinproteins was utilized clinically and preclinically in pretar-geting approach for the imaging and therapy of pancreaticadenocarcinoma [232] glioblastoma [256] and lymphoma[257] However this pretargeting technique may requirethree steps in order to eliminate the excess of antibody-(strept)avidin conjugate circulating in the blood and notbound to the target by adding clearing agent Anotherapplication of the technique was monitoring transplantationof islets of Langerhans in the treatment for type 1 diabetesmellitus wherein the cells or cellmimetics were conjugated to(strept)avidin prior to the transplantation [216 217] Severalanalogues of biotin comprising DOTA chelate moiety forlabelling with 68Ga and ethylene glycol linker of variouslength demonstrated the influence of the latter on the affinitytowards avidin
Particular example of hapten molecules is the ones com-prising histamine-succinyl-glycine (HSG) motif and chelatemoiety [251ndash253 258] for the complexationwith 68Ga Severalanalogues were developed for the imaging of carcinoem-bryonic antigen (CEA) pretargeted with anti-CEA bsmAb[254 259 260] and two clinical studies of medullary thyroidcarcinoma and breast carcinoma positive for CEA using68Ga-labelled hapten molecules and bsmAb were initiated[261]
Bioorthogonal reactions are fast regioselective requiringsmall reagent concentration and occurring under mild con-ditions often in aqueous solution and temperature below 37∘C[262 263] Amongst various biorthogonal reaction types thecycloaddition of tetrazines and various dienophiles referredto as inverse-electron-demandDiels-Alder (IEDDA) reactionis themost successful in the context of pretargeting Antibod-ies functionalized with trans-cyclooctene (TCO) and a radi-olabelled tetrazine that can interact in vivo based on IEDDAreaction were studied [264ndash267] In particular 68Ga-labelledtetrazine dextran demonstrated favorable pharmacokineticsin a healthy mouse [264] However the proof of concept is tobe performed in a xenografted animal Accumulation of anti-TAG72 [265] and anti-A33 [266] antibodies functionalizedwith TCO in mouse xenografts was visualized respectivelyby an 111In and 64Cu-labelled tetrazine analogues Anti-CA199 antibody-TCO in combination with 177Lu-labelledtetrazine demonstrated radiotherapeutic effect in pancreaticcancer murine model [267]
Thepretargeted imaging techniquesmay contribute to theexpansion of immuno-PET with 68Ga providing the intrinsicadvantages of 68Ga and PET As mentioned above mostof the developed radiolabelled counterparts of pretargetingtechniques have demonstrated promising results There are
14 Contrast Media amp Molecular Imaging
H
ON
NN
O
OO
OO
NH
NS
NH
ONH
O
HO
ONH
O
Ga
HN
NH
NH
O
OO
HNN
HN
NH
NH
O
OO
HNN
（2
(a)
NH
O
O
NH
N
NNGa
O O
O O
O
O
O
N N
NN
OO
（2
(b)
N
N
O
O
N
N
O
O
O
NH
O
O
ONH
NHS
O
H
HO
NH
+
minus
(c)
Figure 8 Schematic presentation of pretargeting techniques (a) bispecific antibodies engineered to specifically bind with radiolabelledhapten molecules (b) bioorthogonal click chemistry for fast and specific covalent binding between for example a trans-cyclooctenefunctionalized antibody and a radiolabelled tetrazine (c) interaction between antibody-(strept)avidin conjugate and radiolabelled biotinutilizing extremely high affinity of (strept)avidin and biotin
Contrast Media amp Molecular Imaging 15
a considerable number of potential antibody biomarkersthat could be considered for the imaging of infection andinflammation
10 Theranostics Potential
Theranostics [268] embraces realization of personalizedmedicine by conducting diagnosis on individual basis andproviding possibility of predicting the efficacy of a specifictreatment and following up the response to the treatmentenabling adjustment of the latter very early in the processIn the context of nuclear medicine wherein the radiophar-maceuticals targeted at biomarkers specific to a disease cancarry either diagnostic radionuclides or therapeutic ones theconcept can be denoted as radiotheranostics [28] The tar-geted molecular imaging such as PET can offer noninvasivediagnosis specific to the disease for example tumour-typespecific and provide accurate localization of the lesions Thestrongest advantage of PET is the potential for quantificationof the target for example receptor expression investigationof the uptake kinetics and estimation of the dosimetryThesecharacteristics of PET allow for individualized treatmentselection and planning monitoring of treatment responseand detection of recurrent diseaseThe individualized patientmanagement provides such advantages as optimization ofthe treatment regimen for the improved response and exclu-sion of futile treatments minimization of risks and toxicitywith overall outcome of reduced cost and patient distressThe importance of individualized patient management wasdemonstrated by clinical studies wherein the influence ofdose of the administered radiopharmaceutical targeted atreceptors overexpressed in cancer lesions on the diagnosticoutcome was investigated in the same patient [85 269270] 68Ga-labelled SST analogues [26ndash28 271] and Affibodymolecules [5 272ndash274] used respectively in NENs andbreast cancer patients are the most prominent examplesof (radio)theranostics involving 68GaPET wherein 68Ga-labelled analogues were used not only for localization of thelesions but also for staging patient stratification prognosistherapy selection and monitoring of the response to thetreatment of NETs and other cancer types [2ndash4 6 85 176275ndash277]
The methodology can be translated to inflammationand infection allowing for accurate and specific selection oftreatment regimen and for follow-up and evaluation of theresponse to therapy resulting in improved treatment efficacyand decreased cost and side effects The accommodation ofboth imaging function and antibiotic function in the samemolecule is a novel example of a theranostic agent [278]A series of siderophores conjugated with DOTA moiety forthe radiolabelling and with antibiotics for the treatmentof bacterial infection were investigated preclinically Theaccumulation of the intravenously administered ampicillinconjugate in the site of subcutaneously injected P aeruginosain mice was clearly and focally visualized within 06 h withretention for at least 24 h These results obtained usinganalogues carrying dye for optical imaging can be translatedto 68Ga-labelled counterparts for PET
11 Conclusions
The medical need for specific agents for noninvasive quan-titative and whole-body imaging of inflammation and infec-tion has not been met yet despite decades of research How-ever the prerequisites in terms of identification of potentialtargets design and synthesis of the respective ligands andimaging technologies are evolving very fast The potentialof accurate and quantitative lesion localization as well asmonitoring of the treatment response promises personalizedpatient management
The use of 68Ga in oncology is established proving thestrong potential of 68Ga for the promotion of PET technol-ogy for effective and efficient diagnostics and personalizedmedicineThe experience of oncological 68Ga-based agents isgetting translated to inflammation and infection Pretargetedimaging technology opens wide possibilities based on anti-body biomarkers
Conflicts of Interest
The author declares that there are no conflicts of interestregarding the publication of this article
References
[1] I Velikyan ldquoContinued rapid growth inGa applications update2013 to June 2014rdquo Journal of Labelled CompoundsampRadiophar-maceuticals pp 99ndash121 2015
[2] I Velikyan ldquo 68Ga-based radiopharmaceuticals Production andapplication relationshiprdquo Molecules vol 20 no 7 pp 12913ndash12943 2015
[3] M Fani P Peitl and I Velikyan ldquoCurrent status of radiophar-maceuticals for the theranostics of neuroendocrine neoplasmsrdquoPharmaceuticals vol 10 no 1 article no 30 2017
[4] I Velikyan ldquoPositron emitting [68Ga]Ga-based imaging agentsChemistry and diversityrdquoMedicinal Chemistry vol 7 no 5 pp345ndash379 2011
[5] J Sorensen I Velikyan D Sandberg et al ldquoMeasuringHER2-receptor expression in metastatic breast cancer using[68Ga]ABY-025 Affibody PETCTrdquo Theranostics vol 6 no 2pp 262ndash271 2016
[6] I Velikyan ldquoProspective of 68Ga-Radiopharmaceutical devel-opmentrdquoTheranostics vol 4 no 1 pp 47ndash80 2014
[7] P Lankinen T J Makinen T A Poyhonen et al ldquo68Ga-DOTAVAP-P1 PET imaging capable of demonstrating the phaseof inflammation in healing bones and the progress of infectionin osteomyelitic bonesrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 35 no 2 pp 352ndash364 2008
[8] T UjulaMHuttunen P Luoto et al ldquoMatrixmetalloproteinase9 targeting peptides Syntheses 68Ga-labeling and preliminaryevaluation in a rat melanoma xenograft modelrdquo BioconjugateChemistry vol 21 no 9 pp 1612ndash1621 2010
[9] A Autio T Ujula P Luoto S Salomaki S Jalkanen and ARoivainen ldquoPET imaging of inflammation and adenocarcinomaxenografts using vascular adhesion protein 1 targeting peptide68Ga-DOTAVAP-P1 Comparison with 18F-FDGrdquo EuropeanJournal of Nuclear Medicine and Molecular Imaging vol 37 no10 pp 1918ndash1925 2010
16 Contrast Media amp Molecular Imaging
[10] J Silvola A Autio P Luoto S Jalkanen andA Roivainen ldquoPre-liminary evaluation of novel 68Ga-DOTAVAP-PEG-P2 peptidetargeting vascular adhesion protein-1rdquo Clinical Physiology andFunctional Imaging vol 30 no 1 pp 75ndash78 2010
[11] T Ujula S Salomaki P Virsu et al ldquoSynthesis 68Ga labelingand preliminary evaluation of DOTA peptide binding vascularadhesion protein-1 a potential PET imaging agent for diagnos-ing osteomyelitisrdquo Nuclear Medicine and Biology vol 36 no 6pp 631ndash641 2009
[12] A Autio T Henttinen H J Sipila S Jalkanen and ARoivainen ldquoMini-PEG spacering of VAP-1-targeting 68Ga-DOTAVAP-P1 peptide improves PET imaging of inflamma-tionrdquo EJNMMI Research vol 1 no 1 pp 1ndash7 2011
[13] K Aalto A Autio E A Kiss et al ldquoSiglec-9 is a novel leukocyteligand for vascular adhesion protein-1 and can be used in PETimaging of inflammation and cancerrdquo Blood vol 118 no 13 pp3725ndash3733 2011
[14] V Kumar D K Boddeti S G Evans F Roesch and RHowman-Giles ldquoPotential use of 68Ga-apo-transferrin as a PETimaging agent for detecting Staphylococcus aureus infectionrdquoNuclear Medicine and Biology vol 38 no 3 pp 393ndash398 2011
[15] M Petrik H Haas G Dobrozemsky et al ldquo68Ga-siderophoresfor PET imaging of invasive pulmonary aspergillosis Proof ofprinciplerdquo Journal of Nuclear Medicine vol 51 no 4 pp 639ndash645 2010
[16] M Petrik H Haas M Schrettl A Helbok M Blatzer and CDecristoforo ldquoIn vitro and in vivo evaluation of selected 68Ga-siderophores for infection imagingrdquo Nuclear Medicine andBiology vol 39 no 3 pp 361ndash369 2012
[17] M Petrik GM Franssen H Haas et al ldquoPreclinical evaluationof two 68Ga-siderophores as potential radiopharmaceuticals forAspergillus fumigatus infection imagingrdquo European Journal ofNuclearMedicine andMolecular Imaging vol 39 no 7 pp 1175ndash1183 2012
[18] A Rizzello D Di Pierro F Lodi et al ldquoSynthesis and qualitycontrol of 68Ga citrate for routine clinical PETrdquo NuclearMedicine Communications vol 30 no 7 pp 542ndash545 2009
[19] C Nanni C Errani and L Boriani ldquo 68Ga-citrate PETCT forevaluating patients with infections of the bone preliminaryresultsrdquo Journal of Nuclear Medicine vol 51 no 12 pp 1932ndash1936 2010
[20] S S Das A V Hall D W Wareham and K E Britton ldquoInfec-tion imaging with radiopharmaceuticals in the 21st centuryrdquoBrazilian Archives of Biology and Technology vol 45 no spepp 25ndash37 2002
[21] A Signore and A W J M Glaudemans ldquoThe molecularimaging approach to image infections and inflammation bynuclear medicine techniquesrdquo Annals of Nuclear Medicine vol25 no 10 pp 681ndash700 2011
[22] T Yusa K Tateda A Ohara and S Miyazaki ldquoNew possiblebiomarkers for diagnosis of infections and diagnostic distinc-tion between bacterial and viral infections in childrenrdquo Journalof Infection and Chemotherapy vol 23 no 2 pp 96ndash100 2017
[23] A Signore A W J M Glaudemans O Gheysens C Lauriand O A Catalano ldquoNuclear Medicine Imaging in PediatricInfection or Chronic Inflammatory Diseasesrdquo Seminars inNuclear Medicine vol 47 no 3 pp 286ndash303 2017
[24] I Velikyan ldquoMolecular imaging and radiotherapyTheranosticsfor personalized patient managementrdquo Theranostics vol 2 no5 pp 424ndash426 2012
[25] F Rosch and R P Baum ldquoGenerator-based PET radiophar-maceuticals for molecular imaging of tumours On the way
to THERANOSTICSrdquo Dalton Transactions vol 40 no 23 pp6104ndash6111 2011
[26] R P Baum H R Kulkarni and C Carreras ldquoPeptides andreceptors in image-guided therapy Theranostics for neuroen-docrine neoplasmsrdquo Seminars in Nuclear Medicine vol 42 no3 pp 190ndash207 2012
[27] R P Baum and H R Kulkarni ldquoTheranostics From molecularimaging using Ga-68 labeled tracers and PETCT to per-sonalized radionuclide therapy - the bad berka experiencerdquoTheranostics vol 2 no 5 pp 437ndash447 2012
[28] I Velikyan ldquoRadionuclides for Imaging andTherapy in Oncol-ogyrdquo Cancer Theranostics pp 285ndash325 2014
[29] J Czernin andWAWeber ldquoIssues and controversies in nuclearmedicine Introductionrdquo Journal of Nuclear Medicine vol 52no Supplement 2 pp 1Sndash2S 2011
[30] S J Goldsmith and S Vallabhajosula ldquoClinically proven radio-pharmaceuticals for infection imaging mechanisms and appli-cationsrdquo Seminars in Nuclear Medicine vol 39 no 1 pp 2ndash102009
[31] M F Tsan ldquoMechanism of gallium-67 accumulation in inflam-matory lesionsrdquo Journal of Nuclear Medicine vol 26 no 1 pp88ndash92 1985
[32] S L Kipper ldquoRadiolabelled leukocyte imaging of the abdomenrdquoin Nuclear Medicine Annual J Freeman Ed pp 81ndash126 RavenPress New York NY USA 1995
[33] F Jamar J Buscombe A Chiti et al ldquoEANMSNMMI guidelinefor 18F-FDG use in inflammation and infectionrdquo Journal ofNuclear Medicine vol 54 no 4 pp 647ndash658 2013
[34] C J Palestro ldquoThe current role of gallium imaging in infectionrdquoSeminars in Nuclear Medicine vol 24 no 2 pp 128ndash141 1994
[35] M S Akhtar M B Imran M A Nadeem and A ShahidldquoAntimicrobial peptides as infection imaging agents better thanradiolabeled antibioticsrdquo International Journal of Peptides vol2012 Article ID 965238 19 pages 2012
[36] D Delbeke and G M Segall ldquoStatus of and trends in nuclearmedicine in the United Statesrdquo Journal of Nuclear Medicine vol52 no 2 2011
[37] S S Gambhir J Czernin J Schwimmer D H Silverman R EColeman and M E Phelps ldquoA tabulated summary of the FDGPET literaturerdquo Journal of Nuclear Medicine vol 42 pp 1Sndash93S2001
[38] M J Lindsay B A Siegel S R Tunis et al ldquoThe NationalOncologic PET Registry ExpandedMedicare coverage for PETunder coverage with evidence developmentrdquo American Journalof Roentgenology vol 188 no 4 pp 1109ndash1113 2007
[39] F Gemmel H Van Den Wyngaert C Love M M Welling PGemmel and C J Palestro ldquoProsthetic joint infectionsradionuclide state-of-the-art imagingrdquo European Journal ofNuclearMedicine andMolecular Imaging vol 39 no 5 pp 892ndash909 2012
[40] J Sorensen ldquoHow does the patient benefit from clinical PETrdquoTheranostics vol 2 no 5 pp 427ndash436 2012
[41] S L Rice C A Roney P Daumar and J S Lewis ldquoThe nextgeneration of positron emission tomography radiopharmaceu-ticals in oncologyrdquo Seminars in Nuclear Medicine vol 41 no 4pp 265ndash282 2011
[42] R LWahl JMHerman and E Ford ldquoThePromise and Pitfallsof Positron Emission Tomography and Single-Photon EmissionComputed Tomography Molecular Imaging-Guided RadiationTherapyrdquo Seminars in Radiation Oncology vol 21 no 2 pp 88ndash100 2011
Contrast Media amp Molecular Imaging 17
[43] A W J M Glaudemans R H J A Slart J M Van Dijl MVan Oosten and G M Van Dam ldquoMolecular imaging of infec-tious and inflammatory diseases A terra incognitardquo Journal ofNuclear Medicine vol 56 no 5 pp 659ndash661 2015
[44] X Li W Bauer I Israel et al ldquoTargeting p-selectin by gallium-68-labeled fucoidan positron emission tomography for nonin-vasive characterization of vulnerable plaques Correlation within vivo 176t mrirdquo Arteriosclerosis Thrombosis and VascularBiology vol 34 no 8 pp 1661ndash1667 2014
[45] S Eichendorff P Svendsen D Bender et al ldquoBiodistributionand PET Imaging of a Novel [68Ga]-Anti-CD163-AntibodyConjugate in Rats with Collagen-Induced Arthritis and inControlsrdquoMolecular Imaging and Biology vol 17 no 1 pp 87ndash93 2014
[46] Z Zhu Y Yin K Zheng et al ldquoEvaluation of synovial angiogen-esis in patients with rheumatoid arthritis using 68Ga-PRGD2PETCT A prospective proof-of-concept cohort studyrdquo Annalsof the Rheumatic Diseases vol 73 no 6 pp 1269ndash1272 2014
[47] J S Eo J C Paeng S Lee et al ldquoAngiogenesis imaging inmyocardial infarction using 68Ga-NOTA- RGD PET Charac-terization and application to therapeutic efficacy monitoring inratsrdquo Coronary Artery Disease vol 24 no 4 pp 303ndash311 2013
[48] J H Kim Y-H Kim Y J Kim et al ldquoQuantitative positronemission tomography imaging of angiogenesis in rats with fore-limb ischemia using 68Ga-NOTA-c(RGDyK)rdquo Angiogenesisvol 16 no 4 pp 837ndash846 2013
[49] I Laitinen J Notni K Pohle et al ldquoComparison of cyclicRGD peptides for 120572v1205733 integrin detection in a rat model ofmyocardial infarctionrdquo EJNMMI Research vol 3 no 1 pp 1ndash9 2013
[50] M Kiugel I Dijkgraaf V Kyto et al ldquoDimeric [68Ga]DOTA-RGD Peptide Targeting 120572 ltinfgtvltinfgt 120573 ltinfgt3ltinfgt Inte-grin Reveals Extracellular Matrix Alterations after MyocardialInfarctionrdquo Molecular Imaging and Biology vol 16 no 6 pp793ndash801 2014
[51] M Gronman M Tarkia T Kiviniemi et al ldquoImaging of 120572v1205733integrin expression in experimental myocardial ischemia with[68Ga]NODAGA-RGD positron emission tomographyrdquo Jour-nal of Translational Medicine vol 15 no 1 p 144 2017
[52] J Haukkala I Laitinen P Luoto et al ldquo68Ga-DOTA-RGDpep-tide Biodistribution and binding into atherosclerotic plaquesin micerdquo European Journal of Nuclear Medicine and MolecularImaging vol 36 no 12 pp 2058ndash2067 2009
[53] H Virtanen A Autio R Siitonen et al ldquo68Ga-DOTA-Siglec-9- a new imaging tool to detect synovitisrdquo Arthritis Research ampTherapy vol 17 no 1 article no 308 2015
[54] J Retamal J Sorensen M Lubberink et al ldquoFeasibility of(68) Ga-labeled Siglec-9 peptide for the imaging of acutelung inflammation a pilot study in a porcine model of acuterespiratory distress syndromerdquoAm JNuclMedMol Imaging vol6 no 1 pp 18ndash31 2016
[55] J M U Silvola H Virtanen R Siitonen et al ldquoLeukocytetrafficking-associated vascular adhesion protein 1 is expressedand functionally active in atherosclerotic plaquesrdquo ScientificReports vol 6 Article ID 35089 2016
[56] H Ahtinen J Kulkova L Lindholm et al ldquo68Ga-DOTA-Siglec-9 PETCT imaging of peri-implant tissue responses andstaphylococcal infectionsrdquo EJNMMI Research vol 4 no 1article no 45 pp 1ndash11 2014
[57] A Autio S Jalkanen and A Roivainen ldquoNuclear imaging ofinflammation Homing-associated molecules as targetsrdquo EJN-MMI Research vol 3 no 1 pp 1ndash7 2013
[58] J TThackeray T Derlin AHaghikia et al ldquoMolecular Imagingof the Chemokine Receptor CXCR4 after Acute MyocardialInfarctionrdquo JACC Cardiovascular Imaging vol 8 no 12 pp1417ndash1426 2015
[59] J S Schmid A Schirbel A K Buck S Kropf H-J Westerand C Lapa ldquoPentixafor-Positron Emission TomographyComputed Tomography Detects Chemokine Receptor CXCR4Expression after Ischemic Strokerdquo Circulation CardiovascularImaging vol 9 no 9 Article ID e005217 2016
[60] J Zhou G Hao H Weng et al ldquoIn vivo evaluation ofmedical device-associated inflammation using a macrophage-specific positron emission tomography (PET) imaging proberdquoBioorganic amp Medicinal Chemistry Letters vol 23 no 7 pp2044ndash2047 2013
[61] S A Kularatne M-J Belanger X Meng et al ldquoComparativeanalysis of folate derived PET imaging agents with [ 18F]-2-fluoro-2-deoxy-d-glucose using a rodent inflammatory pawmodelrdquo Molecular Pharmaceutics vol 10 no 8 pp 3103ndash31112013
[62] V Ambrosini M Zompatori F De Luca et al ldquo68Ga-DOTANOCPETCTAllows Somatostatin Receptor Imaging inIdiopathic Pulmonary Fibrosis Preliminary Resultsrdquo Journal ofNuclear Medicine vol 51 no 12 pp 1950ndash1955 2010
[63] T Lincke J Singer R Kluge O Sabri and R Paschke ldquoRela-tive quantification of indium-111 pentetreotide and gallium-68DOTATOC uptake in the thyroid gland and association withthyroid pathologiesrdquoThyroid vol 19 no 4 pp 381ndash389 2009
[64] A Rominger T Saam E Vogl et al ldquoIn vivo imaging ofmacrophage activity in the coronary arteries using 68Ga-DOTATATE PETCT correlation with coronary calcium bur-den and risk factorsrdquo Journal of Nuclear Medicine vol 51 no 2pp 193ndash197 2010
[65] J M Tarkin F R Joshi N R Evans et al ldquoDetection ofAtherosclerotic Inflammation by 68Ga-DOTATATE PET Com-pared to [18F]FDG PET Imagingrdquo Journal of the AmericanCollege of Cardiology vol 69 no 14 pp 1774ndash1791 2017
[66] S-P Lee H-J Im S Kang et al ldquoNoninvasive imaging ofmyocardial inflammation in myocarditis using 68Ga-taggedmannosylated human serum albumin positron emissiontomographyrdquoTheranostics vol 7 no 2 pp 413ndash424 2017
[67] Z Zha J Song S R Choi et al ldquo68Ga-Bivalent PolypegylatedStyrylpyridine Conjugates for Imaging A120573 Plaques in CerebralAmyloid Angiopathyrdquo Bioconjugate Chemistry vol 27 no 5 pp1314ndash1323 2016
[68] H Watanabe M Ono S Iikuni et al ldquoA 68Ga complex basedon benzofuran scaffold for the detection of 120573-amyloid plaquesrdquoBioorganic amp Medicinal Chemistry Letters vol 24 no 20 pp4834ndash4837 2014
[69] D Cressier M Dhilly T T Cao Pham et al ldquoGallium-68 Com-plexes Conjugated to Pittsburgh Compound B Radiolabelingand Biological EvaluationrdquoMolecular Imaging and Biology vol18 no 3 pp 334ndash343 2016
[70] D Satpati CArjun R KrishnamohanG Samuel and S Baner-jee ldquo68Ga-labeledCiprofloxacinConjugates as Radiotracers forTargeting Bacterial InfectionrdquoChemical Biology ampDrug Designvol 87 no 5 pp 680ndash686 2016
[71] T Ebenhan N Chadwick and M M Sathekge ldquoPeptidesynthesis characterization and 68Ga-radiolabeling of NOTA-conjugated ubiquicidin fragments for prospective infectionimaging with PETCTrdquo Nuclear Medicine and Biology vol 41no 5 pp 390ndash400 2014
18 Contrast Media amp Molecular Imaging
[72] T Ebenhan J R Zeevaart and J D Venter ldquoPreclinicalevaluation of 68Ga-labeled 1 4 7-triazacyclononane-1 4 7-triacetic acid-ubiquicidin as a radioligand for PET infectionimagingrdquo Journal of Nuclear Medicine vol 55 no 2 pp 308ndash314 2014
[73] B B Mokaleng T Ebenhan S Ramesh et al ldquoSynthesis 68Ga-radiolabeling and preliminary in vivo assessment of adepsipeptide-derived compound as a potential PETCTinfection imaging agentrdquo BioMed Research International vol2015 Article ID 284354 2015
[74] T Ebenhan B Mokaleng J Venter H Kruger J Zeevaart andM Sathekge ldquoPreclinical Assessment of a 68Ga-DOTA-Functionalized Depsipeptide as a Radiodiagnostic InfectionImaging AgentrdquoMolecules vol 22 no 9 p 1403 2017
[75] S Chopra B Singh A Koul A Mishra and H Wester ldquoSyn-thesis of DOTA conjugated GF-17 and RAWVAWR-NH2 andradiolabeling with 68Ga as a potential PET tracer for infectionimagingrdquo J Nucl Med vol 57 Supplement 2 p 1115 2016
[76] M Petrik HHaas P Laverman et al ldquo 68Ga-triacetylfusarinineC and 68Ga-ferrioxamine e for aspergillus infection imaginguptake specificity in various microorganismsrdquoMolecular Imag-ing and Biology vol 16 no 1 pp 102ndash108 2014
[77] V Kumar and D K Boddeti ldquo 68Ga-radiopharmaceuticals forPET imaging of infection and inflammationrdquo Recent Results inCancer Research vol 194 pp 189ndash219 2013
[78] M Vorster A Maes A Jacobs et al ldquoEvaluating the possiblerole of 68Ga-citrate PETCT in the characterization of indeter-minate lung lesionsrdquo Annals of Nuclear Medicine vol 28 no 6pp 523ndash530 2014
[79] M Vorster B Mokaleng M M Sathekge and T Ebenhan ldquoAmodified technique for efficient radiolabeling of 68Ga-citratefrom a SnO2-based 68Ge68Ga generator for better infectionimagingrdquoHellenic Journal of Nuclear Medicine vol 16 no 3 pp193ndash198 2013
[80] S Salomaeki J Kemppainen U Hohenthal et al ldquoHead-to-head comparison of 68Ga-Citrate and 18F-FDG PETCT fordetection of infectious foci in patients with staphylococcusaureus bacteraemiardquo Contrast Media amp Molecular Imaging vol2017 p 8 2017
[81] L Fass ldquoImaging and cancer a reviewrdquoMolecular Oncology vol2 no 2 pp 115ndash152 2008
[82] A Chopra L Shan W C Eckelman et al ldquoMolecular imagingand contrast agent database (MICAD) Evolution and progressrdquoMolecular Imaging and Biology vol 14 no 1 pp 4ndash13 2012
[83] A Sanchez-Crespo P Andreo and S A Larsson ldquoPositronflight in human tissues and its influence on PET image spatialresolutionrdquo European Journal of Nuclear Medicine and Molecu-lar Imaging vol 31 no 1 pp 44ndash51 2004
[84] H W A M De Jong L Perk G W M Visser R Boellaard GAM S Van Dongen and A A Lammertsma ldquoHigh resolutionPET imaging characteristics of68Ga 124i and89Zr comparedto18Frdquo in Proceedings of the Nuclear Science Symposium Con-ference Record 2005 IEEE pp 1624ndash1627 Puerto Rico October2005
[85] I Velikyan A Sundin B Eriksson et al ldquoIn vivo bindingof [68Ga]-DOTATOC to somatostatin receptors in neuroen-docrine tumours - impact of peptide massrdquo Nuclear Medicineand Biology vol 37 no 3 pp 265ndash275 2010
[86] U Eberlein and M Lassmann ldquoDosimetry of [68Ga]-labeledcompoundsrdquo Applied Radiation and Isotopes vol 76 pp 70ndash742013
[87] C PettinatoA SarnelliMDiDonna et al ldquo68Ga-DOTANOCBiodistribution and dosimetry in patients affected by neuroen-docrine tumorsrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 35 no 1 pp 72ndash79 2008
[88] B P Burke G S Clemente and S J Archibald ldquoRecentadvances in chelator design and labelling methodology for68Ga radiopharmaceuticalsrdquo Journal of Labelled Compoundsand Radiopharmaceuticals vol 57 no 4 pp 239ndash243 2014
[89] I Velikyan U Rosenstrom S Estrada et al ldquoSynthesis andpreclinical evaluation of 68Ga-labeled collagelin analogs forimaging and quantification of fibrosisrdquo Nuclear Medicine andBiology vol 41 no 9 pp 728ndash736 2014
[90] M F Ferreira G Pereira J P Andre and etal C ldquoGa[NO2A-N-(120572-amino)propionate] chelates Synthesis and evaluation aspotential tracers for 68Ga PETrdquoDalton Transactions vol 43 no21 pp 8037ndash8047 2014
[91] J Notni J Simecek and H-J Wester ldquoPhosphinic acid func-tionalized polyazacycloalkane chelators for radiodiagnosticsand radiotherapeutics Unique characteristics and applicationsrdquoChemMedChem vol 9 no 6 pp 1107ndash1115 2014
[92] J Simecek O Zemek P Hermann J Notni and H J WesterldquoTailored gallium( III) chelator NOPO synthesis characteriza-tion bioconjugation and application in preclinical Ga-68-PETimagingrdquoMolecular Pharmaceutics 2013
[93] D Parker B P Waldron and D S Yufit ldquoCrystallographicand solution NMR structural analyses of four hexacoordinatedgallium(iii) complexes based on ligands derived from 6-amino-perhydro-14-diazepinerdquo Dalton Transactions vol 42 no 22pp 8001ndash8008 2013
[94] B P Waldron D Parker C Burchardt D S Yufit M ZimnyandF Roesch ldquoStructure and stability of hexadentate complexesof ligands based on AAZTA for efficient PET labelling withgallium-68rdquo Chemical Communications vol 49 no 6 pp 579ndash581 2013
[95] D Parker and B PWaldron ldquoConformational analysis and syn-thetic approaches to polydentate perhydro-diazepine ligandsfor the complexation of gallium(iii)rdquo Organic amp BiomolecularChemistry vol 11 no 17 pp 2827ndash2838 2013
[96] I Velikyan H Maecke and B Langstrom ldquoConvenient prepa-ration of 68Ga-based PET-radiopharmaceuticals at room tem-peraturerdquo Bioconjugate Chemistry vol 19 no 2 pp 569ndash5732008
[97] J Erchegyi R Cescato B Waser J E Rivier and J C ReubildquoN-Imidazolebenzyl-histidine substitution in somatostatin andin its octapeptide analogue modulates receptor selectivity andfunctionrdquo Journal of Medicinal Chemistry vol 54 no 17 pp5981ndash5987 2011
[98] R Saha N Saha R S Donofrio and L L Bestervelt ldquoMicrobialsiderophores Amini reviewrdquo Journal of Basic Microbiology vol53 no 4 pp 303ndash317 2013
[99] V Nikolova S Angelova N Markova and T Dudev ldquoGalliumas a Therapeutic Agent A Thermodynamic Evaluation of theCompetition between Ga3+ and Fe3+ Ions in MetalloproteinsrdquoThe Journal of Physical Chemistry B vol 120 no 9 pp 2241ndash2248 2016
[100] C R Chitambar ldquoGallium and its competing roles with ironin biological systemsrdquo Biochimica et Biophysica Acta (BBA) -Molecular Cell Research vol 1863 no 8 pp 2044ndash2053 2016
[101] J A Lessa M A Soares and R G dos Santos ldquoGallium(III)complexes with 2-acetylpyridine-derived thiosemicarbazonesantimicrobial and cytotoxic effects and investigation on theinteractions with tubulinrdquo BioMetals vol 26 pp 151ndash165 2013
Contrast Media amp Molecular Imaging 19
[102] M van Oosten M Hahn L M A Crane et al ldquoTargetedimaging of bacterial infections Advances hurdles and hopesrdquoFEMS Microbiology Reviews vol 39 no 6 pp 892ndash916 2015
[103] M Vorster AMaes C V DWiele andM Sathekge ldquoGallium-68 PET A Powerful Generator-based Alternative to Infectionand Inflammation Imagingrdquo Seminars in Nuclear Medicine vol46 no 5 pp 436ndash447 2016
[104] M Kircher and C Lapa ldquoNovel Noninvasive Nuclear MedicineImaging Techniques for Cardiac Inflammationrdquo Current Car-diovascular Imaging Reports vol 10 no 2 article no 6 2017
[105] D AHammoud ldquoMolecular imaging of inflammation Currentstatusrdquo Journal of Nuclear Medicine vol 57 no 8 pp 1161ndash11652016
[106] D R Brenner D Scherer K Muir et al ldquoA review of the appli-cation of inflammatory biomarkers in epidemiologic cancerresearchrdquo Cancer Epidemiology Biomarkers amp Prevention vol23 no 9 pp 1729ndash1751 2014
[107] M D Turner B Nedjai T Hurst and D J PenningtonldquoCytokines and chemokines at the crossroads of cell signallingand inflammatory diseaserdquo Biochimica et Biophysica Acta (BBA)- Molecular Cell Research vol 1843 no 11 pp 2563ndash2582 2014
[108] L Werner H Guzner-Gur and I Dotan ldquoInvolvement ofCXCR4CXCR7CXCL12 interactions in inflammatory boweldiseaserdquoTheranostics vol 3 no 1 pp 40ndash46 2013
[109] S Jalkanen and M Salmi ldquoVAP-1 and CD73 endothelial cellsurface enzymes in leukocyte extravasationrdquo ArteriosclerosisThrombosis and Vascular Biology vol 28 no 1 pp 18ndash26 2008
[110] G Malviya F Galli I Sonni and A Signore ldquoImaging T-lymphocytes in inflammatory diseases A nuclear medicineapproachrdquo The Quarterly Journal of Nuclear Medicine andMolecular Imaging vol 58 no 3 pp 237ndash257 2014
[111] S Gratz H J RennenO C BoermanW J Oyen and P Burmaldquo(99m)Tc-interleukin-8 for imaging acute osteomyelitisrdquo Jour-nal of Nuclear Medicine vol 42 no 8 pp 1257ndash1264 2001
[112] S Gratz H J Rennen O C Boerman W J Oyen andF H Corstens ldquoRapid imaging of experimental colitis with(99m)Tc-interleukin-8 in rabbitsrdquo Journal of Nuclear Medicnevol 42 no 6 pp 917ndash923 2001
[113] C Alkim H Alkim A R Koksal S Boga and I SenldquoAngiogenesis in inflammatory bowel diseaserdquo InternationalJournal of Inflammation vol 2015 Article ID 970890 2015
[114] I S Alam T H Witney G Tomasi et al ldquoRadiolabeled RGDtracer kinetics annotates differential 120572v1205733 integrin expressionlinked to cell intrinsic and vessel expressionrdquoMolecular Imagingand Biology vol 16 no 4 pp 558ndash566 2014
[115] J Notni K Pohle and H-J Wester ldquoBe spoilt for choice withradiolabelled RGD peptides Preclinical evaluation of 68Ga-TRAP(RGD)3rdquoNuclear Medicine and Biology vol 40 no 1 pp33ndash41 2013
[116] J Oxboel M Brandt-Larsen C Schjoeth-Eskesen et al ldquoCom-parison of two new angiogenesis PET tracers 68Ga-NODAGA-E[c(RGDyK)]2 and 64Cu-NODAGA-E[c(RGDyK)]2 in vivoimaging studies in human xenograft tumorsrdquo Nuclear Medicineand Biology vol 41 no 3 pp 259ndash267 2014
[117] J Simecek J Notni T G Kapp H Kessler and H-J WesterldquoBenefits of NOPO as chelator in gallium-68 peptides exempli-fied by preclinical characterization of 68Ga-NOPO-c(RGDfK)rdquoMolecular Pharmaceutics vol 11 no 5 pp 1687ndash1695 2014
[118] M Trajkovic-Arsic P Mohajerani A Sarantopoulos et alldquoMultimodal molecular imaging of integrin avb3 for in vivodetection of pancreatic cancerrdquo Journal of NuclearMedicine vol55 no 3 pp 446ndash451 2014
[119] H Cai and P S Conti ldquoRGD-based PET tracers for imagingreceptor integrin 120572 v1205733 expressionrdquo Journal of Labelled Com-pounds and Radiopharmaceuticals vol 56 no 5 pp 264ndash2792013
[120] I Dijkgraaf S Y A Terry W J Mcbride et al ldquoImagingintegrin alpha-v-beta-3 expression in tumors with an 18F-labeled dimeric RGD peptiderdquo Contrast Media amp MolecularImaging vol 8 no 3 pp 238ndash245 2013
[121] P A Knetsch M Petrik C Rangger et al ldquo[68Ga]NS3-RGD and [68Ga] Oxo-DO3A-RGD for imaging 120572v1205733 integrinexpression Synthesis evaluation and comparisonrdquo NuclearMedicine and Biology vol 40 no 1 pp 65ndash72 2013
[122] Z Liu and F Wang ldquoDevelopment of RGD-based radiotracersfor tumor imaging and therapy Translating from bench tobedsiderdquo Current Molecular Medicine vol 13 no 10 pp 1487ndash1505 2013
[123] H Choi J H Phi J C Paeng et al ldquoImaging of integrin 120572v1205733expression using 68Ga-RGD positron emission tomography inpediatric cerebral infarctrdquoMolecular Imaging vol 12 no 4 pp213ndash217 2013
[124] H-J Yoon K W Kang I K Chun et al ldquoCorrelation of breastcancer subtypes based on estrogen receptor progesteronereceptor and HER2 with functional imaging parameters from68Ga-RGD PETCT and 18F-FDG PETCTrdquo European Journalof Nuclear Medicine and Molecular Imaging vol 41 no 8 pp1534ndash1543 2014
[125] R P Baum H R Kulkarni D Muller et al ldquoFirst-in-human study demonstrating tumor-angiogenesis by PETCTimaging with 68Ga-NODAGA-THERANOST a high-affinitypeptidomimetic for 120572v1205733 integrin receptor targetingrdquo CancerBiotherapy andRadiopharmaceuticals vol 30 no 4 pp 152ndash1592015
[126] R Haubner A Finkenstedt A Stegmayr et alldquo[68Ga]NODAGA-RGD ndash Metabolic stability biodistributionand dosimetry data from patients with hepatocellularcarcinoma and liver cirrhosisrdquo European Journal of NuclearMedicine and Molecular Imaging vol 43 no 11 pp 2005ndash20132016
[127] V Lopez-Rodrıguez C Galindo-Sarco F O Garcıa-Perez GFerro-Flores O Arrieta and M A Avila-Rodrıguez ldquoPET-based human dosimetry of the dimeric 120572v1205733 integrin ligand68Ga-DOTA-E-[c(RGDfK)]2 a potential tracer for imagingtumor angiogenesisrdquo Journal of Nuclear Medicine vol 57 no 3pp 404ndash409 2016
[128] M V Backer Z Levashova V Patel et al ldquoMolecular imagingof VEGF receptors in angiogenic vasculature with single-chainVEGF-based probesrdquo Nature Medicine vol 13 no 4 pp 504ndash509 2007
[129] MV Backer Z Levashova R Levenson F G Blankenberg andJ M Backer ldquoCysteine-containing fusion tag for site-specificconjugation of therapeutic and imaging agents to targetingproteinsrdquoMethods in Molecular Biology (Clifton NJ) vol 494pp 275ndash294 2008
[130] M Eder A V Krivoshein M Backer J M Backer UHaberkorn and M Eisenhut ldquoScVEGF-PEG-HBED-CC andscVEGF-PEG-NOTA conjugates comparison of easy-to-labelrecombinant proteins for [68Ga]PET imaging of VEGF recep-tors in angiogenic vasculaturerdquo Nuclear Medicine and Biologyvol 37 no 4 pp 405ndash412 2010
[131] E Blom I Velikyan A Monazzam P Razifar et al ldquoSynthe-sis and characterization of scVEGF-PEG-[ 68Ga]NOTA andscVEGF-PEG-[ 68Ga]DOTA PET tracersrdquo Journal of Labelled
20 Contrast Media amp Molecular Imaging
Compounds and Radiopharmaceuticals vol 54 no 11 pp 685ndash692 2011
[132] S Gratz M Behe and O C Boerman ldquo 99119898Tc-E-selectinbinding peptide for imaging acute osteomyelitis in a novel ratmodelrdquo Nuclear Medicine Communications vol 22 no 9 pp1003ndash1013 2001
[133] S B Jensen M Kakela L Joslashdal et al ldquoExploring the radiosyn-thesis and in vitro characteristics of [68Ga]Ga-DOTA-Siglec-9rdquoJournal of Labelled Compounds and Radiopharmaceuticals vol60 no 9 pp 439ndash449 2017
[134] B A Teicher and S P Fricker ldquoCXCL12 (SDF-1)CXCR4pathway in cancerrdquo Clinical Cancer Research vol 16 no 11 pp2927ndash2931 2010
[135] O Jacobson I D Weiss D O Kiesewetter J M Farber andX Chen ldquoPET of tumor CXCR4 expression with 4-18F-T140rdquoJournal of Nuclear Medicine vol 51 no 11 pp 1796ndash1804 2010
[136] A Aghanejad A R Jalilian Y Fazaeli et al ldquoSynthesis andevaluation of [67Ga]-AMD3100 A novel imaging agent fortargeting the chemokine receptorCXCR4rdquo Scientia Pharmaceu-tica vol 82 no 1 pp 29ndash42 2014
[137] O Jacobson I D Weiss L P Szajek et al ldquoPET imaging ofCXCR4 using copper-64 labeled peptide antagonistrdquoTheranos-tics vol 1 pp 251ndash262 2011
[138] O Jacobson I D Weiss L P Szajek et al ldquoImprovement ofCXCR4 tracer specificity for PET imagingrdquo Journal of Con-trolled Release vol 157 no 2 pp 216ndash223 2012
[139] H J Wester U Keller M Schottelius et al ldquoDisclosing theCXCR4 expression in lymphoproliferative diseases by targetedmolecular imagingrdquo Theranostics vol 5 no 6 pp 618ndash6302015
[140] E Gourni O Demmer M Schottelius et al ldquoPET of CXCR4expression by a 68Ga-labeled highly specific targeted contrastagentrdquo Journal of NuclearMedicine vol 52 no 11 pp 1803ndash18102011
[141] O Demmer I Dijkgraaf U Schumacher et al ldquoDesignsynthesis and functionalization of dimeric peptides targetingchemokine receptor CXCR4rdquo Journal of Medicinal Chemistryvol 54 no 21 pp 7648ndash7662 2011
[142] O Demmer E Gourni U Schumacher H Kessler and H-JWester ldquoPET Imaging of CXCR4 Receptors in Cancer by a NewOptimized Ligandrdquo ChemMedChem vol 6 no 10 pp 1789ndash1791 2011
[143] U Hennrich L Seyler M Schafer et al ldquoSynthesis and invitro evaluation of 68Ga-DOTA-4-FBn-TN14003 a novel tracerfor the imaging of CXCR4 expressionrdquo Bioorganic amp MedicinalChemistry vol 20 no 4 pp 1502ndash1510 2012
[144] G P C George E Stevens O Aberg et al ldquoPreclinical evalua-tion of a CXCR4-specific 68Ga-labelled TN14003 derivative forcancer PET imagingrdquo Bioorganic amp Medicinal Chemistry vol22 no 2 pp 796ndash803 2014
[145] S Poty E Gourni P Desogere et al ldquoAMD3100 A VersatilePlatform for CXCR4 Targeting 68Ga-Based Radiopharmaceu-ticalsrdquo Bioconjugate Chemistry vol 27 no 3 pp 752ndash761 2016
[146] K Philipp-Abbrederis K Herrmann S Knop et al ldquoIn vivomolecular imaging of chemokine receptor CXCR4 expressionin patients with advancedmultiple myelomardquo EMBOMolecularMedicine vol 7 no 4 pp 477ndash487 2015
[147] Z Wang M Zhang L Wang et al ldquoProspective study of 68Ga-NOTA-NFB Radiation dosimetry in healthy volunteers andfirst application in glioma patientsrdquo Theranostics vol 5 no 8pp 882ndash889 2015
[148] I M Jackson P J Scott and S Thompson ldquoClinical Applica-tions of Radiolabeled Peptides for PETrdquo Seminars in NuclearMedicine vol 47 no 5 pp 493ndash523 2017
[149] C Lapa T Reiter R A Werner et al ldquo[68Ga]Pentixafor-PETCT for Imaging of Chemokine Receptor 4 Expression afterMyocardial Infarctionrdquo JACC Cardiovascular Imaging vol 8no 12 pp 1466ndash1468 2015
[150] C Rischpler S G Nekolla H Kossmann et al ldquoUpregu-lated myocardial CXCR4-expression after myocardial infarc-tion assessed by simultaneous GA-68 pentixafor PETMRIrdquoJournal of Nuclear Cardiology vol 23 no 1 pp 131ndash133 2016
[151] F Hyafil J Pelisek I Laitinen et al ldquoImaging the CytokineReceptorCXCR4 in atherosclerotic plaqueswith the radiotracer68Ga-Pentixafor for PETrdquo Journal of Nuclear Medicine vol 58no 3 pp 499ndash506 2017
[152] Y Yi ldquoFolate receptor-targeted diagnostics and therapeutics forinflammatory diseasesrdquo ImmuneNetwork vol 16 no 6 pp 337ndash343 2016
[153] C M Paulos M J Turk G J Breur and P S Low ldquoFolatereceptor-mediated targeting of therapeutic and imaging agentsto activated macrophages in rheumatoid arthritisrdquo AdvancedDrug Delivery Reviews vol 56 no 8 pp 1205ndash1217 2004
[154] W Han R Zaynagetdinov F E Yull et al ldquoMolecular imagingof folate receptor 120573-positive macrophages during acute lunginflammationrdquo American Journal of Respiratory Cell and Molec-ular Biology vol 53 no 1 pp 50ndash59 2015
[155] B Kuhle C Muller and T L Ross ldquoA Novel 68Ga-Labeledpteroic acid-based PET tracer for tumor imaging via the folatereceptorrdquo Recent Results in Cancer Research vol 194 pp 257ndash267 2013
[156] C Brand V A Longo M Groaning W A Weber and TReiner ldquoDevelopment of a New Folate-Derived Ga-68-BasedPET Imaging AgentrdquoMolecular Imaging and Biology vol 19 no5 pp 754ndash761 2017
[157] M Fani XWang G Nicolas et al ldquoDevelopment of new folate-based PET radiotracers Preclinical evaluation of 68Ga-DOTA-folate conjugatesrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 38 no 1 pp 108ndash119 2011
[158] C J Mathias M R Lewis D E Reichert et al ldquoPreparationof 66Ga- and 68Ga-labeled Ga(III)-deferoxamine-folate aspotential folate-receptor-targeted PET radiopharmaceuticalsrdquoNuclear Medicine and Biology vol 30 no 7 pp 725ndash731 2003
[159] S-M Kim N Choi S Hwang et al ldquoFolate receptor-specific positron emission tomography imaging with folic acid-conjugated tissue inhibitor of metalloproteinase-2rdquo Bulletin ofthe Korean Chemical Society vol 34 no 11 pp 3243ndash3248 2013
[160] M Fani M-L Tamma G P Nicolas et al ldquoIn vivo imagingof folate receptor positive tumor xenografts using novel 68Ga-NODAGA-folate conjugatesrdquo Molecular Pharmaceutics vol 9no 5 pp 1136ndash1145 2012
[161] C Muller and R Schibli ldquoProspects in folate receptor-targetedradionuclide therapyrdquo Frontiers in Oncology vol 3 Article IDArticle 249 2013
[162] A Jain A Mathur U Pandey et al ldquoSynthesis and evaluationof a 68Ga labeled folic acid derivative for targeting folatereceptorsrdquo Applied Radiation and Isotopes vol 116 pp 77ndash842016
[163] W Xia A R Hilgenbrink E L Matteson M B Lockwood J-X Cheng and P S Low ldquoA functional folate receptor is inducedduring macrophage activation and can be used to target drugsto activated macrophagesrdquo Blood vol 113 no 2 pp 438ndash4462009
Contrast Media amp Molecular Imaging 21
[164] E P Krenning W A P Breeman P P M Kooij et alldquoLocalisation of endocrine-related tumours with radioiodi-nated analogue of somatostatinrdquoThe Lancet vol 1 no 8632 pp242ndash244 1989
[165] E P Krenning D J KwekkeboomWH Bakker et al ldquoSomato-statin receptor scintigraphy with [111In-DTPA-d-Phe1]- and[123I-Tyr3]-octreotide the Rotterdam experience with morethan 1000 patientsrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 20 no 8 pp 716ndash731 1993
[166] A Stahl G Meisetschlager M Schottelius et al ldquo[123I]Mtr-TOCA a radioiodinated and carbohydrated analogue ofoctreotide Scintigraphic comparison with [111In]octreotiderdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 33 no 1 pp 45ndash52 2006
[167] R Lebtahi J le Cloirec C Houzard et al ldquoDetection of neu-roendocrine tumors 99mTc-P829 scintigraphy compared with111In-pentetreotide scintigraphyrdquo Journal of Nuclear Medicinevol 43 no 7 pp 889ndash895 2002
[168] C Decristoforo T Maina B Nock M Gabriel P Cordopatisand R Moncayo ldquo99mTc-demotate 1 First data in tumourpatients - Results of a pilotphase I studyrdquo European Journal ofNuclearMedicine andMolecular Imaging vol 30 no 9 pp 1211ndash1219 2003
[169] C Decristoforo S J Mather W Cholewinski E DonnemillerG Riccabona and R Moncayo ldquo(99m)Tc-EDDAHYNIC-TOC A new (99m)Tc-labelled radiopharmaceutical forimaging somatostatin receptor-positive tumours First clinicalresults and intra-patient comparison with 111In-labelledoctreotide derivativesrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 27 no 9 pp 1318ndash1325 2000
[170] A Hubalewska-Dydejczyk K Fross-Baron R Mikołajczak etal ldquo99mTc-EDDAHYNIC-octreotate scintigraphy an efficientmethod for the detection and staging of carcinoid tumoursResults of 3 yearsrsquo experiencerdquo European Journal of NuclearMedicine and Molecular Imaging vol 33 no 10 pp 1123ndash11332006
[171] M Bangard M Behe S Guhlke et al ldquoDetection of somato-statin receptor-positive tumours using the new 99mC-tricine-HYNIC-D-Phe1-Tyr3-octreotide First results in patients andcomparison with 111In-DTPA-D-Phe1-octreotiderdquo EuropeanJournal of Nuclear Medicine and Molecular Imaging vol 27 no6 pp 628ndash637 2000
[172] A Helisch G J Forster H Reber et al ldquoPre-therapeuticdosimetry and biodistribution of 86Y-DOTA- Phe1-Tyr3-octreotide versus 111In-pentetreotide in patients with advancedneuroendocrine tumoursrdquo European Journal of NuclearMedicine and Molecular Imaging vol 31 no 10 pp 1386ndash13922004
[173] M Henze J Schuhmacher P Hipp et al ldquoPET imaging ofsomatostatin receptors using [68GA]DOTA-D-Phe1-Tyr3-Octreotide First results in patients with meningiomasrdquo Journalof Nuclear Medicine vol 42 no 7 pp 1053ndash1056 2001
[174] I Kayani J B Bomanji A Groves et al ldquoFunctional imaging ofneuroendocrine tumors with combined PETCT using 68Ga-DOTATATE (Dota-DPhe1 Tyr3-octreotate) and 18F-FDGrdquoCancer vol 112 no 11 pp 2447ndash2455 2008
[175] A Al-Nahhas ldquoNuclear medicine imaging of neuroendocrinetumoursrdquo Clinical Medicine vol 12 no 4 pp 377ndash380 2012
[176] V Ambrosini S Nicolini P Caroli et al ldquoPETCT imaging indifferent types of lung cancer an overviewrdquo European Journal ofRadiology vol 81 no 5 pp 988ndash1001 2012
[177] V Ambrosini D Campana P Tomassetti and S Fanti ldquo68Ga-labelled peptides for diagnosis of gastroenteropancreatic NETrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 39 no 1 pp S52ndashS60 2012
[178] K E Oberg J-C Reubi D J Kwekkeboom and E P KrenningldquoRole of somatostatins in gastroenteropancreatic neuroen-docrine tumor development and therapyrdquoGastroenterology vol139 no 3 pp 753-753 2010
[179] K Oberg ldquoGallium-68 somatostatin receptor PETCT Is ittime to replace 111Indium DTPA octreotide for patients withneuroendocrine tumorsrdquo Endocrine Journal vol 42 no 1 pp3-4 2012
[180] R Srirajaskanthan I Kayani A M Quigley J Soh M ECaplin and J Bomanji ldquoThe role of 68Ga-DOTATATE PET inpatients with neuroendocrine tumors and negative or equivocalfindings on 111In-DTPA-octreotide scintigraphyrdquo Journal ofNuclear Medicine vol 51 no 6 pp 875ndash882 2010
[181] A Kroiss D Putzer and C Uprimny ldquoFunctional imag-ing in phaeochromocytoma and neuroblastoma with 68Ga-DOTA-Tyr3-octreotide positron emission tomography and123I-metaiodobenzylguanidinerdquo European Journal of NuclearMedicine and Molecular Imaging vol 38 no 5 pp 865ndash8732011
[182] M Naji C Zhao S J Welsh et al ldquo68Ga-DOTA-TATE PETvs 123I-MIBG in identifying malignant neural crest tumoursrdquoMolecular Imaging and Biology vol 13 no 4 pp 769ndash775 2011
[183] V Ambrosini P Tomassetti P Castellucci et al ldquoComparisonbetween 68Ga-DOTA-NOC and 18F-DOPA PET for the detec-tion of gastro-entero-pancreatic and lung neuro-endocrinetumoursrdquo European Journal of Nuclear Medicine and MolecularImaging vol 35 no 8 pp 1431ndash1438 2008
[184] D Putzer M Gabriel B Henninger et al ldquoBone metastasesin patients with neuroendocrine tumor 68Ga- DOTA-Tyr3-octreotide PET in comparison to CT and bone scintigraphyrdquoJournal of Nuclear Medicine vol 50 no 8 pp 1214ndash1221 2009
[185] L K Anzola-Fuentes M Chianelli F Galli et al ldquoSomatostatinreceptor scintigraphy in patients with rheumatoid arthritis andsecondary Sjogrenrsquos syndrome treated with Infliximab a pilotstudyrdquo EJNMMI Research vol 6 no 1 article no 49 2016
[186] T Nobashi Y Nakamoto T Kubo et al ldquoThe utility of PETCTwith 68Ga-DOTATOC in sarcoidosis comparison with 67Ga-scintigraphyrdquoAnnals ofNuclearMedicine vol 30 no 8 pp 544ndash552 2016
[187] C Boy T A Heusner T D Poeppel et al ldquo68Ga-DOTATOCPETCT and somatostatin receptor (sst1-sst5) expression innormal human tissue Correlation of sst2mRNAand SUVmaxrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 38 no 7 pp 1224ndash1236 2011
[188] P Rinne S Hellberg M Kiugel et al ldquoComparison of Somato-statin Receptor 2-Targeting PET Tracers in the Detection ofMouse Atherosclerotic Plaquesrdquo Molecular Imaging and Biol-ogy vol 18 no 1 pp 99ndash108 2016
[189] M Asti E Ferrari S Croci et al ldquoSynthesis and characteri-zation of 68Ga-labeled curcumin and curcuminoid complexesas potential radiotracers for imaging of cancer and alzheimersdiseaserdquo Inorganic Chemistry vol 53 no 10 pp 4922ndash49332014
[190] A Signore I Santino and A W J M Glaudemans ldquoIn vivoimaging of microorganismsrdquo Clinical and Translational Imag-ing vol 4 no 3 pp 161-162 2016
[191] S Auletta F Galli C Lauri D Martinelli I Santino andA Signore ldquoImaging bacteria with radiolabelled quinolones
22 Contrast Media amp Molecular Imaging
cephalosporins and siderophores for imaging infection a sys-tematic reviewrdquo Clinical and Translational Imaging vol 4 no 4pp 229ndash252 2016
[192] X Ning S Lee Z Wang et al ldquoMaltodextrin-based imagingprobes detect bacteria in vivo with high sensitivity and speci-ficityrdquo Nature Materials vol 10 no 8 pp 602ndash607 2011
[193] J Ady andY Fong ldquoImaging for infection Fromvisualization ofinflammation to visualization of microbesrdquo Surgical Infectionsvol 15 no 6 pp 700ndash707 2014
[194] J M Sierra D Rodriguez-Puig A Soriano J Mensa C Pieraand J Vila ldquoAccumulation of 99mTc-ciprofloxacin in Staphy-lococcus aureus and Pseudomonas aeruginosardquo AntimicrobialAgents and Chemotherapy vol 52 no 7 pp 2691-2692 2008
[195] D I Andersson and D Hughes ldquoMicrobiological effects ofsublethal levels of antibioticsrdquoNature ReviewsMicrobiology vol12 no 7 pp 465ndash478 2014
[196] N Dumarey D Blocklet T Appelboom L Tant and ASchoutens ldquoInfecton is not specific for bacterial osteo-articularinfective pathologyrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 29 no 4 pp 530ndash535 2002
[197] K E Britton D W Wareham S S Das et al ldquoImaging bacte-rial infection with 99mTc-ciprofloxacin (Infecton)rdquo Journal ofClinical Pathology vol 55 no 11 pp 817ndash823 2002
[198] G Ferro-Flores M A Avila-Rodrıguez and F O Garcıa-PerezldquoImaging of bacteria with radiolabeled ubiquicidin by SPECTand PET techniquesrdquo Clinical and Translational Imaging vol 4no 3 pp 175ndash182 2016
[199] P S Hiemstra M T van den Barselaar M Roest P H Nibber-ing and R van Furth ldquoUbiquicidin a novel murine microbi-cidal protein present in the cytosolic fraction of macrophagesrdquoJournal of Leukocyte Biology vol 66 no 3 pp 423ndash428 1999
[200] M S Akhtar A Qaisar J Irfanullah et al ldquoAntimicrobialpeptide 99mTc-ubiquicidin 29ndash41 as human infection-imagingagent clinical trialrdquo Journal of Nuclear Medicne vol 46 no 4pp 567ndash573 2005
[201] M Assadi K Vahdat I Nabipour et al ldquoDiagnostic value of99mTc-ubiquicidin scintigraphy for osteomyelitis and compar-isons with 99mTc-methylene diphosphonate scintigraphy andmagnetic resonance imagingrdquo Nuclear Medicine Communica-tions vol 32 no 8 pp 716ndash723 2011
[202] T Emery ldquoExchange of Iron by Gallium in SiderophoresrdquoBiochemistry vol 25 no 16 pp 4629ndash4633 1986
[203] M Petrik C Zhai H Haas and C Decristoforo ldquoSiderophoresfor molecular imaging applicationsrdquo Clinical and TranslationalImaging vol 5 no 1 pp 15ndash27 2017
[204] H J Flint E A BayerM T Rincon R Lamed and B AWhiteldquoPolysaccharide utilization by gut bacteria potential for newinsights from genomic analysisrdquo Nature Reviews Microbiologyvol 6 no 2 pp 121ndash131 2008
[205] GGowrishankarMNamavari E B Jouannot et al ldquoInvestiga-tion of 6-[18F]-fluoromaltose as a novel PET tracer for imagingbacterial infectionrdquo PLoS ONE vol 9 no 9 Article ID e1079512014
[206] N Gholipour M Akhlaghi A M Kheirabadi et al ldquoChelator-free radiolabeling of dextran with 68Ga for PET studiesrdquoJournal of Radioanalytical and Nuclear Chemistry vol 311 no3 pp 1811ndash1817 2017
[207] C Bettegowda C A Foss I Cheong et al ldquoImaging bac-terial infections with radiolabeled 1-(21015840-deoxy-21015840- fluoro-120573-D-arabinofuranosyl)-5-iodouracilrdquo Proceedings of the NationalAcadamy of Sciences of the United States of America vol 102 no4 pp 1145ndash1150 2005
[208] S A Soghomonyan M Doubrovin J Pike et al ldquoPositronemission tomography (PET) imaging of tumor-localizedSalmonella expressing HSV1-TKrdquo Cancer GeneTherapy vol 12no 1 pp 101ndash108 2005
[209] C Palestro K Nichols S Sheikh-Fayyaz S Dewey P Singhaland K Bhargava ldquoCan Gallium-68 PET differentiate acuteinterstitial nephritis from acute tubular necrosisrdquo Journal ofNuclear Medicne vol 57 Supplement 2 p 551 2016
[210] A J Morguet D L Munz V Ivancevic et al ldquoImmunoscintig-raphy using technetium-99m-labeled anti-NCA-95 antigranu-locyte antibodies as an adjunct to echocardiography in subacuteinfective endocarditisrdquo Journal of the American College ofCardiology vol 23 no 5 pp 1171ndash1178 1994
[211] C van der Laken O Boerman W Oyen et al ldquoIn Vivo Expres-sion of Interleukin-1 Receptors during Various ExperimentallyInduced Inflammatory Conditionsrdquo The Journal of InfectiousDiseases vol 177 no 5 pp 1398ndash1401 1998
[212] C J Van Der Laken O C Boerman W J G Oyen M T PVan De Ven J W M Van Der Meer and F H M CorstensldquoScintigraphic detection of infection and inflammation Newdevelopments with special emphasis on receptor interactionrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 25 no 5 pp 535ndash546 1998
[213] C J van der LakenOC BoermanW J GOyenM T P van deVen J W M van der Meer and F H M Corstens ldquoImaging ofinfection in rabbits with radioiodinated interleukin-1 (120572 and 120573)its receptor antagonist and a chemotactic peptide a comparativestudyrdquo European Journal of Nuclear Medicine and MolecularImaging vol 25 no 4 pp 347ndash352 1998
[214] C J Van Der Laken O C BoermanW J G Oyen M T P VanDe Ven F H M Corstens and J W M Ven Der Meer ldquoThekinetics of radiolabelled interleukin-8 in infection and sterileinflammationrdquo Nuclear Medicine Communications vol 19 no3 pp 271ndash282 1998
[215] E Lazzeri P Erba M Perri et al ldquoScintigraphic imaging ofvertebral osteomyelitis with 111in-biotinrdquoThe Spine Journal vol33 no 7 pp E198ndashE204 2008
[216] E Blom B Langstrom and I Velikyan ldquo68Ga-labeling of biotinanalogues and their characterizationrdquo Bioconjugate Chemistryvol 20 no 6 pp 1146ndash1151 2009
[217] O Eriksson F Carlsson E Blom et al ldquoPreclinical evaluationof a 68Ga-labeled biotin analogue for applications in islettransplantationrdquo Nuclear Medicine and Biology vol 39 no 3pp 415ndash421 2012
[218] E A Weinstein A A Ordonez V P DeMarco et alldquoImaging Enterobacteriaceae infection in vivo with 18F-fluoro-deoxysorbitol positron emission tomographyrdquo Science Transla-tional Medicine vol 6 no 259 p 259ra146 2014
[219] K M Nielsen M H Kyneb A K O Alstrup et alldquo68Ga-labeled phage-display selected peptides as tracers forpositron emission tomography imaging of Staphylococcusaureus biofilm-associated infections Selection radiolabellingand preliminary biological evaluationrdquo Nuclear Medicine andBiology vol 43 no 10 pp 593ndash605 2016
[220] T J Makinen P Lankinen T Poyhonen J Jalava H T Aroand A Roivainen ldquoComparison of 18F-FDG and 68Ga PETimaging in the assessment of experimental osteomyelitis due toStaphylococcus aureusrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 32 no 11 pp 1259ndash1268 2005
[221] JMU Silvola I LaitinenH J Sipila et al ldquoUptake of 68galliumin atherosclerotic plaques in LDLRminusminusApoB100100micerdquo EJN-MMI Research vol 1 no 1 pp 1ndash8 2011
Contrast Media amp Molecular Imaging 23
[222] T A Wynn ldquoCellular and molecular mechanisms of fibrosisrdquoThe Journal of Pathology vol 214 no 2 pp 199ndash210 2008
[223] T Derlin D Jonigk J Bauersachs and FM Bengel ldquoMolecularImaging of Chemokine Receptor CXCR4 in NonndashSmall CellLung Cancer Using 68Ga-Pentixafor PETCT ComparisonWith 18F-FDGrdquo Clinical Nuclear Medicine 2016
[224] I Velikyan U Rosenstrom T N Bulenga O Eriksson andG Antoni ldquoFeasibility of multiple examinations using68ga-labelled collagelin analogues Organ distribution in rat forextrapolation to human organ and whole-body radiationdosimetryrdquo Pharmaceuticals vol 9 no 2 article no 31 2016
[225] S Jadhav M Kakela J Makila et al ldquoSynthesis and in VivoPET Imaging of Hyaluronan Conjugates of OligonucleotidesrdquoBioconjugate Chemistry vol 27 no 2 pp 391ndash403 2016
[226] A Autio A Saraste N Kudomi et al ldquoAssessment of bloodflow with (68) Ga-DOTA PET in experimental inflammation avalidation study using (15) O-waterrdquo American Journal ofNuclear Medicine and Molecular Imaging vol 4 no 6 pp 571ndash579 2014
[227] G Davies A Rolle A Maurer et al ldquoTowards translationalimmunoPETMR imaging of invasive pulmonary aspergillosisthe Humanised Monoclonal Antibody JF5 detects in vivordquoTheranostics vol 7 no 14 pp 3398ndash3414 2017
[228] DGoodwin CMeares GDavid et al ldquoMonoclonal antibodiesas reversible equilibrium carriers of radiopharmaceuticalsrdquoInternational Journal of Radiation Applications and Instrumen-tation Part B Nuclear Medicine and Biology vol 13 no 4 pp383ndash391 1986
[229] D A Goodwin C F Mears M McTigue and G S DavidldquoMonoclonal antibody hapten radiopharmaceutical deliveryrdquoNuclear Medicine Communications vol 7 no 8 pp 569ndash5801986
[230] S E Halpern and R O Dillman ldquoProblems associated withradioimmunodetection and possibilities for future solutionsrdquo JBiol Response Mod vol 6 no 3 pp 235ndash262 1987
[231] H Hong J Sun and W Cai ldquoRadionuclide-based cancerimaging targeting the carcinoembryonic antigenrdquo BiomarkerInsights vol 3 pp 435ndash451 2008
[232] G J Forster E B Santos P M Smith-Jones P Zanzonico andS M Larson ldquoPretargeted radioimmunotherapy with a single-chain antibodystreptavidin construct and radiolabeledDOTA-biotin Strategies for reduction of the renal doserdquo Journal ofNuclear Medicine vol 47 no 1 pp 140ndash149 2006
[233] Z Yao M Zhang H Kobayashi et al ldquoImproved targeting ofradiolabeled streptavidin in tumors pretargeted with biotiny-lated monoclonal antibodies through an avidin chaserdquo Journalof Nuclear Medicine vol 36 no 5 pp 837ndash841 1995
[234] C-H Chang R M Sharkey E A Rossi et al ldquoMolecularAdvances in Pretargeting Radioimunotherapy with BispecificAntibodies 1 Supported in part by USPHS Grant R01-CA-84379from the NIH and Department of Energy Grant DE-FG01-00NE22941 (both to R M S)1rdquo Mol Cancer Ther vol 1 no 7pp 553ndash563 2002
[235] R M Sharkey E A Rossi W J McBride C-H Chang andD M Goldenberg ldquoRecombinant Bispecific Monoclonal Anti-bodies Prepared by theDock-and-Lock Strategy for PretargetedRadioimmunotherapyrdquo Seminars in Nuclear Medicine vol 40no 3 pp 190ndash203 2010
[236] R M Sharkey E A Rossi C-H Chang and D M Golden-berg ldquoImproved cancer therapy and molecular imaging withmultivalent multispecific antibodiesrdquo Cancer Biotherapy andRadiopharmaceuticals vol 25 no 1 pp 1ndash12 2010
[237] D M Goldenberg R M Sharkey G Paganelli J Barbet andJ Chatal ldquoAntibody pretargeting advances cancer radioim-munodetection and radioimmunotherapyrdquo Journal of ClinicalOncology vol 24 no 5 pp 823ndash834 2006
[238] O C Boerman F G van Schaijk W J G Oyen and FH M Corstens ldquoPretargeted radioimmunotherapy of cancerprogress step by steprdquo Journal of Nuclear Medicine vol 44 no3 pp 400ndash411 2003
[239] J Schuhmacher S Kaul G Klivenyi et al ldquoImmunoscintigra-phy with positron emission tomography Gallium-68 chelateimaging of breast cancer pretargeted with bispecific anti-MUC1anti-Ga chelate antibodiesrdquo Cancer Research vol 61 no9 pp 3712ndash3717 2001
[240] J Schuhmacher G Klivenyi S Kaul et al ldquoPretargeting ofhuman mammary carcinoma xenografts with bispecific anti-MUC1anti-Ga chelate antibodies and immunoscintigraphywith PETrdquo Nuclear Medicine and Biology vol 28 no 7 pp 821ndash828 2001
[241] C Somasundaram S Matzku J Schuhmacher and M ZollerldquoDevelopment of a bispecific monoclonal antibody against agallium-67 chelate and the human melanoma-associated anti-gen p97 for potential use in pretargeted immunoscintigraphyrdquoCancer Immunology Immunotherapy vol 36 no 5 pp 337ndash3451993
[242] E A Rossi D L Rossi R Stein D M Goldenberg and C-H Chang ldquoA bispecific antibody-IFN1205722b immunocytokine tar-geting CD20 and HLA-DR is highly toxic to human lymphomaandmultiplemyeloma cellsrdquoCancer Research vol 70 no 19 pp7600ndash7609 2010
[243] R M Sharkey H Karacay S Litwin et al ldquoImproved ther-apeutic results by pretargeted radioimmunotherapy of non-Hodgkinrsquos lymphoma with a new recombinant trivalent anti-CD20 bispecific antibodyrdquo Cancer Research vol 68 no 13 pp5282ndash5290 2008
[244] G L Griffiths C-H Chang W J McBride et al ldquoReagentsandmethods for PETusing bispecific antibody pretargeting and68Ga-radiolabeled bivalent hapten-peptide-chelate conjugatesrdquoJournal of Nuclear Medicine vol 45 no 1 pp 30ndash39 2004
[245] J Watine M Miedouge and B Friedberg ldquoCarcinoembryonicantigen as an independent prognostic factor of recurrence andsurvival in patients resected for colorectal liver metastases Asystematic reviewrdquo Diseases of the Colon amp Rectum vol 44 no12 pp 1791ndash1799 2001
[246] M J Goldstein and E P Mitchell ldquoCarcinoembryonic antigenin the staging and follow-up of patients with colorectal cancerrdquoCancer Investigation vol 23 no 4 pp 338ndash351 2005
[247] D V Gold D M Goldenberg H Karacay et al ldquoA novelbispecific trivalent antibody construct for targeting pancreaticcarcinomardquo Cancer Research vol 68 no 12 pp 4819ndash48262008
[248] J Schuhmacher G Klivenyi R Matys et al ldquoMultistep tumortargeting in nudemice using bispecific antibodies and a galliumchelate suitable for immunoscintigraphy with positron emis-sion tomographyrdquo Cancer Research vol 55 no 1 pp 115ndash1231995
[249] G Klivenyi J Schuhmacher E Patzelt et al ldquoGallium-68chelate imaging of human colon carcinoma xenografts pre-targeted with bispecific anti-CD44(V6)anti-gallium chelateantibodiesrdquo Journal ofNuclearMedicine vol 39 no 10 pp 1769ndash1776 1998
[250] M Zoller J Schuhmacher J Reed W Maier-Borst and SMatzku ldquoEstablishment and characterization of monoclonal
24 Contrast Media amp Molecular Imaging
antibodies against an octahedral gallium chelate suitable forimmunoscintigraphy with PETrdquo Journal of Nuclear Medicinevol 33 no 7 pp 1366ndash1372 1992
[251] R M Sharkey T M Cardillo E A Rossi et al ldquoSignal ampli-fication in molecular imaging by pretargeting a multivalentbispecific antibodyrdquo Nature Medicine vol 11 no 11 pp 1250ndash1255 2005
[252] D M Goldenberg and R M Sharkey ldquoNovel radiolabeledantibody conjugatesrdquo Oncogene vol 26 no 25 pp 3734ndash37442007
[253] D M Goldenberg E A Rossi R M Sharkey W J McBrideand C-H Chang ldquoMultifunctional antibodies by the dock-and-lock method for improved cancer imaging and therapy bypretargetingrdquo Journal of NuclearMedicine vol 49 no 1 pp 158ndash163 2008
[254] R Schoffelen R M Sharkey D M Goldenberg et al ldquoPre-targeted immuno-positron emission tomography imaging ofcarcinoembryonic antigen-expressing tumors with a bispecificantibody and a68Ga- And18F-labeled hapten peptide in micewith human tumor xenograftsrdquoMolecular Cancer Therapeuticsvol 9 no 4 pp 1019ndash1027 2010
[255] E S Bos W H Kuijpers M Meesters-Winters et al ldquoIn vitroevaluation of DNA-DNA hybridization as a two-step approachin radioimmunotherapy of cancerrdquoCancer Research vol 54 no13 pp 3479ndash3486 1994
[256] G Paganelli M Bartolomei M Ferrari et al ldquoPre-TargetedLocoregional Radioimmunotherapy withrdquo Cancer biotherapyand radiopharmaceuticals vol 16 no 3 pp 227ndash235 2001
[257] A Forero P L Weiden J M Vose et al ldquoPhase 1 trial of a novelanti-CD20 fusion protein in pretargeted radioimmunotherapyfor B-cell non-Hodgkin lymphomardquo Blood vol 104 no 1 pp227ndash236 2004
[258] DM Goldenberg C-H Chang E A RossiW J McBride andR M Sharkey ldquoPretargeted molecular imaging and radioim-munotherapyrdquoTheranostics vol 2 no 5 pp 523ndash540 2012
[259] H Karacay R M Sharkey W J McBride E A Rossi C-HChang and D M Goldenberg ldquoOptimization of hapten-peptide labeling for pretargeted immunoPET of bispecificantibody using generator-produced 68Gardquo Journal of NuclearMedicine vol 52 no 4 pp 555ndash559 2011
[260] J R Oh and B C Ahn ldquoFalse-positive uptake on radioiodinewhole-body scintigraphy physiologic and pathologic variantsunrelated to thyroid cancerrdquo American Journal of NuclearMedicine and Molecular Imaging vol 2 no 2 pp 141ndash150 2012
[261] E Frampas C Rousseau C Bodet-Milin J Barbet J-F Chataland F Kraeber-Bodere ldquoImprovement of radioimmunotherapyusing pretargetingrdquo Frontiers in Oncology vol 3 Article ID00159 2013
[262] C S McKay and M G Finn ldquoClick chemistry in complexmixtures Bioorthogonal bioconjugationrdquo Chemistry amp Biologyvol 21 no 9 pp 1075ndash1101 2014
[263] B L Oliveira Z Guo and G J Bernardes ldquoInverse electrondemand DielsndashAlder reactions in chemical biologyrdquo ChemicalSociety Reviews vol 46 no 16 pp 4895ndash4950 2017
[264] B Nichols Z Qin J Yang D R Vera and N K Devaraj ldquo68Gachelating bioorthogonal tetrazine polymers for the multisteplabeling of cancer biomarkersrdquo Chemical Communications vol50 no 40 pp 5215ndash5217 2014
[265] R Rossin P R Verkerk S M van den Bosch et al ldquoInvivo chemistry for pretargeted tumor imaging in live micerdquoAngewandte Chemie International Edition vol 49 no 19 pp3375ndash3378 2010
[266] B M Zeglis K K Sevak T Reiner et al ldquoA pretargetedPET imaging strategy based on bioorthogonal diels-alder clickchemistryrdquo Journal of Nuclear Medicine vol 54 no 8 pp 1389ndash1396 2013
[267] J L Houghton R Membreno D Abdel-Atti et al ldquoEstablish-ment of the invivo efficacy of pretargeted radioimmunotherapyutilizing inverse electron demand diels-alder click chemistryrdquoMolecular Cancer Therapeutics vol 16 no 1 pp 124ndash133 2017
[268] J Funkhouser ldquoReinventing pharma the theranostic revolu-tionrdquo Current Drug Discovery pp 17ndash19 2002
[269] J Sorensen I Velikyan A Wennborg et al ldquoMeasuring HER2-expression in metastatic breast cancer using 68Ga-ABY025PETCTrdquo European Journal of Nuclear Medicine and MolecularImaging vol 41 pp S226ndashS226 2014
[270] I Velikyan A Wennborg J Feldwisch et al ldquoGMP compliantpreparation of a 68Gallium-labeled Affibody analogue forbreast cancer patient examination first-in-manrdquoEur JNuclMedMol Imaging vol 41 pp S228ndashS229 2014
[271] K Oberg ldquoMolecular imaging radiotherapy Theranostics forpersonalized patient management of neuroendocrine tumors(NETs)rdquoTheranostics vol 2 no 5 pp 448ndash458 2012
[272] I Velikyan AWennborg J FeldwischH Lindman J Carlssonand J Sorensen ldquoGood manufacturing practice production of [(68) Ga]Ga-ABY-025 for HER2 specific breast cancer imagingrdquoAmerican Journal of Nuclear Medicine and Molecular Imagingvol 6 no 2 pp 135ndash153 2016
[273] M Sandstrom K Lindskog I Velikyan et al ldquoBiodistributionand radiation dosimetry of the anti-HER2 Affibody molecule68Ga-ABY-025 in breast cancer patientsrdquo Journal of NuclearMedicine vol 57 no 6 pp 867ndash871 2016
[274] D Sandberg V Tolmachev I Velikyan et al ldquoIntra-imagereferencing for simplified assessment of HER2-expression inbreast cancer metastases using the Affibody molecule ABY-025with PET and SPECTrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 44 no 8 pp 1337ndash1346 2017
[275] H ZhangM AMoroz I Serganova et al ldquoImaging expressionof the human somatostatin receptor subtype-2 reporter genewith 68Ga-DOTATOCrdquo Journal ofNuclearMedicine vol 52 no1 pp 123ndash131 2011
[276] M Naji and A Al-Nahhas ldquo68Ga-labelled peptides in themanagement of neuroectodermal tumoursrdquo European Journalof Nuclear Medicine and Molecular Imaging vol 39 no 1 ppS61ndashS67 2012
[277] I Velikyan ldquoThe diversity of 68Ga-Based imaging agentsrdquoRecent Results in Cancer Research vol 194 pp 101ndash131 2013
[278] K Ferreira H-Y Hu V Fetz et al ldquoMultivalent siderophore-dotam conjugates as theranostics for imaging and treatment ofbacterial infectionsrdquo Angewandte Chemie International Editionvol 56 no 28 pp 8272ndash8276 2017
Computational and Mathematical Methods in Medicine
Hindawiwwwhindawicom Volume 2018
Behavioural Neurology
OphthalmologyJournal of
Hindawiwwwhindawicom Volume 2018
Diabetes ResearchJournal of
Hindawiwwwhindawicom Volume 2018
Hindawiwwwhindawicom Volume 2018
Research and TreatmentAIDS
Hindawiwwwhindawicom Volume 2018
Gastroenterology Research and Practice
Hindawiwwwhindawicom Volume 2018
Parkinsonrsquos Disease
Evidence-Based Complementary andAlternative Medicine
Volume 2018Hindawiwwwhindawicom
Submit your manuscripts atwwwhindawicom
Contrast Media amp Molecular Imaging 11
N
O
N
ON
HN
O
O
O
OO O
NH
O
O
O
O
NH
O
OGa
（3
（3
（3
（3
（3
（3
（2
(a) (b) (c)
Figure 5 Molecular structure of [68Ga]Ga-triacetylfusarinine C (a) used for the in vivo imaging of a rat with Aspergillus fumigatus infection(b) and negative control of noninfected rat (c) White arrows point at the infected (b) and normal (c) lungs Adapted from [76]
the development of 68Ga-labelled nucleosides that wouldmaintain their biological activity is challenging and fewexamples known from the literature confirm that [4 6]
7 68Ga-Citrate
As mentioned above 68GaPET provides a number of advan-tages over 67GaSPECT and following publications demon-strate it in clinical and preclinical studies [68Ga]Ga-citratedemonstrated high diagnostic accuracy of 90of osteomyeli-tis and diskitis in clinical studies (Figure 6) [18 19] Thisstudy demonstrates that [68Ga]Ga-citrate can be employedfor monitoring the response to treatment [68Ga]Ga-citratewas used clinically to follow-up surgical intervention inpatients with acute osteomyelitis and intra-abdominal infec-tion [77] The agent was also used to successfully visualizelungmalignancy and tuberculosis in patients however in caseof high prevalence of granulomatous diseases the distinctionbetween malignant and benign lung lesions was unclear [7879] Another clinical study conducted head-to-head compar-ison of [68Ga]Ga-citrate (Figure 7) and [18F]FDG in patientswith Staphylococcus aureus bacteremia [80] The detectionrate of osteomyelitis was similar and further investigationof [68Ga]Ga-citrate applicability in cases of osteomyelitisinduced by other pathogens as well as for monitoring healingprocess is warranted
Comparative study of [68Ga]Ga-citrate and [67Ga]Ga-citrate was performed in healthy and infection model rats[77] The performance of [68Ga]Ga-citrate was found supe-rior in terms of image contrast in the lower abdomen and
extremities Potential of [68Ga]Ga-citrate for the differentia-tion of acute interstitial nephritis from acute tubular necrosiswas studied in rat model of the disease and it was demon-strated that the kidney uptake correlated with the extentof mononuclear cell infiltration accompanying inflammation[209] 68Ga-labelled Apo-transferrin demonstrated bacterialinfection detection capacity in rat model with Staphylococcusaureus wherein the infection site was visualized 1 h afteradministration of the agent [14]
71 Radiolabelled Antibodies and Antibody FragmentsHuman immunoglobulin (HIG) binds to bacteria but alsoaccumulates at the sites of fungal and viral infection aswell as sterile inflammation due to binding to leukocytesThe improved specificity for bacteria was achieved for thefragments of HIG It is feasible to develop specific antibodiesto various antigens present on the bacterial cell surface [102]Monoclonal antibodies labelled with 99mTc were used forinfection imaging via granulocytes targeting NCA-95 [210]Various cytokines of interleukin family (IL-1 IL-8) labelledwith 123I or 99mTc demonstrated accumulation in the sitesof infection in various animal models [111 112 211ndash214]Registered antigranulocyte radiopharmaceuticals suchas LeuTech Scintimun and Leukoscan are based on99mTc-labelled antibodies This experience can be translatedto 68Ga however either the size of the antibodies mustbe reduced or pretargeting techniques must be appliedin order to overcome the discrepancy between the shortphysical half-life of 68Ga and slow pharmacokinetics ofantibodies
12 Contrast Media amp Molecular Imaging
(a) (b) (c) (d)
Figure 6 [68Ga]Ga-citrate PETCT examination of a patient affected by acute osteomyelitis before (left panel) and after (right panel) surgicalcurettage showing uptake in the transaxial (a c) and 3D reconstruction images (b d red area) Absence of the uptake after the therapyconfirms complete response to the treatment Adapted from [19]
Figure 7 Vertebral osteomyelitis (spondylodiscitis red arrow-heads) and abscesses in the iliopsoas and paravertebral area (redarrows) were detected by [68Ga]Ga-citrate in a patient admittedto the hospital with back pain and general symptoms The PETacquisition was performed 88min after administration of 245MBqof [68Ga]Ga-citrate Adapted from [80]
72 Radiolabelled Biotin Biotin is a growth factor utilizedin many bacteria An 111In-labelled analogue of biotin wassuccessfully utilized for diagnosis of vertebral infections ina clinical study [215] It would be rational to explore therelevance of 68Ga-labelled analogues given the advantagesof 68Ga over 111In and promising [68Ga]Ga-DOTA-Biotinanalogues [216 217] developed for monitoring survival oftransplanted avidin-coated islets
8 Miscellaneous
Stable Ga(III) complex with thiosemicarbazones demon-strated antimicrobial effect against P aeruginosa and Calbicans due to most probably both displacement of essentialFe(III) with Ga(III) and thiosemicarbazones [101] Substitu-tion of the stable Ga(III) by radioactive 68Ga might result ina specific infection imaging agent
Selective imaging of Enterobacteriaceae using 2-[18F]-fluorodeoxysorbitol (18F-FDS)was demonstrated in amurine
myositis model [218] The uptake of 18F-FDS was correlatedwith bacterial burden moreover the agent differentiatedinfection from sterile inflammation Given the potential of68Ga for the labelling of small biologically active molecules[4] it might be plausible to develop a respective analoguewith added value of the advantages that 68Ga offers includingsimpler production chemistry lowered radiation dose repet-itive examination and accessibility at clinical centers withoutcyclotrons and remote from [18F]-FDG distribution sites Asmentioned above the poor access to bacteria aggregated ina biofilm might make the imaging task challenging Severalpeptide candidates with affinity for S aureus biofilm weredesigned and labelled with 68Ga [219] The resulting agentsdemonstrated binding in vitro however it was not possible toblock the binding with excess of the cold peptide
Ionic 68Ga was found superior to [18F]-FDG in infectiondetection in the rat model with diffuse osteomyelitis [220] Inanother study the uptake of ionic 68Ga was observed in theaortic plaques of atherosclerotic mice specifically at the sitesrich inmacrophages [221] However the slow blood clearanceof ionic 68Ga presents a limitation
Chronic inflammation is the major reason of fibro-sis [222] 68Ga-labelled SST analogue ([68Ga]Ga-DOTA-NOC) demonstrated uptake in pathogenic areas in patientsaffected by idiopathic pulmonary fibrosis with potentialfor monitoring response to treatment and drug develop-ment [62] Another clinical study using [68Ga]Ga-pentixaforalso showed potential of the agent for monitoring dis-ease activity and response to treatment in idiopathic pul-monary fibrosis [223] Peptide based agents CNO2A-PEG2-c[CPGRVMHGLHLGDDEGPC] and [68Ga]Ga-NODAGA-PEG2-c[CPGRVMHGLHLGDDEGPC] for the imaging andquantification of fibrosis by PET were developed and char-acterized preclinically showing fast clearance from normal
Contrast Media amp Molecular Imaging 13
tissue and blood and binding specificity [89] Dosimetrycalculations demonstrated possibility of six examinations peryear in humans assuring disease monitoring in longitudinalstudies and routine clinical setup [224]
Several hyaluronan conjugates of oligonucleotides target-ing CD44 positive cells were developed and tested in healthyrats sham-operated rats and rats with myocardial infarction[225]The uptake of the agents was higher for the latter groupand varied dependent on the difference in the oligonucleotidestructure
TLR2 and TLR4 expression levels in neutrophils werefound higher in individuals with bacterial and viral infectionsthan those in control samples There is a possibility that IL-4IL-8 IL-10 IL-12 and TNF-a might serve as biomarkers forinfections and that IL-2 IL-8 or IL-10 is potentially able todistinguish between bacterial and viral infections [22]
Mannosylated human serum albumin labelled with 68Gavia NOTA chelator moiety ([68Ga]Ga-NOTA-MSA) wastested in a rat model of myocarditis targetingmannose recep-tors expressed onmacrophages infiltratingmyocardium [66]The uptake in the diseased myocardium was considerablyhigher than that of the normal one and it was precludedby administration of excess of nonlabelled MSA indicatingbinding specificity The tracer build-up was also observed inthe organs of macrophage accumulation
[68Ga]Ga-DOTA was investigated for the quantificationof increased blood flow which is one of the key events ininflammation [226] The uptake kinetics of [68Ga]Ga-DOTAin the site of inflammation in rats with induced inflamma-tion correlated well with that of 15O-water suggesting highrelevance [68Ga]Ga-DOTA
9 Pretargeted Imaging
The half-life of 68Ga is shorter than that of 64Cu 67Ga 99mTc89Zr 111In and 123124125I and thus in contrast to the latterit is not compatible with slow pharmacokinetics of largemolecules such as antibodies and glycoproteins The rangeof antigen-specific antibodies relevant to inflammation andinfection is broad and a number of 99mTc-labelled antibodieswere used clinically [20 21 227] The respective range of68Ga-based agents could be similarThe solution to overcomethe incompatibility of half-life time frames could be eitherthe reduction of the antibody size or the application of thepretargeting concept
The history of the pretargeting concept spans threedecades predominantly in the field of oncology [228ndash230]It was developed to improve image contrast and dosimetryin immunoimaging and radioimmunotherapy when usingradiolabelled antibody ligands with slow pharmacokinetics[231] The arsenal of antibodies is vast and diverse encourag-ing extensive investment into development of techniques thatwould allow their exploration to the fullest Pretargeting con-siders at least two major steps wherein a functionalized anti-body is first administered for target localization and clearancefrom blood and normal tissue and thereafter a radiolabelledsmall molecule capable of binding to the functionalized
antibody due to high affinity or covalent interaction is admin-istered The key properties of the radiolabelled molecules arefast pharmacokinetic and clearance Several techniques havebeen developed for the realization of pretargeting conceptincluding avidinstreptavidin-biotin systems [216 217 232233] bispecific antibodies (bsmAb) with haptens [232 234ndash254] antibody-oligonucleotide conjugates with complemen-tary oligonucleotides [255] biorthogonal systems allowingcovalent chemical reactions in vivo (Figure 8)
The high affinity of biotin to avidin and streptavidinproteins was utilized clinically and preclinically in pretar-geting approach for the imaging and therapy of pancreaticadenocarcinoma [232] glioblastoma [256] and lymphoma[257] However this pretargeting technique may requirethree steps in order to eliminate the excess of antibody-(strept)avidin conjugate circulating in the blood and notbound to the target by adding clearing agent Anotherapplication of the technique was monitoring transplantationof islets of Langerhans in the treatment for type 1 diabetesmellitus wherein the cells or cellmimetics were conjugated to(strept)avidin prior to the transplantation [216 217] Severalanalogues of biotin comprising DOTA chelate moiety forlabelling with 68Ga and ethylene glycol linker of variouslength demonstrated the influence of the latter on the affinitytowards avidin
Particular example of hapten molecules is the ones com-prising histamine-succinyl-glycine (HSG) motif and chelatemoiety [251ndash253 258] for the complexationwith 68Ga Severalanalogues were developed for the imaging of carcinoem-bryonic antigen (CEA) pretargeted with anti-CEA bsmAb[254 259 260] and two clinical studies of medullary thyroidcarcinoma and breast carcinoma positive for CEA using68Ga-labelled hapten molecules and bsmAb were initiated[261]
Bioorthogonal reactions are fast regioselective requiringsmall reagent concentration and occurring under mild con-ditions often in aqueous solution and temperature below 37∘C[262 263] Amongst various biorthogonal reaction types thecycloaddition of tetrazines and various dienophiles referredto as inverse-electron-demandDiels-Alder (IEDDA) reactionis themost successful in the context of pretargeting Antibod-ies functionalized with trans-cyclooctene (TCO) and a radi-olabelled tetrazine that can interact in vivo based on IEDDAreaction were studied [264ndash267] In particular 68Ga-labelledtetrazine dextran demonstrated favorable pharmacokineticsin a healthy mouse [264] However the proof of concept is tobe performed in a xenografted animal Accumulation of anti-TAG72 [265] and anti-A33 [266] antibodies functionalizedwith TCO in mouse xenografts was visualized respectivelyby an 111In and 64Cu-labelled tetrazine analogues Anti-CA199 antibody-TCO in combination with 177Lu-labelledtetrazine demonstrated radiotherapeutic effect in pancreaticcancer murine model [267]
Thepretargeted imaging techniquesmay contribute to theexpansion of immuno-PET with 68Ga providing the intrinsicadvantages of 68Ga and PET As mentioned above mostof the developed radiolabelled counterparts of pretargetingtechniques have demonstrated promising results There are
14 Contrast Media amp Molecular Imaging
H
ON
NN
O
OO
OO
NH
NS
NH
ONH
O
HO
ONH
O
Ga
HN
NH
NH
O
OO
HNN
HN
NH
NH
O
OO
HNN
（2
(a)
NH
O
O
NH
N
NNGa
O O
O O
O
O
O
N N
NN
OO
（2
(b)
N
N
O
O
N
N
O
O
O
NH
O
O
ONH
NHS
O
H
HO
NH
+
minus
(c)
Figure 8 Schematic presentation of pretargeting techniques (a) bispecific antibodies engineered to specifically bind with radiolabelledhapten molecules (b) bioorthogonal click chemistry for fast and specific covalent binding between for example a trans-cyclooctenefunctionalized antibody and a radiolabelled tetrazine (c) interaction between antibody-(strept)avidin conjugate and radiolabelled biotinutilizing extremely high affinity of (strept)avidin and biotin
Contrast Media amp Molecular Imaging 15
a considerable number of potential antibody biomarkersthat could be considered for the imaging of infection andinflammation
10 Theranostics Potential
Theranostics [268] embraces realization of personalizedmedicine by conducting diagnosis on individual basis andproviding possibility of predicting the efficacy of a specifictreatment and following up the response to the treatmentenabling adjustment of the latter very early in the processIn the context of nuclear medicine wherein the radiophar-maceuticals targeted at biomarkers specific to a disease cancarry either diagnostic radionuclides or therapeutic ones theconcept can be denoted as radiotheranostics [28] The tar-geted molecular imaging such as PET can offer noninvasivediagnosis specific to the disease for example tumour-typespecific and provide accurate localization of the lesions Thestrongest advantage of PET is the potential for quantificationof the target for example receptor expression investigationof the uptake kinetics and estimation of the dosimetryThesecharacteristics of PET allow for individualized treatmentselection and planning monitoring of treatment responseand detection of recurrent diseaseThe individualized patientmanagement provides such advantages as optimization ofthe treatment regimen for the improved response and exclu-sion of futile treatments minimization of risks and toxicitywith overall outcome of reduced cost and patient distressThe importance of individualized patient management wasdemonstrated by clinical studies wherein the influence ofdose of the administered radiopharmaceutical targeted atreceptors overexpressed in cancer lesions on the diagnosticoutcome was investigated in the same patient [85 269270] 68Ga-labelled SST analogues [26ndash28 271] and Affibodymolecules [5 272ndash274] used respectively in NENs andbreast cancer patients are the most prominent examplesof (radio)theranostics involving 68GaPET wherein 68Ga-labelled analogues were used not only for localization of thelesions but also for staging patient stratification prognosistherapy selection and monitoring of the response to thetreatment of NETs and other cancer types [2ndash4 6 85 176275ndash277]
The methodology can be translated to inflammationand infection allowing for accurate and specific selection oftreatment regimen and for follow-up and evaluation of theresponse to therapy resulting in improved treatment efficacyand decreased cost and side effects The accommodation ofboth imaging function and antibiotic function in the samemolecule is a novel example of a theranostic agent [278]A series of siderophores conjugated with DOTA moiety forthe radiolabelling and with antibiotics for the treatmentof bacterial infection were investigated preclinically Theaccumulation of the intravenously administered ampicillinconjugate in the site of subcutaneously injected P aeruginosain mice was clearly and focally visualized within 06 h withretention for at least 24 h These results obtained usinganalogues carrying dye for optical imaging can be translatedto 68Ga-labelled counterparts for PET
11 Conclusions
The medical need for specific agents for noninvasive quan-titative and whole-body imaging of inflammation and infec-tion has not been met yet despite decades of research How-ever the prerequisites in terms of identification of potentialtargets design and synthesis of the respective ligands andimaging technologies are evolving very fast The potentialof accurate and quantitative lesion localization as well asmonitoring of the treatment response promises personalizedpatient management
The use of 68Ga in oncology is established proving thestrong potential of 68Ga for the promotion of PET technol-ogy for effective and efficient diagnostics and personalizedmedicineThe experience of oncological 68Ga-based agents isgetting translated to inflammation and infection Pretargetedimaging technology opens wide possibilities based on anti-body biomarkers
Conflicts of Interest
The author declares that there are no conflicts of interestregarding the publication of this article
References
[1] I Velikyan ldquoContinued rapid growth inGa applications update2013 to June 2014rdquo Journal of Labelled CompoundsampRadiophar-maceuticals pp 99ndash121 2015
[2] I Velikyan ldquo 68Ga-based radiopharmaceuticals Production andapplication relationshiprdquo Molecules vol 20 no 7 pp 12913ndash12943 2015
[3] M Fani P Peitl and I Velikyan ldquoCurrent status of radiophar-maceuticals for the theranostics of neuroendocrine neoplasmsrdquoPharmaceuticals vol 10 no 1 article no 30 2017
[4] I Velikyan ldquoPositron emitting [68Ga]Ga-based imaging agentsChemistry and diversityrdquoMedicinal Chemistry vol 7 no 5 pp345ndash379 2011
[5] J Sorensen I Velikyan D Sandberg et al ldquoMeasuringHER2-receptor expression in metastatic breast cancer using[68Ga]ABY-025 Affibody PETCTrdquo Theranostics vol 6 no 2pp 262ndash271 2016
[6] I Velikyan ldquoProspective of 68Ga-Radiopharmaceutical devel-opmentrdquoTheranostics vol 4 no 1 pp 47ndash80 2014
[7] P Lankinen T J Makinen T A Poyhonen et al ldquo68Ga-DOTAVAP-P1 PET imaging capable of demonstrating the phaseof inflammation in healing bones and the progress of infectionin osteomyelitic bonesrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 35 no 2 pp 352ndash364 2008
[8] T UjulaMHuttunen P Luoto et al ldquoMatrixmetalloproteinase9 targeting peptides Syntheses 68Ga-labeling and preliminaryevaluation in a rat melanoma xenograft modelrdquo BioconjugateChemistry vol 21 no 9 pp 1612ndash1621 2010
[9] A Autio T Ujula P Luoto S Salomaki S Jalkanen and ARoivainen ldquoPET imaging of inflammation and adenocarcinomaxenografts using vascular adhesion protein 1 targeting peptide68Ga-DOTAVAP-P1 Comparison with 18F-FDGrdquo EuropeanJournal of Nuclear Medicine and Molecular Imaging vol 37 no10 pp 1918ndash1925 2010
16 Contrast Media amp Molecular Imaging
[10] J Silvola A Autio P Luoto S Jalkanen andA Roivainen ldquoPre-liminary evaluation of novel 68Ga-DOTAVAP-PEG-P2 peptidetargeting vascular adhesion protein-1rdquo Clinical Physiology andFunctional Imaging vol 30 no 1 pp 75ndash78 2010
[11] T Ujula S Salomaki P Virsu et al ldquoSynthesis 68Ga labelingand preliminary evaluation of DOTA peptide binding vascularadhesion protein-1 a potential PET imaging agent for diagnos-ing osteomyelitisrdquo Nuclear Medicine and Biology vol 36 no 6pp 631ndash641 2009
[12] A Autio T Henttinen H J Sipila S Jalkanen and ARoivainen ldquoMini-PEG spacering of VAP-1-targeting 68Ga-DOTAVAP-P1 peptide improves PET imaging of inflamma-tionrdquo EJNMMI Research vol 1 no 1 pp 1ndash7 2011
[13] K Aalto A Autio E A Kiss et al ldquoSiglec-9 is a novel leukocyteligand for vascular adhesion protein-1 and can be used in PETimaging of inflammation and cancerrdquo Blood vol 118 no 13 pp3725ndash3733 2011
[14] V Kumar D K Boddeti S G Evans F Roesch and RHowman-Giles ldquoPotential use of 68Ga-apo-transferrin as a PETimaging agent for detecting Staphylococcus aureus infectionrdquoNuclear Medicine and Biology vol 38 no 3 pp 393ndash398 2011
[15] M Petrik H Haas G Dobrozemsky et al ldquo68Ga-siderophoresfor PET imaging of invasive pulmonary aspergillosis Proof ofprinciplerdquo Journal of Nuclear Medicine vol 51 no 4 pp 639ndash645 2010
[16] M Petrik H Haas M Schrettl A Helbok M Blatzer and CDecristoforo ldquoIn vitro and in vivo evaluation of selected 68Ga-siderophores for infection imagingrdquo Nuclear Medicine andBiology vol 39 no 3 pp 361ndash369 2012
[17] M Petrik GM Franssen H Haas et al ldquoPreclinical evaluationof two 68Ga-siderophores as potential radiopharmaceuticals forAspergillus fumigatus infection imagingrdquo European Journal ofNuclearMedicine andMolecular Imaging vol 39 no 7 pp 1175ndash1183 2012
[18] A Rizzello D Di Pierro F Lodi et al ldquoSynthesis and qualitycontrol of 68Ga citrate for routine clinical PETrdquo NuclearMedicine Communications vol 30 no 7 pp 542ndash545 2009
[19] C Nanni C Errani and L Boriani ldquo 68Ga-citrate PETCT forevaluating patients with infections of the bone preliminaryresultsrdquo Journal of Nuclear Medicine vol 51 no 12 pp 1932ndash1936 2010
[20] S S Das A V Hall D W Wareham and K E Britton ldquoInfec-tion imaging with radiopharmaceuticals in the 21st centuryrdquoBrazilian Archives of Biology and Technology vol 45 no spepp 25ndash37 2002
[21] A Signore and A W J M Glaudemans ldquoThe molecularimaging approach to image infections and inflammation bynuclear medicine techniquesrdquo Annals of Nuclear Medicine vol25 no 10 pp 681ndash700 2011
[22] T Yusa K Tateda A Ohara and S Miyazaki ldquoNew possiblebiomarkers for diagnosis of infections and diagnostic distinc-tion between bacterial and viral infections in childrenrdquo Journalof Infection and Chemotherapy vol 23 no 2 pp 96ndash100 2017
[23] A Signore A W J M Glaudemans O Gheysens C Lauriand O A Catalano ldquoNuclear Medicine Imaging in PediatricInfection or Chronic Inflammatory Diseasesrdquo Seminars inNuclear Medicine vol 47 no 3 pp 286ndash303 2017
[24] I Velikyan ldquoMolecular imaging and radiotherapyTheranosticsfor personalized patient managementrdquo Theranostics vol 2 no5 pp 424ndash426 2012
[25] F Rosch and R P Baum ldquoGenerator-based PET radiophar-maceuticals for molecular imaging of tumours On the way
to THERANOSTICSrdquo Dalton Transactions vol 40 no 23 pp6104ndash6111 2011
[26] R P Baum H R Kulkarni and C Carreras ldquoPeptides andreceptors in image-guided therapy Theranostics for neuroen-docrine neoplasmsrdquo Seminars in Nuclear Medicine vol 42 no3 pp 190ndash207 2012
[27] R P Baum and H R Kulkarni ldquoTheranostics From molecularimaging using Ga-68 labeled tracers and PETCT to per-sonalized radionuclide therapy - the bad berka experiencerdquoTheranostics vol 2 no 5 pp 437ndash447 2012
[28] I Velikyan ldquoRadionuclides for Imaging andTherapy in Oncol-ogyrdquo Cancer Theranostics pp 285ndash325 2014
[29] J Czernin andWAWeber ldquoIssues and controversies in nuclearmedicine Introductionrdquo Journal of Nuclear Medicine vol 52no Supplement 2 pp 1Sndash2S 2011
[30] S J Goldsmith and S Vallabhajosula ldquoClinically proven radio-pharmaceuticals for infection imaging mechanisms and appli-cationsrdquo Seminars in Nuclear Medicine vol 39 no 1 pp 2ndash102009
[31] M F Tsan ldquoMechanism of gallium-67 accumulation in inflam-matory lesionsrdquo Journal of Nuclear Medicine vol 26 no 1 pp88ndash92 1985
[32] S L Kipper ldquoRadiolabelled leukocyte imaging of the abdomenrdquoin Nuclear Medicine Annual J Freeman Ed pp 81ndash126 RavenPress New York NY USA 1995
[33] F Jamar J Buscombe A Chiti et al ldquoEANMSNMMI guidelinefor 18F-FDG use in inflammation and infectionrdquo Journal ofNuclear Medicine vol 54 no 4 pp 647ndash658 2013
[34] C J Palestro ldquoThe current role of gallium imaging in infectionrdquoSeminars in Nuclear Medicine vol 24 no 2 pp 128ndash141 1994
[35] M S Akhtar M B Imran M A Nadeem and A ShahidldquoAntimicrobial peptides as infection imaging agents better thanradiolabeled antibioticsrdquo International Journal of Peptides vol2012 Article ID 965238 19 pages 2012
[36] D Delbeke and G M Segall ldquoStatus of and trends in nuclearmedicine in the United Statesrdquo Journal of Nuclear Medicine vol52 no 2 2011
[37] S S Gambhir J Czernin J Schwimmer D H Silverman R EColeman and M E Phelps ldquoA tabulated summary of the FDGPET literaturerdquo Journal of Nuclear Medicine vol 42 pp 1Sndash93S2001
[38] M J Lindsay B A Siegel S R Tunis et al ldquoThe NationalOncologic PET Registry ExpandedMedicare coverage for PETunder coverage with evidence developmentrdquo American Journalof Roentgenology vol 188 no 4 pp 1109ndash1113 2007
[39] F Gemmel H Van Den Wyngaert C Love M M Welling PGemmel and C J Palestro ldquoProsthetic joint infectionsradionuclide state-of-the-art imagingrdquo European Journal ofNuclearMedicine andMolecular Imaging vol 39 no 5 pp 892ndash909 2012
[40] J Sorensen ldquoHow does the patient benefit from clinical PETrdquoTheranostics vol 2 no 5 pp 427ndash436 2012
[41] S L Rice C A Roney P Daumar and J S Lewis ldquoThe nextgeneration of positron emission tomography radiopharmaceu-ticals in oncologyrdquo Seminars in Nuclear Medicine vol 41 no 4pp 265ndash282 2011
[42] R LWahl JMHerman and E Ford ldquoThePromise and Pitfallsof Positron Emission Tomography and Single-Photon EmissionComputed Tomography Molecular Imaging-Guided RadiationTherapyrdquo Seminars in Radiation Oncology vol 21 no 2 pp 88ndash100 2011
Contrast Media amp Molecular Imaging 17
[43] A W J M Glaudemans R H J A Slart J M Van Dijl MVan Oosten and G M Van Dam ldquoMolecular imaging of infec-tious and inflammatory diseases A terra incognitardquo Journal ofNuclear Medicine vol 56 no 5 pp 659ndash661 2015
[44] X Li W Bauer I Israel et al ldquoTargeting p-selectin by gallium-68-labeled fucoidan positron emission tomography for nonin-vasive characterization of vulnerable plaques Correlation within vivo 176t mrirdquo Arteriosclerosis Thrombosis and VascularBiology vol 34 no 8 pp 1661ndash1667 2014
[45] S Eichendorff P Svendsen D Bender et al ldquoBiodistributionand PET Imaging of a Novel [68Ga]-Anti-CD163-AntibodyConjugate in Rats with Collagen-Induced Arthritis and inControlsrdquoMolecular Imaging and Biology vol 17 no 1 pp 87ndash93 2014
[46] Z Zhu Y Yin K Zheng et al ldquoEvaluation of synovial angiogen-esis in patients with rheumatoid arthritis using 68Ga-PRGD2PETCT A prospective proof-of-concept cohort studyrdquo Annalsof the Rheumatic Diseases vol 73 no 6 pp 1269ndash1272 2014
[47] J S Eo J C Paeng S Lee et al ldquoAngiogenesis imaging inmyocardial infarction using 68Ga-NOTA- RGD PET Charac-terization and application to therapeutic efficacy monitoring inratsrdquo Coronary Artery Disease vol 24 no 4 pp 303ndash311 2013
[48] J H Kim Y-H Kim Y J Kim et al ldquoQuantitative positronemission tomography imaging of angiogenesis in rats with fore-limb ischemia using 68Ga-NOTA-c(RGDyK)rdquo Angiogenesisvol 16 no 4 pp 837ndash846 2013
[49] I Laitinen J Notni K Pohle et al ldquoComparison of cyclicRGD peptides for 120572v1205733 integrin detection in a rat model ofmyocardial infarctionrdquo EJNMMI Research vol 3 no 1 pp 1ndash9 2013
[50] M Kiugel I Dijkgraaf V Kyto et al ldquoDimeric [68Ga]DOTA-RGD Peptide Targeting 120572 ltinfgtvltinfgt 120573 ltinfgt3ltinfgt Inte-grin Reveals Extracellular Matrix Alterations after MyocardialInfarctionrdquo Molecular Imaging and Biology vol 16 no 6 pp793ndash801 2014
[51] M Gronman M Tarkia T Kiviniemi et al ldquoImaging of 120572v1205733integrin expression in experimental myocardial ischemia with[68Ga]NODAGA-RGD positron emission tomographyrdquo Jour-nal of Translational Medicine vol 15 no 1 p 144 2017
[52] J Haukkala I Laitinen P Luoto et al ldquo68Ga-DOTA-RGDpep-tide Biodistribution and binding into atherosclerotic plaquesin micerdquo European Journal of Nuclear Medicine and MolecularImaging vol 36 no 12 pp 2058ndash2067 2009
[53] H Virtanen A Autio R Siitonen et al ldquo68Ga-DOTA-Siglec-9- a new imaging tool to detect synovitisrdquo Arthritis Research ampTherapy vol 17 no 1 article no 308 2015
[54] J Retamal J Sorensen M Lubberink et al ldquoFeasibility of(68) Ga-labeled Siglec-9 peptide for the imaging of acutelung inflammation a pilot study in a porcine model of acuterespiratory distress syndromerdquoAm JNuclMedMol Imaging vol6 no 1 pp 18ndash31 2016
[55] J M U Silvola H Virtanen R Siitonen et al ldquoLeukocytetrafficking-associated vascular adhesion protein 1 is expressedand functionally active in atherosclerotic plaquesrdquo ScientificReports vol 6 Article ID 35089 2016
[56] H Ahtinen J Kulkova L Lindholm et al ldquo68Ga-DOTA-Siglec-9 PETCT imaging of peri-implant tissue responses andstaphylococcal infectionsrdquo EJNMMI Research vol 4 no 1article no 45 pp 1ndash11 2014
[57] A Autio S Jalkanen and A Roivainen ldquoNuclear imaging ofinflammation Homing-associated molecules as targetsrdquo EJN-MMI Research vol 3 no 1 pp 1ndash7 2013
[58] J TThackeray T Derlin AHaghikia et al ldquoMolecular Imagingof the Chemokine Receptor CXCR4 after Acute MyocardialInfarctionrdquo JACC Cardiovascular Imaging vol 8 no 12 pp1417ndash1426 2015
[59] J S Schmid A Schirbel A K Buck S Kropf H-J Westerand C Lapa ldquoPentixafor-Positron Emission TomographyComputed Tomography Detects Chemokine Receptor CXCR4Expression after Ischemic Strokerdquo Circulation CardiovascularImaging vol 9 no 9 Article ID e005217 2016
[60] J Zhou G Hao H Weng et al ldquoIn vivo evaluation ofmedical device-associated inflammation using a macrophage-specific positron emission tomography (PET) imaging proberdquoBioorganic amp Medicinal Chemistry Letters vol 23 no 7 pp2044ndash2047 2013
[61] S A Kularatne M-J Belanger X Meng et al ldquoComparativeanalysis of folate derived PET imaging agents with [ 18F]-2-fluoro-2-deoxy-d-glucose using a rodent inflammatory pawmodelrdquo Molecular Pharmaceutics vol 10 no 8 pp 3103ndash31112013
[62] V Ambrosini M Zompatori F De Luca et al ldquo68Ga-DOTANOCPETCTAllows Somatostatin Receptor Imaging inIdiopathic Pulmonary Fibrosis Preliminary Resultsrdquo Journal ofNuclear Medicine vol 51 no 12 pp 1950ndash1955 2010
[63] T Lincke J Singer R Kluge O Sabri and R Paschke ldquoRela-tive quantification of indium-111 pentetreotide and gallium-68DOTATOC uptake in the thyroid gland and association withthyroid pathologiesrdquoThyroid vol 19 no 4 pp 381ndash389 2009
[64] A Rominger T Saam E Vogl et al ldquoIn vivo imaging ofmacrophage activity in the coronary arteries using 68Ga-DOTATATE PETCT correlation with coronary calcium bur-den and risk factorsrdquo Journal of Nuclear Medicine vol 51 no 2pp 193ndash197 2010
[65] J M Tarkin F R Joshi N R Evans et al ldquoDetection ofAtherosclerotic Inflammation by 68Ga-DOTATATE PET Com-pared to [18F]FDG PET Imagingrdquo Journal of the AmericanCollege of Cardiology vol 69 no 14 pp 1774ndash1791 2017
[66] S-P Lee H-J Im S Kang et al ldquoNoninvasive imaging ofmyocardial inflammation in myocarditis using 68Ga-taggedmannosylated human serum albumin positron emissiontomographyrdquoTheranostics vol 7 no 2 pp 413ndash424 2017
[67] Z Zha J Song S R Choi et al ldquo68Ga-Bivalent PolypegylatedStyrylpyridine Conjugates for Imaging A120573 Plaques in CerebralAmyloid Angiopathyrdquo Bioconjugate Chemistry vol 27 no 5 pp1314ndash1323 2016
[68] H Watanabe M Ono S Iikuni et al ldquoA 68Ga complex basedon benzofuran scaffold for the detection of 120573-amyloid plaquesrdquoBioorganic amp Medicinal Chemistry Letters vol 24 no 20 pp4834ndash4837 2014
[69] D Cressier M Dhilly T T Cao Pham et al ldquoGallium-68 Com-plexes Conjugated to Pittsburgh Compound B Radiolabelingand Biological EvaluationrdquoMolecular Imaging and Biology vol18 no 3 pp 334ndash343 2016
[70] D Satpati CArjun R KrishnamohanG Samuel and S Baner-jee ldquo68Ga-labeledCiprofloxacinConjugates as Radiotracers forTargeting Bacterial InfectionrdquoChemical Biology ampDrug Designvol 87 no 5 pp 680ndash686 2016
[71] T Ebenhan N Chadwick and M M Sathekge ldquoPeptidesynthesis characterization and 68Ga-radiolabeling of NOTA-conjugated ubiquicidin fragments for prospective infectionimaging with PETCTrdquo Nuclear Medicine and Biology vol 41no 5 pp 390ndash400 2014
18 Contrast Media amp Molecular Imaging
[72] T Ebenhan J R Zeevaart and J D Venter ldquoPreclinicalevaluation of 68Ga-labeled 1 4 7-triazacyclononane-1 4 7-triacetic acid-ubiquicidin as a radioligand for PET infectionimagingrdquo Journal of Nuclear Medicine vol 55 no 2 pp 308ndash314 2014
[73] B B Mokaleng T Ebenhan S Ramesh et al ldquoSynthesis 68Ga-radiolabeling and preliminary in vivo assessment of adepsipeptide-derived compound as a potential PETCTinfection imaging agentrdquo BioMed Research International vol2015 Article ID 284354 2015
[74] T Ebenhan B Mokaleng J Venter H Kruger J Zeevaart andM Sathekge ldquoPreclinical Assessment of a 68Ga-DOTA-Functionalized Depsipeptide as a Radiodiagnostic InfectionImaging AgentrdquoMolecules vol 22 no 9 p 1403 2017
[75] S Chopra B Singh A Koul A Mishra and H Wester ldquoSyn-thesis of DOTA conjugated GF-17 and RAWVAWR-NH2 andradiolabeling with 68Ga as a potential PET tracer for infectionimagingrdquo J Nucl Med vol 57 Supplement 2 p 1115 2016
[76] M Petrik HHaas P Laverman et al ldquo 68Ga-triacetylfusarinineC and 68Ga-ferrioxamine e for aspergillus infection imaginguptake specificity in various microorganismsrdquoMolecular Imag-ing and Biology vol 16 no 1 pp 102ndash108 2014
[77] V Kumar and D K Boddeti ldquo 68Ga-radiopharmaceuticals forPET imaging of infection and inflammationrdquo Recent Results inCancer Research vol 194 pp 189ndash219 2013
[78] M Vorster A Maes A Jacobs et al ldquoEvaluating the possiblerole of 68Ga-citrate PETCT in the characterization of indeter-minate lung lesionsrdquo Annals of Nuclear Medicine vol 28 no 6pp 523ndash530 2014
[79] M Vorster B Mokaleng M M Sathekge and T Ebenhan ldquoAmodified technique for efficient radiolabeling of 68Ga-citratefrom a SnO2-based 68Ge68Ga generator for better infectionimagingrdquoHellenic Journal of Nuclear Medicine vol 16 no 3 pp193ndash198 2013
[80] S Salomaeki J Kemppainen U Hohenthal et al ldquoHead-to-head comparison of 68Ga-Citrate and 18F-FDG PETCT fordetection of infectious foci in patients with staphylococcusaureus bacteraemiardquo Contrast Media amp Molecular Imaging vol2017 p 8 2017
[81] L Fass ldquoImaging and cancer a reviewrdquoMolecular Oncology vol2 no 2 pp 115ndash152 2008
[82] A Chopra L Shan W C Eckelman et al ldquoMolecular imagingand contrast agent database (MICAD) Evolution and progressrdquoMolecular Imaging and Biology vol 14 no 1 pp 4ndash13 2012
[83] A Sanchez-Crespo P Andreo and S A Larsson ldquoPositronflight in human tissues and its influence on PET image spatialresolutionrdquo European Journal of Nuclear Medicine and Molecu-lar Imaging vol 31 no 1 pp 44ndash51 2004
[84] H W A M De Jong L Perk G W M Visser R Boellaard GAM S Van Dongen and A A Lammertsma ldquoHigh resolutionPET imaging characteristics of68Ga 124i and89Zr comparedto18Frdquo in Proceedings of the Nuclear Science Symposium Con-ference Record 2005 IEEE pp 1624ndash1627 Puerto Rico October2005
[85] I Velikyan A Sundin B Eriksson et al ldquoIn vivo bindingof [68Ga]-DOTATOC to somatostatin receptors in neuroen-docrine tumours - impact of peptide massrdquo Nuclear Medicineand Biology vol 37 no 3 pp 265ndash275 2010
[86] U Eberlein and M Lassmann ldquoDosimetry of [68Ga]-labeledcompoundsrdquo Applied Radiation and Isotopes vol 76 pp 70ndash742013
[87] C PettinatoA SarnelliMDiDonna et al ldquo68Ga-DOTANOCBiodistribution and dosimetry in patients affected by neuroen-docrine tumorsrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 35 no 1 pp 72ndash79 2008
[88] B P Burke G S Clemente and S J Archibald ldquoRecentadvances in chelator design and labelling methodology for68Ga radiopharmaceuticalsrdquo Journal of Labelled Compoundsand Radiopharmaceuticals vol 57 no 4 pp 239ndash243 2014
[89] I Velikyan U Rosenstrom S Estrada et al ldquoSynthesis andpreclinical evaluation of 68Ga-labeled collagelin analogs forimaging and quantification of fibrosisrdquo Nuclear Medicine andBiology vol 41 no 9 pp 728ndash736 2014
[90] M F Ferreira G Pereira J P Andre and etal C ldquoGa[NO2A-N-(120572-amino)propionate] chelates Synthesis and evaluation aspotential tracers for 68Ga PETrdquoDalton Transactions vol 43 no21 pp 8037ndash8047 2014
[91] J Notni J Simecek and H-J Wester ldquoPhosphinic acid func-tionalized polyazacycloalkane chelators for radiodiagnosticsand radiotherapeutics Unique characteristics and applicationsrdquoChemMedChem vol 9 no 6 pp 1107ndash1115 2014
[92] J Simecek O Zemek P Hermann J Notni and H J WesterldquoTailored gallium( III) chelator NOPO synthesis characteriza-tion bioconjugation and application in preclinical Ga-68-PETimagingrdquoMolecular Pharmaceutics 2013
[93] D Parker B P Waldron and D S Yufit ldquoCrystallographicand solution NMR structural analyses of four hexacoordinatedgallium(iii) complexes based on ligands derived from 6-amino-perhydro-14-diazepinerdquo Dalton Transactions vol 42 no 22pp 8001ndash8008 2013
[94] B P Waldron D Parker C Burchardt D S Yufit M ZimnyandF Roesch ldquoStructure and stability of hexadentate complexesof ligands based on AAZTA for efficient PET labelling withgallium-68rdquo Chemical Communications vol 49 no 6 pp 579ndash581 2013
[95] D Parker and B PWaldron ldquoConformational analysis and syn-thetic approaches to polydentate perhydro-diazepine ligandsfor the complexation of gallium(iii)rdquo Organic amp BiomolecularChemistry vol 11 no 17 pp 2827ndash2838 2013
[96] I Velikyan H Maecke and B Langstrom ldquoConvenient prepa-ration of 68Ga-based PET-radiopharmaceuticals at room tem-peraturerdquo Bioconjugate Chemistry vol 19 no 2 pp 569ndash5732008
[97] J Erchegyi R Cescato B Waser J E Rivier and J C ReubildquoN-Imidazolebenzyl-histidine substitution in somatostatin andin its octapeptide analogue modulates receptor selectivity andfunctionrdquo Journal of Medicinal Chemistry vol 54 no 17 pp5981ndash5987 2011
[98] R Saha N Saha R S Donofrio and L L Bestervelt ldquoMicrobialsiderophores Amini reviewrdquo Journal of Basic Microbiology vol53 no 4 pp 303ndash317 2013
[99] V Nikolova S Angelova N Markova and T Dudev ldquoGalliumas a Therapeutic Agent A Thermodynamic Evaluation of theCompetition between Ga3+ and Fe3+ Ions in MetalloproteinsrdquoThe Journal of Physical Chemistry B vol 120 no 9 pp 2241ndash2248 2016
[100] C R Chitambar ldquoGallium and its competing roles with ironin biological systemsrdquo Biochimica et Biophysica Acta (BBA) -Molecular Cell Research vol 1863 no 8 pp 2044ndash2053 2016
[101] J A Lessa M A Soares and R G dos Santos ldquoGallium(III)complexes with 2-acetylpyridine-derived thiosemicarbazonesantimicrobial and cytotoxic effects and investigation on theinteractions with tubulinrdquo BioMetals vol 26 pp 151ndash165 2013
Contrast Media amp Molecular Imaging 19
[102] M van Oosten M Hahn L M A Crane et al ldquoTargetedimaging of bacterial infections Advances hurdles and hopesrdquoFEMS Microbiology Reviews vol 39 no 6 pp 892ndash916 2015
[103] M Vorster AMaes C V DWiele andM Sathekge ldquoGallium-68 PET A Powerful Generator-based Alternative to Infectionand Inflammation Imagingrdquo Seminars in Nuclear Medicine vol46 no 5 pp 436ndash447 2016
[104] M Kircher and C Lapa ldquoNovel Noninvasive Nuclear MedicineImaging Techniques for Cardiac Inflammationrdquo Current Car-diovascular Imaging Reports vol 10 no 2 article no 6 2017
[105] D AHammoud ldquoMolecular imaging of inflammation Currentstatusrdquo Journal of Nuclear Medicine vol 57 no 8 pp 1161ndash11652016
[106] D R Brenner D Scherer K Muir et al ldquoA review of the appli-cation of inflammatory biomarkers in epidemiologic cancerresearchrdquo Cancer Epidemiology Biomarkers amp Prevention vol23 no 9 pp 1729ndash1751 2014
[107] M D Turner B Nedjai T Hurst and D J PenningtonldquoCytokines and chemokines at the crossroads of cell signallingand inflammatory diseaserdquo Biochimica et Biophysica Acta (BBA)- Molecular Cell Research vol 1843 no 11 pp 2563ndash2582 2014
[108] L Werner H Guzner-Gur and I Dotan ldquoInvolvement ofCXCR4CXCR7CXCL12 interactions in inflammatory boweldiseaserdquoTheranostics vol 3 no 1 pp 40ndash46 2013
[109] S Jalkanen and M Salmi ldquoVAP-1 and CD73 endothelial cellsurface enzymes in leukocyte extravasationrdquo ArteriosclerosisThrombosis and Vascular Biology vol 28 no 1 pp 18ndash26 2008
[110] G Malviya F Galli I Sonni and A Signore ldquoImaging T-lymphocytes in inflammatory diseases A nuclear medicineapproachrdquo The Quarterly Journal of Nuclear Medicine andMolecular Imaging vol 58 no 3 pp 237ndash257 2014
[111] S Gratz H J RennenO C BoermanW J Oyen and P Burmaldquo(99m)Tc-interleukin-8 for imaging acute osteomyelitisrdquo Jour-nal of Nuclear Medicine vol 42 no 8 pp 1257ndash1264 2001
[112] S Gratz H J Rennen O C Boerman W J Oyen andF H Corstens ldquoRapid imaging of experimental colitis with(99m)Tc-interleukin-8 in rabbitsrdquo Journal of Nuclear Medicnevol 42 no 6 pp 917ndash923 2001
[113] C Alkim H Alkim A R Koksal S Boga and I SenldquoAngiogenesis in inflammatory bowel diseaserdquo InternationalJournal of Inflammation vol 2015 Article ID 970890 2015
[114] I S Alam T H Witney G Tomasi et al ldquoRadiolabeled RGDtracer kinetics annotates differential 120572v1205733 integrin expressionlinked to cell intrinsic and vessel expressionrdquoMolecular Imagingand Biology vol 16 no 4 pp 558ndash566 2014
[115] J Notni K Pohle and H-J Wester ldquoBe spoilt for choice withradiolabelled RGD peptides Preclinical evaluation of 68Ga-TRAP(RGD)3rdquoNuclear Medicine and Biology vol 40 no 1 pp33ndash41 2013
[116] J Oxboel M Brandt-Larsen C Schjoeth-Eskesen et al ldquoCom-parison of two new angiogenesis PET tracers 68Ga-NODAGA-E[c(RGDyK)]2 and 64Cu-NODAGA-E[c(RGDyK)]2 in vivoimaging studies in human xenograft tumorsrdquo Nuclear Medicineand Biology vol 41 no 3 pp 259ndash267 2014
[117] J Simecek J Notni T G Kapp H Kessler and H-J WesterldquoBenefits of NOPO as chelator in gallium-68 peptides exempli-fied by preclinical characterization of 68Ga-NOPO-c(RGDfK)rdquoMolecular Pharmaceutics vol 11 no 5 pp 1687ndash1695 2014
[118] M Trajkovic-Arsic P Mohajerani A Sarantopoulos et alldquoMultimodal molecular imaging of integrin avb3 for in vivodetection of pancreatic cancerrdquo Journal of NuclearMedicine vol55 no 3 pp 446ndash451 2014
[119] H Cai and P S Conti ldquoRGD-based PET tracers for imagingreceptor integrin 120572 v1205733 expressionrdquo Journal of Labelled Com-pounds and Radiopharmaceuticals vol 56 no 5 pp 264ndash2792013
[120] I Dijkgraaf S Y A Terry W J Mcbride et al ldquoImagingintegrin alpha-v-beta-3 expression in tumors with an 18F-labeled dimeric RGD peptiderdquo Contrast Media amp MolecularImaging vol 8 no 3 pp 238ndash245 2013
[121] P A Knetsch M Petrik C Rangger et al ldquo[68Ga]NS3-RGD and [68Ga] Oxo-DO3A-RGD for imaging 120572v1205733 integrinexpression Synthesis evaluation and comparisonrdquo NuclearMedicine and Biology vol 40 no 1 pp 65ndash72 2013
[122] Z Liu and F Wang ldquoDevelopment of RGD-based radiotracersfor tumor imaging and therapy Translating from bench tobedsiderdquo Current Molecular Medicine vol 13 no 10 pp 1487ndash1505 2013
[123] H Choi J H Phi J C Paeng et al ldquoImaging of integrin 120572v1205733expression using 68Ga-RGD positron emission tomography inpediatric cerebral infarctrdquoMolecular Imaging vol 12 no 4 pp213ndash217 2013
[124] H-J Yoon K W Kang I K Chun et al ldquoCorrelation of breastcancer subtypes based on estrogen receptor progesteronereceptor and HER2 with functional imaging parameters from68Ga-RGD PETCT and 18F-FDG PETCTrdquo European Journalof Nuclear Medicine and Molecular Imaging vol 41 no 8 pp1534ndash1543 2014
[125] R P Baum H R Kulkarni D Muller et al ldquoFirst-in-human study demonstrating tumor-angiogenesis by PETCTimaging with 68Ga-NODAGA-THERANOST a high-affinitypeptidomimetic for 120572v1205733 integrin receptor targetingrdquo CancerBiotherapy andRadiopharmaceuticals vol 30 no 4 pp 152ndash1592015
[126] R Haubner A Finkenstedt A Stegmayr et alldquo[68Ga]NODAGA-RGD ndash Metabolic stability biodistributionand dosimetry data from patients with hepatocellularcarcinoma and liver cirrhosisrdquo European Journal of NuclearMedicine and Molecular Imaging vol 43 no 11 pp 2005ndash20132016
[127] V Lopez-Rodrıguez C Galindo-Sarco F O Garcıa-Perez GFerro-Flores O Arrieta and M A Avila-Rodrıguez ldquoPET-based human dosimetry of the dimeric 120572v1205733 integrin ligand68Ga-DOTA-E-[c(RGDfK)]2 a potential tracer for imagingtumor angiogenesisrdquo Journal of Nuclear Medicine vol 57 no 3pp 404ndash409 2016
[128] M V Backer Z Levashova V Patel et al ldquoMolecular imagingof VEGF receptors in angiogenic vasculature with single-chainVEGF-based probesrdquo Nature Medicine vol 13 no 4 pp 504ndash509 2007
[129] MV Backer Z Levashova R Levenson F G Blankenberg andJ M Backer ldquoCysteine-containing fusion tag for site-specificconjugation of therapeutic and imaging agents to targetingproteinsrdquoMethods in Molecular Biology (Clifton NJ) vol 494pp 275ndash294 2008
[130] M Eder A V Krivoshein M Backer J M Backer UHaberkorn and M Eisenhut ldquoScVEGF-PEG-HBED-CC andscVEGF-PEG-NOTA conjugates comparison of easy-to-labelrecombinant proteins for [68Ga]PET imaging of VEGF recep-tors in angiogenic vasculaturerdquo Nuclear Medicine and Biologyvol 37 no 4 pp 405ndash412 2010
[131] E Blom I Velikyan A Monazzam P Razifar et al ldquoSynthe-sis and characterization of scVEGF-PEG-[ 68Ga]NOTA andscVEGF-PEG-[ 68Ga]DOTA PET tracersrdquo Journal of Labelled
20 Contrast Media amp Molecular Imaging
Compounds and Radiopharmaceuticals vol 54 no 11 pp 685ndash692 2011
[132] S Gratz M Behe and O C Boerman ldquo 99119898Tc-E-selectinbinding peptide for imaging acute osteomyelitis in a novel ratmodelrdquo Nuclear Medicine Communications vol 22 no 9 pp1003ndash1013 2001
[133] S B Jensen M Kakela L Joslashdal et al ldquoExploring the radiosyn-thesis and in vitro characteristics of [68Ga]Ga-DOTA-Siglec-9rdquoJournal of Labelled Compounds and Radiopharmaceuticals vol60 no 9 pp 439ndash449 2017
[134] B A Teicher and S P Fricker ldquoCXCL12 (SDF-1)CXCR4pathway in cancerrdquo Clinical Cancer Research vol 16 no 11 pp2927ndash2931 2010
[135] O Jacobson I D Weiss D O Kiesewetter J M Farber andX Chen ldquoPET of tumor CXCR4 expression with 4-18F-T140rdquoJournal of Nuclear Medicine vol 51 no 11 pp 1796ndash1804 2010
[136] A Aghanejad A R Jalilian Y Fazaeli et al ldquoSynthesis andevaluation of [67Ga]-AMD3100 A novel imaging agent fortargeting the chemokine receptorCXCR4rdquo Scientia Pharmaceu-tica vol 82 no 1 pp 29ndash42 2014
[137] O Jacobson I D Weiss L P Szajek et al ldquoPET imaging ofCXCR4 using copper-64 labeled peptide antagonistrdquoTheranos-tics vol 1 pp 251ndash262 2011
[138] O Jacobson I D Weiss L P Szajek et al ldquoImprovement ofCXCR4 tracer specificity for PET imagingrdquo Journal of Con-trolled Release vol 157 no 2 pp 216ndash223 2012
[139] H J Wester U Keller M Schottelius et al ldquoDisclosing theCXCR4 expression in lymphoproliferative diseases by targetedmolecular imagingrdquo Theranostics vol 5 no 6 pp 618ndash6302015
[140] E Gourni O Demmer M Schottelius et al ldquoPET of CXCR4expression by a 68Ga-labeled highly specific targeted contrastagentrdquo Journal of NuclearMedicine vol 52 no 11 pp 1803ndash18102011
[141] O Demmer I Dijkgraaf U Schumacher et al ldquoDesignsynthesis and functionalization of dimeric peptides targetingchemokine receptor CXCR4rdquo Journal of Medicinal Chemistryvol 54 no 21 pp 7648ndash7662 2011
[142] O Demmer E Gourni U Schumacher H Kessler and H-JWester ldquoPET Imaging of CXCR4 Receptors in Cancer by a NewOptimized Ligandrdquo ChemMedChem vol 6 no 10 pp 1789ndash1791 2011
[143] U Hennrich L Seyler M Schafer et al ldquoSynthesis and invitro evaluation of 68Ga-DOTA-4-FBn-TN14003 a novel tracerfor the imaging of CXCR4 expressionrdquo Bioorganic amp MedicinalChemistry vol 20 no 4 pp 1502ndash1510 2012
[144] G P C George E Stevens O Aberg et al ldquoPreclinical evalua-tion of a CXCR4-specific 68Ga-labelled TN14003 derivative forcancer PET imagingrdquo Bioorganic amp Medicinal Chemistry vol22 no 2 pp 796ndash803 2014
[145] S Poty E Gourni P Desogere et al ldquoAMD3100 A VersatilePlatform for CXCR4 Targeting 68Ga-Based Radiopharmaceu-ticalsrdquo Bioconjugate Chemistry vol 27 no 3 pp 752ndash761 2016
[146] K Philipp-Abbrederis K Herrmann S Knop et al ldquoIn vivomolecular imaging of chemokine receptor CXCR4 expressionin patients with advancedmultiple myelomardquo EMBOMolecularMedicine vol 7 no 4 pp 477ndash487 2015
[147] Z Wang M Zhang L Wang et al ldquoProspective study of 68Ga-NOTA-NFB Radiation dosimetry in healthy volunteers andfirst application in glioma patientsrdquo Theranostics vol 5 no 8pp 882ndash889 2015
[148] I M Jackson P J Scott and S Thompson ldquoClinical Applica-tions of Radiolabeled Peptides for PETrdquo Seminars in NuclearMedicine vol 47 no 5 pp 493ndash523 2017
[149] C Lapa T Reiter R A Werner et al ldquo[68Ga]Pentixafor-PETCT for Imaging of Chemokine Receptor 4 Expression afterMyocardial Infarctionrdquo JACC Cardiovascular Imaging vol 8no 12 pp 1466ndash1468 2015
[150] C Rischpler S G Nekolla H Kossmann et al ldquoUpregu-lated myocardial CXCR4-expression after myocardial infarc-tion assessed by simultaneous GA-68 pentixafor PETMRIrdquoJournal of Nuclear Cardiology vol 23 no 1 pp 131ndash133 2016
[151] F Hyafil J Pelisek I Laitinen et al ldquoImaging the CytokineReceptorCXCR4 in atherosclerotic plaqueswith the radiotracer68Ga-Pentixafor for PETrdquo Journal of Nuclear Medicine vol 58no 3 pp 499ndash506 2017
[152] Y Yi ldquoFolate receptor-targeted diagnostics and therapeutics forinflammatory diseasesrdquo ImmuneNetwork vol 16 no 6 pp 337ndash343 2016
[153] C M Paulos M J Turk G J Breur and P S Low ldquoFolatereceptor-mediated targeting of therapeutic and imaging agentsto activated macrophages in rheumatoid arthritisrdquo AdvancedDrug Delivery Reviews vol 56 no 8 pp 1205ndash1217 2004
[154] W Han R Zaynagetdinov F E Yull et al ldquoMolecular imagingof folate receptor 120573-positive macrophages during acute lunginflammationrdquo American Journal of Respiratory Cell and Molec-ular Biology vol 53 no 1 pp 50ndash59 2015
[155] B Kuhle C Muller and T L Ross ldquoA Novel 68Ga-Labeledpteroic acid-based PET tracer for tumor imaging via the folatereceptorrdquo Recent Results in Cancer Research vol 194 pp 257ndash267 2013
[156] C Brand V A Longo M Groaning W A Weber and TReiner ldquoDevelopment of a New Folate-Derived Ga-68-BasedPET Imaging AgentrdquoMolecular Imaging and Biology vol 19 no5 pp 754ndash761 2017
[157] M Fani XWang G Nicolas et al ldquoDevelopment of new folate-based PET radiotracers Preclinical evaluation of 68Ga-DOTA-folate conjugatesrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 38 no 1 pp 108ndash119 2011
[158] C J Mathias M R Lewis D E Reichert et al ldquoPreparationof 66Ga- and 68Ga-labeled Ga(III)-deferoxamine-folate aspotential folate-receptor-targeted PET radiopharmaceuticalsrdquoNuclear Medicine and Biology vol 30 no 7 pp 725ndash731 2003
[159] S-M Kim N Choi S Hwang et al ldquoFolate receptor-specific positron emission tomography imaging with folic acid-conjugated tissue inhibitor of metalloproteinase-2rdquo Bulletin ofthe Korean Chemical Society vol 34 no 11 pp 3243ndash3248 2013
[160] M Fani M-L Tamma G P Nicolas et al ldquoIn vivo imagingof folate receptor positive tumor xenografts using novel 68Ga-NODAGA-folate conjugatesrdquo Molecular Pharmaceutics vol 9no 5 pp 1136ndash1145 2012
[161] C Muller and R Schibli ldquoProspects in folate receptor-targetedradionuclide therapyrdquo Frontiers in Oncology vol 3 Article IDArticle 249 2013
[162] A Jain A Mathur U Pandey et al ldquoSynthesis and evaluationof a 68Ga labeled folic acid derivative for targeting folatereceptorsrdquo Applied Radiation and Isotopes vol 116 pp 77ndash842016
[163] W Xia A R Hilgenbrink E L Matteson M B Lockwood J-X Cheng and P S Low ldquoA functional folate receptor is inducedduring macrophage activation and can be used to target drugsto activated macrophagesrdquo Blood vol 113 no 2 pp 438ndash4462009
Contrast Media amp Molecular Imaging 21
[164] E P Krenning W A P Breeman P P M Kooij et alldquoLocalisation of endocrine-related tumours with radioiodi-nated analogue of somatostatinrdquoThe Lancet vol 1 no 8632 pp242ndash244 1989
[165] E P Krenning D J KwekkeboomWH Bakker et al ldquoSomato-statin receptor scintigraphy with [111In-DTPA-d-Phe1]- and[123I-Tyr3]-octreotide the Rotterdam experience with morethan 1000 patientsrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 20 no 8 pp 716ndash731 1993
[166] A Stahl G Meisetschlager M Schottelius et al ldquo[123I]Mtr-TOCA a radioiodinated and carbohydrated analogue ofoctreotide Scintigraphic comparison with [111In]octreotiderdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 33 no 1 pp 45ndash52 2006
[167] R Lebtahi J le Cloirec C Houzard et al ldquoDetection of neu-roendocrine tumors 99mTc-P829 scintigraphy compared with111In-pentetreotide scintigraphyrdquo Journal of Nuclear Medicinevol 43 no 7 pp 889ndash895 2002
[168] C Decristoforo T Maina B Nock M Gabriel P Cordopatisand R Moncayo ldquo99mTc-demotate 1 First data in tumourpatients - Results of a pilotphase I studyrdquo European Journal ofNuclearMedicine andMolecular Imaging vol 30 no 9 pp 1211ndash1219 2003
[169] C Decristoforo S J Mather W Cholewinski E DonnemillerG Riccabona and R Moncayo ldquo(99m)Tc-EDDAHYNIC-TOC A new (99m)Tc-labelled radiopharmaceutical forimaging somatostatin receptor-positive tumours First clinicalresults and intra-patient comparison with 111In-labelledoctreotide derivativesrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 27 no 9 pp 1318ndash1325 2000
[170] A Hubalewska-Dydejczyk K Fross-Baron R Mikołajczak etal ldquo99mTc-EDDAHYNIC-octreotate scintigraphy an efficientmethod for the detection and staging of carcinoid tumoursResults of 3 yearsrsquo experiencerdquo European Journal of NuclearMedicine and Molecular Imaging vol 33 no 10 pp 1123ndash11332006
[171] M Bangard M Behe S Guhlke et al ldquoDetection of somato-statin receptor-positive tumours using the new 99mC-tricine-HYNIC-D-Phe1-Tyr3-octreotide First results in patients andcomparison with 111In-DTPA-D-Phe1-octreotiderdquo EuropeanJournal of Nuclear Medicine and Molecular Imaging vol 27 no6 pp 628ndash637 2000
[172] A Helisch G J Forster H Reber et al ldquoPre-therapeuticdosimetry and biodistribution of 86Y-DOTA- Phe1-Tyr3-octreotide versus 111In-pentetreotide in patients with advancedneuroendocrine tumoursrdquo European Journal of NuclearMedicine and Molecular Imaging vol 31 no 10 pp 1386ndash13922004
[173] M Henze J Schuhmacher P Hipp et al ldquoPET imaging ofsomatostatin receptors using [68GA]DOTA-D-Phe1-Tyr3-Octreotide First results in patients with meningiomasrdquo Journalof Nuclear Medicine vol 42 no 7 pp 1053ndash1056 2001
[174] I Kayani J B Bomanji A Groves et al ldquoFunctional imaging ofneuroendocrine tumors with combined PETCT using 68Ga-DOTATATE (Dota-DPhe1 Tyr3-octreotate) and 18F-FDGrdquoCancer vol 112 no 11 pp 2447ndash2455 2008
[175] A Al-Nahhas ldquoNuclear medicine imaging of neuroendocrinetumoursrdquo Clinical Medicine vol 12 no 4 pp 377ndash380 2012
[176] V Ambrosini S Nicolini P Caroli et al ldquoPETCT imaging indifferent types of lung cancer an overviewrdquo European Journal ofRadiology vol 81 no 5 pp 988ndash1001 2012
[177] V Ambrosini D Campana P Tomassetti and S Fanti ldquo68Ga-labelled peptides for diagnosis of gastroenteropancreatic NETrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 39 no 1 pp S52ndashS60 2012
[178] K E Oberg J-C Reubi D J Kwekkeboom and E P KrenningldquoRole of somatostatins in gastroenteropancreatic neuroen-docrine tumor development and therapyrdquoGastroenterology vol139 no 3 pp 753-753 2010
[179] K Oberg ldquoGallium-68 somatostatin receptor PETCT Is ittime to replace 111Indium DTPA octreotide for patients withneuroendocrine tumorsrdquo Endocrine Journal vol 42 no 1 pp3-4 2012
[180] R Srirajaskanthan I Kayani A M Quigley J Soh M ECaplin and J Bomanji ldquoThe role of 68Ga-DOTATATE PET inpatients with neuroendocrine tumors and negative or equivocalfindings on 111In-DTPA-octreotide scintigraphyrdquo Journal ofNuclear Medicine vol 51 no 6 pp 875ndash882 2010
[181] A Kroiss D Putzer and C Uprimny ldquoFunctional imag-ing in phaeochromocytoma and neuroblastoma with 68Ga-DOTA-Tyr3-octreotide positron emission tomography and123I-metaiodobenzylguanidinerdquo European Journal of NuclearMedicine and Molecular Imaging vol 38 no 5 pp 865ndash8732011
[182] M Naji C Zhao S J Welsh et al ldquo68Ga-DOTA-TATE PETvs 123I-MIBG in identifying malignant neural crest tumoursrdquoMolecular Imaging and Biology vol 13 no 4 pp 769ndash775 2011
[183] V Ambrosini P Tomassetti P Castellucci et al ldquoComparisonbetween 68Ga-DOTA-NOC and 18F-DOPA PET for the detec-tion of gastro-entero-pancreatic and lung neuro-endocrinetumoursrdquo European Journal of Nuclear Medicine and MolecularImaging vol 35 no 8 pp 1431ndash1438 2008
[184] D Putzer M Gabriel B Henninger et al ldquoBone metastasesin patients with neuroendocrine tumor 68Ga- DOTA-Tyr3-octreotide PET in comparison to CT and bone scintigraphyrdquoJournal of Nuclear Medicine vol 50 no 8 pp 1214ndash1221 2009
[185] L K Anzola-Fuentes M Chianelli F Galli et al ldquoSomatostatinreceptor scintigraphy in patients with rheumatoid arthritis andsecondary Sjogrenrsquos syndrome treated with Infliximab a pilotstudyrdquo EJNMMI Research vol 6 no 1 article no 49 2016
[186] T Nobashi Y Nakamoto T Kubo et al ldquoThe utility of PETCTwith 68Ga-DOTATOC in sarcoidosis comparison with 67Ga-scintigraphyrdquoAnnals ofNuclearMedicine vol 30 no 8 pp 544ndash552 2016
[187] C Boy T A Heusner T D Poeppel et al ldquo68Ga-DOTATOCPETCT and somatostatin receptor (sst1-sst5) expression innormal human tissue Correlation of sst2mRNAand SUVmaxrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 38 no 7 pp 1224ndash1236 2011
[188] P Rinne S Hellberg M Kiugel et al ldquoComparison of Somato-statin Receptor 2-Targeting PET Tracers in the Detection ofMouse Atherosclerotic Plaquesrdquo Molecular Imaging and Biol-ogy vol 18 no 1 pp 99ndash108 2016
[189] M Asti E Ferrari S Croci et al ldquoSynthesis and characteri-zation of 68Ga-labeled curcumin and curcuminoid complexesas potential radiotracers for imaging of cancer and alzheimersdiseaserdquo Inorganic Chemistry vol 53 no 10 pp 4922ndash49332014
[190] A Signore I Santino and A W J M Glaudemans ldquoIn vivoimaging of microorganismsrdquo Clinical and Translational Imag-ing vol 4 no 3 pp 161-162 2016
[191] S Auletta F Galli C Lauri D Martinelli I Santino andA Signore ldquoImaging bacteria with radiolabelled quinolones
22 Contrast Media amp Molecular Imaging
cephalosporins and siderophores for imaging infection a sys-tematic reviewrdquo Clinical and Translational Imaging vol 4 no 4pp 229ndash252 2016
[192] X Ning S Lee Z Wang et al ldquoMaltodextrin-based imagingprobes detect bacteria in vivo with high sensitivity and speci-ficityrdquo Nature Materials vol 10 no 8 pp 602ndash607 2011
[193] J Ady andY Fong ldquoImaging for infection Fromvisualization ofinflammation to visualization of microbesrdquo Surgical Infectionsvol 15 no 6 pp 700ndash707 2014
[194] J M Sierra D Rodriguez-Puig A Soriano J Mensa C Pieraand J Vila ldquoAccumulation of 99mTc-ciprofloxacin in Staphy-lococcus aureus and Pseudomonas aeruginosardquo AntimicrobialAgents and Chemotherapy vol 52 no 7 pp 2691-2692 2008
[195] D I Andersson and D Hughes ldquoMicrobiological effects ofsublethal levels of antibioticsrdquoNature ReviewsMicrobiology vol12 no 7 pp 465ndash478 2014
[196] N Dumarey D Blocklet T Appelboom L Tant and ASchoutens ldquoInfecton is not specific for bacterial osteo-articularinfective pathologyrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 29 no 4 pp 530ndash535 2002
[197] K E Britton D W Wareham S S Das et al ldquoImaging bacte-rial infection with 99mTc-ciprofloxacin (Infecton)rdquo Journal ofClinical Pathology vol 55 no 11 pp 817ndash823 2002
[198] G Ferro-Flores M A Avila-Rodrıguez and F O Garcıa-PerezldquoImaging of bacteria with radiolabeled ubiquicidin by SPECTand PET techniquesrdquo Clinical and Translational Imaging vol 4no 3 pp 175ndash182 2016
[199] P S Hiemstra M T van den Barselaar M Roest P H Nibber-ing and R van Furth ldquoUbiquicidin a novel murine microbi-cidal protein present in the cytosolic fraction of macrophagesrdquoJournal of Leukocyte Biology vol 66 no 3 pp 423ndash428 1999
[200] M S Akhtar A Qaisar J Irfanullah et al ldquoAntimicrobialpeptide 99mTc-ubiquicidin 29ndash41 as human infection-imagingagent clinical trialrdquo Journal of Nuclear Medicne vol 46 no 4pp 567ndash573 2005
[201] M Assadi K Vahdat I Nabipour et al ldquoDiagnostic value of99mTc-ubiquicidin scintigraphy for osteomyelitis and compar-isons with 99mTc-methylene diphosphonate scintigraphy andmagnetic resonance imagingrdquo Nuclear Medicine Communica-tions vol 32 no 8 pp 716ndash723 2011
[202] T Emery ldquoExchange of Iron by Gallium in SiderophoresrdquoBiochemistry vol 25 no 16 pp 4629ndash4633 1986
[203] M Petrik C Zhai H Haas and C Decristoforo ldquoSiderophoresfor molecular imaging applicationsrdquo Clinical and TranslationalImaging vol 5 no 1 pp 15ndash27 2017
[204] H J Flint E A BayerM T Rincon R Lamed and B AWhiteldquoPolysaccharide utilization by gut bacteria potential for newinsights from genomic analysisrdquo Nature Reviews Microbiologyvol 6 no 2 pp 121ndash131 2008
[205] GGowrishankarMNamavari E B Jouannot et al ldquoInvestiga-tion of 6-[18F]-fluoromaltose as a novel PET tracer for imagingbacterial infectionrdquo PLoS ONE vol 9 no 9 Article ID e1079512014
[206] N Gholipour M Akhlaghi A M Kheirabadi et al ldquoChelator-free radiolabeling of dextran with 68Ga for PET studiesrdquoJournal of Radioanalytical and Nuclear Chemistry vol 311 no3 pp 1811ndash1817 2017
[207] C Bettegowda C A Foss I Cheong et al ldquoImaging bac-terial infections with radiolabeled 1-(21015840-deoxy-21015840- fluoro-120573-D-arabinofuranosyl)-5-iodouracilrdquo Proceedings of the NationalAcadamy of Sciences of the United States of America vol 102 no4 pp 1145ndash1150 2005
[208] S A Soghomonyan M Doubrovin J Pike et al ldquoPositronemission tomography (PET) imaging of tumor-localizedSalmonella expressing HSV1-TKrdquo Cancer GeneTherapy vol 12no 1 pp 101ndash108 2005
[209] C Palestro K Nichols S Sheikh-Fayyaz S Dewey P Singhaland K Bhargava ldquoCan Gallium-68 PET differentiate acuteinterstitial nephritis from acute tubular necrosisrdquo Journal ofNuclear Medicne vol 57 Supplement 2 p 551 2016
[210] A J Morguet D L Munz V Ivancevic et al ldquoImmunoscintig-raphy using technetium-99m-labeled anti-NCA-95 antigranu-locyte antibodies as an adjunct to echocardiography in subacuteinfective endocarditisrdquo Journal of the American College ofCardiology vol 23 no 5 pp 1171ndash1178 1994
[211] C van der Laken O Boerman W Oyen et al ldquoIn Vivo Expres-sion of Interleukin-1 Receptors during Various ExperimentallyInduced Inflammatory Conditionsrdquo The Journal of InfectiousDiseases vol 177 no 5 pp 1398ndash1401 1998
[212] C J Van Der Laken O C Boerman W J G Oyen M T PVan De Ven J W M Van Der Meer and F H M CorstensldquoScintigraphic detection of infection and inflammation Newdevelopments with special emphasis on receptor interactionrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 25 no 5 pp 535ndash546 1998
[213] C J van der LakenOC BoermanW J GOyenM T P van deVen J W M van der Meer and F H M Corstens ldquoImaging ofinfection in rabbits with radioiodinated interleukin-1 (120572 and 120573)its receptor antagonist and a chemotactic peptide a comparativestudyrdquo European Journal of Nuclear Medicine and MolecularImaging vol 25 no 4 pp 347ndash352 1998
[214] C J Van Der Laken O C BoermanW J G Oyen M T P VanDe Ven F H M Corstens and J W M Ven Der Meer ldquoThekinetics of radiolabelled interleukin-8 in infection and sterileinflammationrdquo Nuclear Medicine Communications vol 19 no3 pp 271ndash282 1998
[215] E Lazzeri P Erba M Perri et al ldquoScintigraphic imaging ofvertebral osteomyelitis with 111in-biotinrdquoThe Spine Journal vol33 no 7 pp E198ndashE204 2008
[216] E Blom B Langstrom and I Velikyan ldquo68Ga-labeling of biotinanalogues and their characterizationrdquo Bioconjugate Chemistryvol 20 no 6 pp 1146ndash1151 2009
[217] O Eriksson F Carlsson E Blom et al ldquoPreclinical evaluationof a 68Ga-labeled biotin analogue for applications in islettransplantationrdquo Nuclear Medicine and Biology vol 39 no 3pp 415ndash421 2012
[218] E A Weinstein A A Ordonez V P DeMarco et alldquoImaging Enterobacteriaceae infection in vivo with 18F-fluoro-deoxysorbitol positron emission tomographyrdquo Science Transla-tional Medicine vol 6 no 259 p 259ra146 2014
[219] K M Nielsen M H Kyneb A K O Alstrup et alldquo68Ga-labeled phage-display selected peptides as tracers forpositron emission tomography imaging of Staphylococcusaureus biofilm-associated infections Selection radiolabellingand preliminary biological evaluationrdquo Nuclear Medicine andBiology vol 43 no 10 pp 593ndash605 2016
[220] T J Makinen P Lankinen T Poyhonen J Jalava H T Aroand A Roivainen ldquoComparison of 18F-FDG and 68Ga PETimaging in the assessment of experimental osteomyelitis due toStaphylococcus aureusrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 32 no 11 pp 1259ndash1268 2005
[221] JMU Silvola I LaitinenH J Sipila et al ldquoUptake of 68galliumin atherosclerotic plaques in LDLRminusminusApoB100100micerdquo EJN-MMI Research vol 1 no 1 pp 1ndash8 2011
Contrast Media amp Molecular Imaging 23
[222] T A Wynn ldquoCellular and molecular mechanisms of fibrosisrdquoThe Journal of Pathology vol 214 no 2 pp 199ndash210 2008
[223] T Derlin D Jonigk J Bauersachs and FM Bengel ldquoMolecularImaging of Chemokine Receptor CXCR4 in NonndashSmall CellLung Cancer Using 68Ga-Pentixafor PETCT ComparisonWith 18F-FDGrdquo Clinical Nuclear Medicine 2016
[224] I Velikyan U Rosenstrom T N Bulenga O Eriksson andG Antoni ldquoFeasibility of multiple examinations using68ga-labelled collagelin analogues Organ distribution in rat forextrapolation to human organ and whole-body radiationdosimetryrdquo Pharmaceuticals vol 9 no 2 article no 31 2016
[225] S Jadhav M Kakela J Makila et al ldquoSynthesis and in VivoPET Imaging of Hyaluronan Conjugates of OligonucleotidesrdquoBioconjugate Chemistry vol 27 no 2 pp 391ndash403 2016
[226] A Autio A Saraste N Kudomi et al ldquoAssessment of bloodflow with (68) Ga-DOTA PET in experimental inflammation avalidation study using (15) O-waterrdquo American Journal ofNuclear Medicine and Molecular Imaging vol 4 no 6 pp 571ndash579 2014
[227] G Davies A Rolle A Maurer et al ldquoTowards translationalimmunoPETMR imaging of invasive pulmonary aspergillosisthe Humanised Monoclonal Antibody JF5 detects in vivordquoTheranostics vol 7 no 14 pp 3398ndash3414 2017
[228] DGoodwin CMeares GDavid et al ldquoMonoclonal antibodiesas reversible equilibrium carriers of radiopharmaceuticalsrdquoInternational Journal of Radiation Applications and Instrumen-tation Part B Nuclear Medicine and Biology vol 13 no 4 pp383ndash391 1986
[229] D A Goodwin C F Mears M McTigue and G S DavidldquoMonoclonal antibody hapten radiopharmaceutical deliveryrdquoNuclear Medicine Communications vol 7 no 8 pp 569ndash5801986
[230] S E Halpern and R O Dillman ldquoProblems associated withradioimmunodetection and possibilities for future solutionsrdquo JBiol Response Mod vol 6 no 3 pp 235ndash262 1987
[231] H Hong J Sun and W Cai ldquoRadionuclide-based cancerimaging targeting the carcinoembryonic antigenrdquo BiomarkerInsights vol 3 pp 435ndash451 2008
[232] G J Forster E B Santos P M Smith-Jones P Zanzonico andS M Larson ldquoPretargeted radioimmunotherapy with a single-chain antibodystreptavidin construct and radiolabeledDOTA-biotin Strategies for reduction of the renal doserdquo Journal ofNuclear Medicine vol 47 no 1 pp 140ndash149 2006
[233] Z Yao M Zhang H Kobayashi et al ldquoImproved targeting ofradiolabeled streptavidin in tumors pretargeted with biotiny-lated monoclonal antibodies through an avidin chaserdquo Journalof Nuclear Medicine vol 36 no 5 pp 837ndash841 1995
[234] C-H Chang R M Sharkey E A Rossi et al ldquoMolecularAdvances in Pretargeting Radioimunotherapy with BispecificAntibodies 1 Supported in part by USPHS Grant R01-CA-84379from the NIH and Department of Energy Grant DE-FG01-00NE22941 (both to R M S)1rdquo Mol Cancer Ther vol 1 no 7pp 553ndash563 2002
[235] R M Sharkey E A Rossi W J McBride C-H Chang andD M Goldenberg ldquoRecombinant Bispecific Monoclonal Anti-bodies Prepared by theDock-and-Lock Strategy for PretargetedRadioimmunotherapyrdquo Seminars in Nuclear Medicine vol 40no 3 pp 190ndash203 2010
[236] R M Sharkey E A Rossi C-H Chang and D M Golden-berg ldquoImproved cancer therapy and molecular imaging withmultivalent multispecific antibodiesrdquo Cancer Biotherapy andRadiopharmaceuticals vol 25 no 1 pp 1ndash12 2010
[237] D M Goldenberg R M Sharkey G Paganelli J Barbet andJ Chatal ldquoAntibody pretargeting advances cancer radioim-munodetection and radioimmunotherapyrdquo Journal of ClinicalOncology vol 24 no 5 pp 823ndash834 2006
[238] O C Boerman F G van Schaijk W J G Oyen and FH M Corstens ldquoPretargeted radioimmunotherapy of cancerprogress step by steprdquo Journal of Nuclear Medicine vol 44 no3 pp 400ndash411 2003
[239] J Schuhmacher S Kaul G Klivenyi et al ldquoImmunoscintigra-phy with positron emission tomography Gallium-68 chelateimaging of breast cancer pretargeted with bispecific anti-MUC1anti-Ga chelate antibodiesrdquo Cancer Research vol 61 no9 pp 3712ndash3717 2001
[240] J Schuhmacher G Klivenyi S Kaul et al ldquoPretargeting ofhuman mammary carcinoma xenografts with bispecific anti-MUC1anti-Ga chelate antibodies and immunoscintigraphywith PETrdquo Nuclear Medicine and Biology vol 28 no 7 pp 821ndash828 2001
[241] C Somasundaram S Matzku J Schuhmacher and M ZollerldquoDevelopment of a bispecific monoclonal antibody against agallium-67 chelate and the human melanoma-associated anti-gen p97 for potential use in pretargeted immunoscintigraphyrdquoCancer Immunology Immunotherapy vol 36 no 5 pp 337ndash3451993
[242] E A Rossi D L Rossi R Stein D M Goldenberg and C-H Chang ldquoA bispecific antibody-IFN1205722b immunocytokine tar-geting CD20 and HLA-DR is highly toxic to human lymphomaandmultiplemyeloma cellsrdquoCancer Research vol 70 no 19 pp7600ndash7609 2010
[243] R M Sharkey H Karacay S Litwin et al ldquoImproved ther-apeutic results by pretargeted radioimmunotherapy of non-Hodgkinrsquos lymphoma with a new recombinant trivalent anti-CD20 bispecific antibodyrdquo Cancer Research vol 68 no 13 pp5282ndash5290 2008
[244] G L Griffiths C-H Chang W J McBride et al ldquoReagentsandmethods for PETusing bispecific antibody pretargeting and68Ga-radiolabeled bivalent hapten-peptide-chelate conjugatesrdquoJournal of Nuclear Medicine vol 45 no 1 pp 30ndash39 2004
[245] J Watine M Miedouge and B Friedberg ldquoCarcinoembryonicantigen as an independent prognostic factor of recurrence andsurvival in patients resected for colorectal liver metastases Asystematic reviewrdquo Diseases of the Colon amp Rectum vol 44 no12 pp 1791ndash1799 2001
[246] M J Goldstein and E P Mitchell ldquoCarcinoembryonic antigenin the staging and follow-up of patients with colorectal cancerrdquoCancer Investigation vol 23 no 4 pp 338ndash351 2005
[247] D V Gold D M Goldenberg H Karacay et al ldquoA novelbispecific trivalent antibody construct for targeting pancreaticcarcinomardquo Cancer Research vol 68 no 12 pp 4819ndash48262008
[248] J Schuhmacher G Klivenyi R Matys et al ldquoMultistep tumortargeting in nudemice using bispecific antibodies and a galliumchelate suitable for immunoscintigraphy with positron emis-sion tomographyrdquo Cancer Research vol 55 no 1 pp 115ndash1231995
[249] G Klivenyi J Schuhmacher E Patzelt et al ldquoGallium-68chelate imaging of human colon carcinoma xenografts pre-targeted with bispecific anti-CD44(V6)anti-gallium chelateantibodiesrdquo Journal ofNuclearMedicine vol 39 no 10 pp 1769ndash1776 1998
[250] M Zoller J Schuhmacher J Reed W Maier-Borst and SMatzku ldquoEstablishment and characterization of monoclonal
24 Contrast Media amp Molecular Imaging
antibodies against an octahedral gallium chelate suitable forimmunoscintigraphy with PETrdquo Journal of Nuclear Medicinevol 33 no 7 pp 1366ndash1372 1992
[251] R M Sharkey T M Cardillo E A Rossi et al ldquoSignal ampli-fication in molecular imaging by pretargeting a multivalentbispecific antibodyrdquo Nature Medicine vol 11 no 11 pp 1250ndash1255 2005
[252] D M Goldenberg and R M Sharkey ldquoNovel radiolabeledantibody conjugatesrdquo Oncogene vol 26 no 25 pp 3734ndash37442007
[253] D M Goldenberg E A Rossi R M Sharkey W J McBrideand C-H Chang ldquoMultifunctional antibodies by the dock-and-lock method for improved cancer imaging and therapy bypretargetingrdquo Journal of NuclearMedicine vol 49 no 1 pp 158ndash163 2008
[254] R Schoffelen R M Sharkey D M Goldenberg et al ldquoPre-targeted immuno-positron emission tomography imaging ofcarcinoembryonic antigen-expressing tumors with a bispecificantibody and a68Ga- And18F-labeled hapten peptide in micewith human tumor xenograftsrdquoMolecular Cancer Therapeuticsvol 9 no 4 pp 1019ndash1027 2010
[255] E S Bos W H Kuijpers M Meesters-Winters et al ldquoIn vitroevaluation of DNA-DNA hybridization as a two-step approachin radioimmunotherapy of cancerrdquoCancer Research vol 54 no13 pp 3479ndash3486 1994
[256] G Paganelli M Bartolomei M Ferrari et al ldquoPre-TargetedLocoregional Radioimmunotherapy withrdquo Cancer biotherapyand radiopharmaceuticals vol 16 no 3 pp 227ndash235 2001
[257] A Forero P L Weiden J M Vose et al ldquoPhase 1 trial of a novelanti-CD20 fusion protein in pretargeted radioimmunotherapyfor B-cell non-Hodgkin lymphomardquo Blood vol 104 no 1 pp227ndash236 2004
[258] DM Goldenberg C-H Chang E A RossiW J McBride andR M Sharkey ldquoPretargeted molecular imaging and radioim-munotherapyrdquoTheranostics vol 2 no 5 pp 523ndash540 2012
[259] H Karacay R M Sharkey W J McBride E A Rossi C-HChang and D M Goldenberg ldquoOptimization of hapten-peptide labeling for pretargeted immunoPET of bispecificantibody using generator-produced 68Gardquo Journal of NuclearMedicine vol 52 no 4 pp 555ndash559 2011
[260] J R Oh and B C Ahn ldquoFalse-positive uptake on radioiodinewhole-body scintigraphy physiologic and pathologic variantsunrelated to thyroid cancerrdquo American Journal of NuclearMedicine and Molecular Imaging vol 2 no 2 pp 141ndash150 2012
[261] E Frampas C Rousseau C Bodet-Milin J Barbet J-F Chataland F Kraeber-Bodere ldquoImprovement of radioimmunotherapyusing pretargetingrdquo Frontiers in Oncology vol 3 Article ID00159 2013
[262] C S McKay and M G Finn ldquoClick chemistry in complexmixtures Bioorthogonal bioconjugationrdquo Chemistry amp Biologyvol 21 no 9 pp 1075ndash1101 2014
[263] B L Oliveira Z Guo and G J Bernardes ldquoInverse electrondemand DielsndashAlder reactions in chemical biologyrdquo ChemicalSociety Reviews vol 46 no 16 pp 4895ndash4950 2017
[264] B Nichols Z Qin J Yang D R Vera and N K Devaraj ldquo68Gachelating bioorthogonal tetrazine polymers for the multisteplabeling of cancer biomarkersrdquo Chemical Communications vol50 no 40 pp 5215ndash5217 2014
[265] R Rossin P R Verkerk S M van den Bosch et al ldquoInvivo chemistry for pretargeted tumor imaging in live micerdquoAngewandte Chemie International Edition vol 49 no 19 pp3375ndash3378 2010
[266] B M Zeglis K K Sevak T Reiner et al ldquoA pretargetedPET imaging strategy based on bioorthogonal diels-alder clickchemistryrdquo Journal of Nuclear Medicine vol 54 no 8 pp 1389ndash1396 2013
[267] J L Houghton R Membreno D Abdel-Atti et al ldquoEstablish-ment of the invivo efficacy of pretargeted radioimmunotherapyutilizing inverse electron demand diels-alder click chemistryrdquoMolecular Cancer Therapeutics vol 16 no 1 pp 124ndash133 2017
[268] J Funkhouser ldquoReinventing pharma the theranostic revolu-tionrdquo Current Drug Discovery pp 17ndash19 2002
[269] J Sorensen I Velikyan A Wennborg et al ldquoMeasuring HER2-expression in metastatic breast cancer using 68Ga-ABY025PETCTrdquo European Journal of Nuclear Medicine and MolecularImaging vol 41 pp S226ndashS226 2014
[270] I Velikyan A Wennborg J Feldwisch et al ldquoGMP compliantpreparation of a 68Gallium-labeled Affibody analogue forbreast cancer patient examination first-in-manrdquoEur JNuclMedMol Imaging vol 41 pp S228ndashS229 2014
[271] K Oberg ldquoMolecular imaging radiotherapy Theranostics forpersonalized patient management of neuroendocrine tumors(NETs)rdquoTheranostics vol 2 no 5 pp 448ndash458 2012
[272] I Velikyan AWennborg J FeldwischH Lindman J Carlssonand J Sorensen ldquoGood manufacturing practice production of [(68) Ga]Ga-ABY-025 for HER2 specific breast cancer imagingrdquoAmerican Journal of Nuclear Medicine and Molecular Imagingvol 6 no 2 pp 135ndash153 2016
[273] M Sandstrom K Lindskog I Velikyan et al ldquoBiodistributionand radiation dosimetry of the anti-HER2 Affibody molecule68Ga-ABY-025 in breast cancer patientsrdquo Journal of NuclearMedicine vol 57 no 6 pp 867ndash871 2016
[274] D Sandberg V Tolmachev I Velikyan et al ldquoIntra-imagereferencing for simplified assessment of HER2-expression inbreast cancer metastases using the Affibody molecule ABY-025with PET and SPECTrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 44 no 8 pp 1337ndash1346 2017
[275] H ZhangM AMoroz I Serganova et al ldquoImaging expressionof the human somatostatin receptor subtype-2 reporter genewith 68Ga-DOTATOCrdquo Journal ofNuclearMedicine vol 52 no1 pp 123ndash131 2011
[276] M Naji and A Al-Nahhas ldquo68Ga-labelled peptides in themanagement of neuroectodermal tumoursrdquo European Journalof Nuclear Medicine and Molecular Imaging vol 39 no 1 ppS61ndashS67 2012
[277] I Velikyan ldquoThe diversity of 68Ga-Based imaging agentsrdquoRecent Results in Cancer Research vol 194 pp 101ndash131 2013
[278] K Ferreira H-Y Hu V Fetz et al ldquoMultivalent siderophore-dotam conjugates as theranostics for imaging and treatment ofbacterial infectionsrdquo Angewandte Chemie International Editionvol 56 no 28 pp 8272ndash8276 2017
Computational and Mathematical Methods in Medicine
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Volume 2018Hindawiwwwhindawicom
Submit your manuscripts atwwwhindawicom
12 Contrast Media amp Molecular Imaging
(a) (b) (c) (d)
Figure 6 [68Ga]Ga-citrate PETCT examination of a patient affected by acute osteomyelitis before (left panel) and after (right panel) surgicalcurettage showing uptake in the transaxial (a c) and 3D reconstruction images (b d red area) Absence of the uptake after the therapyconfirms complete response to the treatment Adapted from [19]
Figure 7 Vertebral osteomyelitis (spondylodiscitis red arrow-heads) and abscesses in the iliopsoas and paravertebral area (redarrows) were detected by [68Ga]Ga-citrate in a patient admittedto the hospital with back pain and general symptoms The PETacquisition was performed 88min after administration of 245MBqof [68Ga]Ga-citrate Adapted from [80]
72 Radiolabelled Biotin Biotin is a growth factor utilizedin many bacteria An 111In-labelled analogue of biotin wassuccessfully utilized for diagnosis of vertebral infections ina clinical study [215] It would be rational to explore therelevance of 68Ga-labelled analogues given the advantagesof 68Ga over 111In and promising [68Ga]Ga-DOTA-Biotinanalogues [216 217] developed for monitoring survival oftransplanted avidin-coated islets
8 Miscellaneous
Stable Ga(III) complex with thiosemicarbazones demon-strated antimicrobial effect against P aeruginosa and Calbicans due to most probably both displacement of essentialFe(III) with Ga(III) and thiosemicarbazones [101] Substitu-tion of the stable Ga(III) by radioactive 68Ga might result ina specific infection imaging agent
Selective imaging of Enterobacteriaceae using 2-[18F]-fluorodeoxysorbitol (18F-FDS)was demonstrated in amurine
myositis model [218] The uptake of 18F-FDS was correlatedwith bacterial burden moreover the agent differentiatedinfection from sterile inflammation Given the potential of68Ga for the labelling of small biologically active molecules[4] it might be plausible to develop a respective analoguewith added value of the advantages that 68Ga offers includingsimpler production chemistry lowered radiation dose repet-itive examination and accessibility at clinical centers withoutcyclotrons and remote from [18F]-FDG distribution sites Asmentioned above the poor access to bacteria aggregated ina biofilm might make the imaging task challenging Severalpeptide candidates with affinity for S aureus biofilm weredesigned and labelled with 68Ga [219] The resulting agentsdemonstrated binding in vitro however it was not possible toblock the binding with excess of the cold peptide
Ionic 68Ga was found superior to [18F]-FDG in infectiondetection in the rat model with diffuse osteomyelitis [220] Inanother study the uptake of ionic 68Ga was observed in theaortic plaques of atherosclerotic mice specifically at the sitesrich inmacrophages [221] However the slow blood clearanceof ionic 68Ga presents a limitation
Chronic inflammation is the major reason of fibro-sis [222] 68Ga-labelled SST analogue ([68Ga]Ga-DOTA-NOC) demonstrated uptake in pathogenic areas in patientsaffected by idiopathic pulmonary fibrosis with potentialfor monitoring response to treatment and drug develop-ment [62] Another clinical study using [68Ga]Ga-pentixaforalso showed potential of the agent for monitoring dis-ease activity and response to treatment in idiopathic pul-monary fibrosis [223] Peptide based agents CNO2A-PEG2-c[CPGRVMHGLHLGDDEGPC] and [68Ga]Ga-NODAGA-PEG2-c[CPGRVMHGLHLGDDEGPC] for the imaging andquantification of fibrosis by PET were developed and char-acterized preclinically showing fast clearance from normal
Contrast Media amp Molecular Imaging 13
tissue and blood and binding specificity [89] Dosimetrycalculations demonstrated possibility of six examinations peryear in humans assuring disease monitoring in longitudinalstudies and routine clinical setup [224]
Several hyaluronan conjugates of oligonucleotides target-ing CD44 positive cells were developed and tested in healthyrats sham-operated rats and rats with myocardial infarction[225]The uptake of the agents was higher for the latter groupand varied dependent on the difference in the oligonucleotidestructure
TLR2 and TLR4 expression levels in neutrophils werefound higher in individuals with bacterial and viral infectionsthan those in control samples There is a possibility that IL-4IL-8 IL-10 IL-12 and TNF-a might serve as biomarkers forinfections and that IL-2 IL-8 or IL-10 is potentially able todistinguish between bacterial and viral infections [22]
Mannosylated human serum albumin labelled with 68Gavia NOTA chelator moiety ([68Ga]Ga-NOTA-MSA) wastested in a rat model of myocarditis targetingmannose recep-tors expressed onmacrophages infiltratingmyocardium [66]The uptake in the diseased myocardium was considerablyhigher than that of the normal one and it was precludedby administration of excess of nonlabelled MSA indicatingbinding specificity The tracer build-up was also observed inthe organs of macrophage accumulation
[68Ga]Ga-DOTA was investigated for the quantificationof increased blood flow which is one of the key events ininflammation [226] The uptake kinetics of [68Ga]Ga-DOTAin the site of inflammation in rats with induced inflamma-tion correlated well with that of 15O-water suggesting highrelevance [68Ga]Ga-DOTA
9 Pretargeted Imaging
The half-life of 68Ga is shorter than that of 64Cu 67Ga 99mTc89Zr 111In and 123124125I and thus in contrast to the latterit is not compatible with slow pharmacokinetics of largemolecules such as antibodies and glycoproteins The rangeof antigen-specific antibodies relevant to inflammation andinfection is broad and a number of 99mTc-labelled antibodieswere used clinically [20 21 227] The respective range of68Ga-based agents could be similarThe solution to overcomethe incompatibility of half-life time frames could be eitherthe reduction of the antibody size or the application of thepretargeting concept
The history of the pretargeting concept spans threedecades predominantly in the field of oncology [228ndash230]It was developed to improve image contrast and dosimetryin immunoimaging and radioimmunotherapy when usingradiolabelled antibody ligands with slow pharmacokinetics[231] The arsenal of antibodies is vast and diverse encourag-ing extensive investment into development of techniques thatwould allow their exploration to the fullest Pretargeting con-siders at least two major steps wherein a functionalized anti-body is first administered for target localization and clearancefrom blood and normal tissue and thereafter a radiolabelledsmall molecule capable of binding to the functionalized
antibody due to high affinity or covalent interaction is admin-istered The key properties of the radiolabelled molecules arefast pharmacokinetic and clearance Several techniques havebeen developed for the realization of pretargeting conceptincluding avidinstreptavidin-biotin systems [216 217 232233] bispecific antibodies (bsmAb) with haptens [232 234ndash254] antibody-oligonucleotide conjugates with complemen-tary oligonucleotides [255] biorthogonal systems allowingcovalent chemical reactions in vivo (Figure 8)
The high affinity of biotin to avidin and streptavidinproteins was utilized clinically and preclinically in pretar-geting approach for the imaging and therapy of pancreaticadenocarcinoma [232] glioblastoma [256] and lymphoma[257] However this pretargeting technique may requirethree steps in order to eliminate the excess of antibody-(strept)avidin conjugate circulating in the blood and notbound to the target by adding clearing agent Anotherapplication of the technique was monitoring transplantationof islets of Langerhans in the treatment for type 1 diabetesmellitus wherein the cells or cellmimetics were conjugated to(strept)avidin prior to the transplantation [216 217] Severalanalogues of biotin comprising DOTA chelate moiety forlabelling with 68Ga and ethylene glycol linker of variouslength demonstrated the influence of the latter on the affinitytowards avidin
Particular example of hapten molecules is the ones com-prising histamine-succinyl-glycine (HSG) motif and chelatemoiety [251ndash253 258] for the complexationwith 68Ga Severalanalogues were developed for the imaging of carcinoem-bryonic antigen (CEA) pretargeted with anti-CEA bsmAb[254 259 260] and two clinical studies of medullary thyroidcarcinoma and breast carcinoma positive for CEA using68Ga-labelled hapten molecules and bsmAb were initiated[261]
Bioorthogonal reactions are fast regioselective requiringsmall reagent concentration and occurring under mild con-ditions often in aqueous solution and temperature below 37∘C[262 263] Amongst various biorthogonal reaction types thecycloaddition of tetrazines and various dienophiles referredto as inverse-electron-demandDiels-Alder (IEDDA) reactionis themost successful in the context of pretargeting Antibod-ies functionalized with trans-cyclooctene (TCO) and a radi-olabelled tetrazine that can interact in vivo based on IEDDAreaction were studied [264ndash267] In particular 68Ga-labelledtetrazine dextran demonstrated favorable pharmacokineticsin a healthy mouse [264] However the proof of concept is tobe performed in a xenografted animal Accumulation of anti-TAG72 [265] and anti-A33 [266] antibodies functionalizedwith TCO in mouse xenografts was visualized respectivelyby an 111In and 64Cu-labelled tetrazine analogues Anti-CA199 antibody-TCO in combination with 177Lu-labelledtetrazine demonstrated radiotherapeutic effect in pancreaticcancer murine model [267]
Thepretargeted imaging techniquesmay contribute to theexpansion of immuno-PET with 68Ga providing the intrinsicadvantages of 68Ga and PET As mentioned above mostof the developed radiolabelled counterparts of pretargetingtechniques have demonstrated promising results There are
14 Contrast Media amp Molecular Imaging
H
ON
NN
O
OO
OO
NH
NS
NH
ONH
O
HO
ONH
O
Ga
HN
NH
NH
O
OO
HNN
HN
NH
NH
O
OO
HNN
（2
(a)
NH
O
O
NH
N
NNGa
O O
O O
O
O
O
N N
NN
OO
（2
(b)
N
N
O
O
N
N
O
O
O
NH
O
O
ONH
NHS
O
H
HO
NH
+
minus
(c)
Figure 8 Schematic presentation of pretargeting techniques (a) bispecific antibodies engineered to specifically bind with radiolabelledhapten molecules (b) bioorthogonal click chemistry for fast and specific covalent binding between for example a trans-cyclooctenefunctionalized antibody and a radiolabelled tetrazine (c) interaction between antibody-(strept)avidin conjugate and radiolabelled biotinutilizing extremely high affinity of (strept)avidin and biotin
Contrast Media amp Molecular Imaging 15
a considerable number of potential antibody biomarkersthat could be considered for the imaging of infection andinflammation
10 Theranostics Potential
Theranostics [268] embraces realization of personalizedmedicine by conducting diagnosis on individual basis andproviding possibility of predicting the efficacy of a specifictreatment and following up the response to the treatmentenabling adjustment of the latter very early in the processIn the context of nuclear medicine wherein the radiophar-maceuticals targeted at biomarkers specific to a disease cancarry either diagnostic radionuclides or therapeutic ones theconcept can be denoted as radiotheranostics [28] The tar-geted molecular imaging such as PET can offer noninvasivediagnosis specific to the disease for example tumour-typespecific and provide accurate localization of the lesions Thestrongest advantage of PET is the potential for quantificationof the target for example receptor expression investigationof the uptake kinetics and estimation of the dosimetryThesecharacteristics of PET allow for individualized treatmentselection and planning monitoring of treatment responseand detection of recurrent diseaseThe individualized patientmanagement provides such advantages as optimization ofthe treatment regimen for the improved response and exclu-sion of futile treatments minimization of risks and toxicitywith overall outcome of reduced cost and patient distressThe importance of individualized patient management wasdemonstrated by clinical studies wherein the influence ofdose of the administered radiopharmaceutical targeted atreceptors overexpressed in cancer lesions on the diagnosticoutcome was investigated in the same patient [85 269270] 68Ga-labelled SST analogues [26ndash28 271] and Affibodymolecules [5 272ndash274] used respectively in NENs andbreast cancer patients are the most prominent examplesof (radio)theranostics involving 68GaPET wherein 68Ga-labelled analogues were used not only for localization of thelesions but also for staging patient stratification prognosistherapy selection and monitoring of the response to thetreatment of NETs and other cancer types [2ndash4 6 85 176275ndash277]
The methodology can be translated to inflammationand infection allowing for accurate and specific selection oftreatment regimen and for follow-up and evaluation of theresponse to therapy resulting in improved treatment efficacyand decreased cost and side effects The accommodation ofboth imaging function and antibiotic function in the samemolecule is a novel example of a theranostic agent [278]A series of siderophores conjugated with DOTA moiety forthe radiolabelling and with antibiotics for the treatmentof bacterial infection were investigated preclinically Theaccumulation of the intravenously administered ampicillinconjugate in the site of subcutaneously injected P aeruginosain mice was clearly and focally visualized within 06 h withretention for at least 24 h These results obtained usinganalogues carrying dye for optical imaging can be translatedto 68Ga-labelled counterparts for PET
11 Conclusions
The medical need for specific agents for noninvasive quan-titative and whole-body imaging of inflammation and infec-tion has not been met yet despite decades of research How-ever the prerequisites in terms of identification of potentialtargets design and synthesis of the respective ligands andimaging technologies are evolving very fast The potentialof accurate and quantitative lesion localization as well asmonitoring of the treatment response promises personalizedpatient management
The use of 68Ga in oncology is established proving thestrong potential of 68Ga for the promotion of PET technol-ogy for effective and efficient diagnostics and personalizedmedicineThe experience of oncological 68Ga-based agents isgetting translated to inflammation and infection Pretargetedimaging technology opens wide possibilities based on anti-body biomarkers
Conflicts of Interest
The author declares that there are no conflicts of interestregarding the publication of this article
References
[1] I Velikyan ldquoContinued rapid growth inGa applications update2013 to June 2014rdquo Journal of Labelled CompoundsampRadiophar-maceuticals pp 99ndash121 2015
[2] I Velikyan ldquo 68Ga-based radiopharmaceuticals Production andapplication relationshiprdquo Molecules vol 20 no 7 pp 12913ndash12943 2015
[3] M Fani P Peitl and I Velikyan ldquoCurrent status of radiophar-maceuticals for the theranostics of neuroendocrine neoplasmsrdquoPharmaceuticals vol 10 no 1 article no 30 2017
[4] I Velikyan ldquoPositron emitting [68Ga]Ga-based imaging agentsChemistry and diversityrdquoMedicinal Chemistry vol 7 no 5 pp345ndash379 2011
[5] J Sorensen I Velikyan D Sandberg et al ldquoMeasuringHER2-receptor expression in metastatic breast cancer using[68Ga]ABY-025 Affibody PETCTrdquo Theranostics vol 6 no 2pp 262ndash271 2016
[6] I Velikyan ldquoProspective of 68Ga-Radiopharmaceutical devel-opmentrdquoTheranostics vol 4 no 1 pp 47ndash80 2014
[7] P Lankinen T J Makinen T A Poyhonen et al ldquo68Ga-DOTAVAP-P1 PET imaging capable of demonstrating the phaseof inflammation in healing bones and the progress of infectionin osteomyelitic bonesrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 35 no 2 pp 352ndash364 2008
[8] T UjulaMHuttunen P Luoto et al ldquoMatrixmetalloproteinase9 targeting peptides Syntheses 68Ga-labeling and preliminaryevaluation in a rat melanoma xenograft modelrdquo BioconjugateChemistry vol 21 no 9 pp 1612ndash1621 2010
[9] A Autio T Ujula P Luoto S Salomaki S Jalkanen and ARoivainen ldquoPET imaging of inflammation and adenocarcinomaxenografts using vascular adhesion protein 1 targeting peptide68Ga-DOTAVAP-P1 Comparison with 18F-FDGrdquo EuropeanJournal of Nuclear Medicine and Molecular Imaging vol 37 no10 pp 1918ndash1925 2010
16 Contrast Media amp Molecular Imaging
[10] J Silvola A Autio P Luoto S Jalkanen andA Roivainen ldquoPre-liminary evaluation of novel 68Ga-DOTAVAP-PEG-P2 peptidetargeting vascular adhesion protein-1rdquo Clinical Physiology andFunctional Imaging vol 30 no 1 pp 75ndash78 2010
[11] T Ujula S Salomaki P Virsu et al ldquoSynthesis 68Ga labelingand preliminary evaluation of DOTA peptide binding vascularadhesion protein-1 a potential PET imaging agent for diagnos-ing osteomyelitisrdquo Nuclear Medicine and Biology vol 36 no 6pp 631ndash641 2009
[12] A Autio T Henttinen H J Sipila S Jalkanen and ARoivainen ldquoMini-PEG spacering of VAP-1-targeting 68Ga-DOTAVAP-P1 peptide improves PET imaging of inflamma-tionrdquo EJNMMI Research vol 1 no 1 pp 1ndash7 2011
[13] K Aalto A Autio E A Kiss et al ldquoSiglec-9 is a novel leukocyteligand for vascular adhesion protein-1 and can be used in PETimaging of inflammation and cancerrdquo Blood vol 118 no 13 pp3725ndash3733 2011
[14] V Kumar D K Boddeti S G Evans F Roesch and RHowman-Giles ldquoPotential use of 68Ga-apo-transferrin as a PETimaging agent for detecting Staphylococcus aureus infectionrdquoNuclear Medicine and Biology vol 38 no 3 pp 393ndash398 2011
[15] M Petrik H Haas G Dobrozemsky et al ldquo68Ga-siderophoresfor PET imaging of invasive pulmonary aspergillosis Proof ofprinciplerdquo Journal of Nuclear Medicine vol 51 no 4 pp 639ndash645 2010
[16] M Petrik H Haas M Schrettl A Helbok M Blatzer and CDecristoforo ldquoIn vitro and in vivo evaluation of selected 68Ga-siderophores for infection imagingrdquo Nuclear Medicine andBiology vol 39 no 3 pp 361ndash369 2012
[17] M Petrik GM Franssen H Haas et al ldquoPreclinical evaluationof two 68Ga-siderophores as potential radiopharmaceuticals forAspergillus fumigatus infection imagingrdquo European Journal ofNuclearMedicine andMolecular Imaging vol 39 no 7 pp 1175ndash1183 2012
[18] A Rizzello D Di Pierro F Lodi et al ldquoSynthesis and qualitycontrol of 68Ga citrate for routine clinical PETrdquo NuclearMedicine Communications vol 30 no 7 pp 542ndash545 2009
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[20] S S Das A V Hall D W Wareham and K E Britton ldquoInfec-tion imaging with radiopharmaceuticals in the 21st centuryrdquoBrazilian Archives of Biology and Technology vol 45 no spepp 25ndash37 2002
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[22] T Yusa K Tateda A Ohara and S Miyazaki ldquoNew possiblebiomarkers for diagnosis of infections and diagnostic distinc-tion between bacterial and viral infections in childrenrdquo Journalof Infection and Chemotherapy vol 23 no 2 pp 96ndash100 2017
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[31] M F Tsan ldquoMechanism of gallium-67 accumulation in inflam-matory lesionsrdquo Journal of Nuclear Medicine vol 26 no 1 pp88ndash92 1985
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[37] S S Gambhir J Czernin J Schwimmer D H Silverman R EColeman and M E Phelps ldquoA tabulated summary of the FDGPET literaturerdquo Journal of Nuclear Medicine vol 42 pp 1Sndash93S2001
[38] M J Lindsay B A Siegel S R Tunis et al ldquoThe NationalOncologic PET Registry ExpandedMedicare coverage for PETunder coverage with evidence developmentrdquo American Journalof Roentgenology vol 188 no 4 pp 1109ndash1113 2007
[39] F Gemmel H Van Den Wyngaert C Love M M Welling PGemmel and C J Palestro ldquoProsthetic joint infectionsradionuclide state-of-the-art imagingrdquo European Journal ofNuclearMedicine andMolecular Imaging vol 39 no 5 pp 892ndash909 2012
[40] J Sorensen ldquoHow does the patient benefit from clinical PETrdquoTheranostics vol 2 no 5 pp 427ndash436 2012
[41] S L Rice C A Roney P Daumar and J S Lewis ldquoThe nextgeneration of positron emission tomography radiopharmaceu-ticals in oncologyrdquo Seminars in Nuclear Medicine vol 41 no 4pp 265ndash282 2011
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Contrast Media amp Molecular Imaging 17
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[45] S Eichendorff P Svendsen D Bender et al ldquoBiodistributionand PET Imaging of a Novel [68Ga]-Anti-CD163-AntibodyConjugate in Rats with Collagen-Induced Arthritis and inControlsrdquoMolecular Imaging and Biology vol 17 no 1 pp 87ndash93 2014
[46] Z Zhu Y Yin K Zheng et al ldquoEvaluation of synovial angiogen-esis in patients with rheumatoid arthritis using 68Ga-PRGD2PETCT A prospective proof-of-concept cohort studyrdquo Annalsof the Rheumatic Diseases vol 73 no 6 pp 1269ndash1272 2014
[47] J S Eo J C Paeng S Lee et al ldquoAngiogenesis imaging inmyocardial infarction using 68Ga-NOTA- RGD PET Charac-terization and application to therapeutic efficacy monitoring inratsrdquo Coronary Artery Disease vol 24 no 4 pp 303ndash311 2013
[48] J H Kim Y-H Kim Y J Kim et al ldquoQuantitative positronemission tomography imaging of angiogenesis in rats with fore-limb ischemia using 68Ga-NOTA-c(RGDyK)rdquo Angiogenesisvol 16 no 4 pp 837ndash846 2013
[49] I Laitinen J Notni K Pohle et al ldquoComparison of cyclicRGD peptides for 120572v1205733 integrin detection in a rat model ofmyocardial infarctionrdquo EJNMMI Research vol 3 no 1 pp 1ndash9 2013
[50] M Kiugel I Dijkgraaf V Kyto et al ldquoDimeric [68Ga]DOTA-RGD Peptide Targeting 120572 ltinfgtvltinfgt 120573 ltinfgt3ltinfgt Inte-grin Reveals Extracellular Matrix Alterations after MyocardialInfarctionrdquo Molecular Imaging and Biology vol 16 no 6 pp793ndash801 2014
[51] M Gronman M Tarkia T Kiviniemi et al ldquoImaging of 120572v1205733integrin expression in experimental myocardial ischemia with[68Ga]NODAGA-RGD positron emission tomographyrdquo Jour-nal of Translational Medicine vol 15 no 1 p 144 2017
[52] J Haukkala I Laitinen P Luoto et al ldquo68Ga-DOTA-RGDpep-tide Biodistribution and binding into atherosclerotic plaquesin micerdquo European Journal of Nuclear Medicine and MolecularImaging vol 36 no 12 pp 2058ndash2067 2009
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[59] J S Schmid A Schirbel A K Buck S Kropf H-J Westerand C Lapa ldquoPentixafor-Positron Emission TomographyComputed Tomography Detects Chemokine Receptor CXCR4Expression after Ischemic Strokerdquo Circulation CardiovascularImaging vol 9 no 9 Article ID e005217 2016
[60] J Zhou G Hao H Weng et al ldquoIn vivo evaluation ofmedical device-associated inflammation using a macrophage-specific positron emission tomography (PET) imaging proberdquoBioorganic amp Medicinal Chemistry Letters vol 23 no 7 pp2044ndash2047 2013
[61] S A Kularatne M-J Belanger X Meng et al ldquoComparativeanalysis of folate derived PET imaging agents with [ 18F]-2-fluoro-2-deoxy-d-glucose using a rodent inflammatory pawmodelrdquo Molecular Pharmaceutics vol 10 no 8 pp 3103ndash31112013
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[63] T Lincke J Singer R Kluge O Sabri and R Paschke ldquoRela-tive quantification of indium-111 pentetreotide and gallium-68DOTATOC uptake in the thyroid gland and association withthyroid pathologiesrdquoThyroid vol 19 no 4 pp 381ndash389 2009
[64] A Rominger T Saam E Vogl et al ldquoIn vivo imaging ofmacrophage activity in the coronary arteries using 68Ga-DOTATATE PETCT correlation with coronary calcium bur-den and risk factorsrdquo Journal of Nuclear Medicine vol 51 no 2pp 193ndash197 2010
[65] J M Tarkin F R Joshi N R Evans et al ldquoDetection ofAtherosclerotic Inflammation by 68Ga-DOTATATE PET Com-pared to [18F]FDG PET Imagingrdquo Journal of the AmericanCollege of Cardiology vol 69 no 14 pp 1774ndash1791 2017
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[68] H Watanabe M Ono S Iikuni et al ldquoA 68Ga complex basedon benzofuran scaffold for the detection of 120573-amyloid plaquesrdquoBioorganic amp Medicinal Chemistry Letters vol 24 no 20 pp4834ndash4837 2014
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[70] D Satpati CArjun R KrishnamohanG Samuel and S Baner-jee ldquo68Ga-labeledCiprofloxacinConjugates as Radiotracers forTargeting Bacterial InfectionrdquoChemical Biology ampDrug Designvol 87 no 5 pp 680ndash686 2016
[71] T Ebenhan N Chadwick and M M Sathekge ldquoPeptidesynthesis characterization and 68Ga-radiolabeling of NOTA-conjugated ubiquicidin fragments for prospective infectionimaging with PETCTrdquo Nuclear Medicine and Biology vol 41no 5 pp 390ndash400 2014
18 Contrast Media amp Molecular Imaging
[72] T Ebenhan J R Zeevaart and J D Venter ldquoPreclinicalevaluation of 68Ga-labeled 1 4 7-triazacyclononane-1 4 7-triacetic acid-ubiquicidin as a radioligand for PET infectionimagingrdquo Journal of Nuclear Medicine vol 55 no 2 pp 308ndash314 2014
[73] B B Mokaleng T Ebenhan S Ramesh et al ldquoSynthesis 68Ga-radiolabeling and preliminary in vivo assessment of adepsipeptide-derived compound as a potential PETCTinfection imaging agentrdquo BioMed Research International vol2015 Article ID 284354 2015
[74] T Ebenhan B Mokaleng J Venter H Kruger J Zeevaart andM Sathekge ldquoPreclinical Assessment of a 68Ga-DOTA-Functionalized Depsipeptide as a Radiodiagnostic InfectionImaging AgentrdquoMolecules vol 22 no 9 p 1403 2017
[75] S Chopra B Singh A Koul A Mishra and H Wester ldquoSyn-thesis of DOTA conjugated GF-17 and RAWVAWR-NH2 andradiolabeling with 68Ga as a potential PET tracer for infectionimagingrdquo J Nucl Med vol 57 Supplement 2 p 1115 2016
[76] M Petrik HHaas P Laverman et al ldquo 68Ga-triacetylfusarinineC and 68Ga-ferrioxamine e for aspergillus infection imaginguptake specificity in various microorganismsrdquoMolecular Imag-ing and Biology vol 16 no 1 pp 102ndash108 2014
[77] V Kumar and D K Boddeti ldquo 68Ga-radiopharmaceuticals forPET imaging of infection and inflammationrdquo Recent Results inCancer Research vol 194 pp 189ndash219 2013
[78] M Vorster A Maes A Jacobs et al ldquoEvaluating the possiblerole of 68Ga-citrate PETCT in the characterization of indeter-minate lung lesionsrdquo Annals of Nuclear Medicine vol 28 no 6pp 523ndash530 2014
[79] M Vorster B Mokaleng M M Sathekge and T Ebenhan ldquoAmodified technique for efficient radiolabeling of 68Ga-citratefrom a SnO2-based 68Ge68Ga generator for better infectionimagingrdquoHellenic Journal of Nuclear Medicine vol 16 no 3 pp193ndash198 2013
[80] S Salomaeki J Kemppainen U Hohenthal et al ldquoHead-to-head comparison of 68Ga-Citrate and 18F-FDG PETCT fordetection of infectious foci in patients with staphylococcusaureus bacteraemiardquo Contrast Media amp Molecular Imaging vol2017 p 8 2017
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[83] A Sanchez-Crespo P Andreo and S A Larsson ldquoPositronflight in human tissues and its influence on PET image spatialresolutionrdquo European Journal of Nuclear Medicine and Molecu-lar Imaging vol 31 no 1 pp 44ndash51 2004
[84] H W A M De Jong L Perk G W M Visser R Boellaard GAM S Van Dongen and A A Lammertsma ldquoHigh resolutionPET imaging characteristics of68Ga 124i and89Zr comparedto18Frdquo in Proceedings of the Nuclear Science Symposium Con-ference Record 2005 IEEE pp 1624ndash1627 Puerto Rico October2005
[85] I Velikyan A Sundin B Eriksson et al ldquoIn vivo bindingof [68Ga]-DOTATOC to somatostatin receptors in neuroen-docrine tumours - impact of peptide massrdquo Nuclear Medicineand Biology vol 37 no 3 pp 265ndash275 2010
[86] U Eberlein and M Lassmann ldquoDosimetry of [68Ga]-labeledcompoundsrdquo Applied Radiation and Isotopes vol 76 pp 70ndash742013
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[88] B P Burke G S Clemente and S J Archibald ldquoRecentadvances in chelator design and labelling methodology for68Ga radiopharmaceuticalsrdquo Journal of Labelled Compoundsand Radiopharmaceuticals vol 57 no 4 pp 239ndash243 2014
[89] I Velikyan U Rosenstrom S Estrada et al ldquoSynthesis andpreclinical evaluation of 68Ga-labeled collagelin analogs forimaging and quantification of fibrosisrdquo Nuclear Medicine andBiology vol 41 no 9 pp 728ndash736 2014
[90] M F Ferreira G Pereira J P Andre and etal C ldquoGa[NO2A-N-(120572-amino)propionate] chelates Synthesis and evaluation aspotential tracers for 68Ga PETrdquoDalton Transactions vol 43 no21 pp 8037ndash8047 2014
[91] J Notni J Simecek and H-J Wester ldquoPhosphinic acid func-tionalized polyazacycloalkane chelators for radiodiagnosticsand radiotherapeutics Unique characteristics and applicationsrdquoChemMedChem vol 9 no 6 pp 1107ndash1115 2014
[92] J Simecek O Zemek P Hermann J Notni and H J WesterldquoTailored gallium( III) chelator NOPO synthesis characteriza-tion bioconjugation and application in preclinical Ga-68-PETimagingrdquoMolecular Pharmaceutics 2013
[93] D Parker B P Waldron and D S Yufit ldquoCrystallographicand solution NMR structural analyses of four hexacoordinatedgallium(iii) complexes based on ligands derived from 6-amino-perhydro-14-diazepinerdquo Dalton Transactions vol 42 no 22pp 8001ndash8008 2013
[94] B P Waldron D Parker C Burchardt D S Yufit M ZimnyandF Roesch ldquoStructure and stability of hexadentate complexesof ligands based on AAZTA for efficient PET labelling withgallium-68rdquo Chemical Communications vol 49 no 6 pp 579ndash581 2013
[95] D Parker and B PWaldron ldquoConformational analysis and syn-thetic approaches to polydentate perhydro-diazepine ligandsfor the complexation of gallium(iii)rdquo Organic amp BiomolecularChemistry vol 11 no 17 pp 2827ndash2838 2013
[96] I Velikyan H Maecke and B Langstrom ldquoConvenient prepa-ration of 68Ga-based PET-radiopharmaceuticals at room tem-peraturerdquo Bioconjugate Chemistry vol 19 no 2 pp 569ndash5732008
[97] J Erchegyi R Cescato B Waser J E Rivier and J C ReubildquoN-Imidazolebenzyl-histidine substitution in somatostatin andin its octapeptide analogue modulates receptor selectivity andfunctionrdquo Journal of Medicinal Chemistry vol 54 no 17 pp5981ndash5987 2011
[98] R Saha N Saha R S Donofrio and L L Bestervelt ldquoMicrobialsiderophores Amini reviewrdquo Journal of Basic Microbiology vol53 no 4 pp 303ndash317 2013
[99] V Nikolova S Angelova N Markova and T Dudev ldquoGalliumas a Therapeutic Agent A Thermodynamic Evaluation of theCompetition between Ga3+ and Fe3+ Ions in MetalloproteinsrdquoThe Journal of Physical Chemistry B vol 120 no 9 pp 2241ndash2248 2016
[100] C R Chitambar ldquoGallium and its competing roles with ironin biological systemsrdquo Biochimica et Biophysica Acta (BBA) -Molecular Cell Research vol 1863 no 8 pp 2044ndash2053 2016
[101] J A Lessa M A Soares and R G dos Santos ldquoGallium(III)complexes with 2-acetylpyridine-derived thiosemicarbazonesantimicrobial and cytotoxic effects and investigation on theinteractions with tubulinrdquo BioMetals vol 26 pp 151ndash165 2013
Contrast Media amp Molecular Imaging 19
[102] M van Oosten M Hahn L M A Crane et al ldquoTargetedimaging of bacterial infections Advances hurdles and hopesrdquoFEMS Microbiology Reviews vol 39 no 6 pp 892ndash916 2015
[103] M Vorster AMaes C V DWiele andM Sathekge ldquoGallium-68 PET A Powerful Generator-based Alternative to Infectionand Inflammation Imagingrdquo Seminars in Nuclear Medicine vol46 no 5 pp 436ndash447 2016
[104] M Kircher and C Lapa ldquoNovel Noninvasive Nuclear MedicineImaging Techniques for Cardiac Inflammationrdquo Current Car-diovascular Imaging Reports vol 10 no 2 article no 6 2017
[105] D AHammoud ldquoMolecular imaging of inflammation Currentstatusrdquo Journal of Nuclear Medicine vol 57 no 8 pp 1161ndash11652016
[106] D R Brenner D Scherer K Muir et al ldquoA review of the appli-cation of inflammatory biomarkers in epidemiologic cancerresearchrdquo Cancer Epidemiology Biomarkers amp Prevention vol23 no 9 pp 1729ndash1751 2014
[107] M D Turner B Nedjai T Hurst and D J PenningtonldquoCytokines and chemokines at the crossroads of cell signallingand inflammatory diseaserdquo Biochimica et Biophysica Acta (BBA)- Molecular Cell Research vol 1843 no 11 pp 2563ndash2582 2014
[108] L Werner H Guzner-Gur and I Dotan ldquoInvolvement ofCXCR4CXCR7CXCL12 interactions in inflammatory boweldiseaserdquoTheranostics vol 3 no 1 pp 40ndash46 2013
[109] S Jalkanen and M Salmi ldquoVAP-1 and CD73 endothelial cellsurface enzymes in leukocyte extravasationrdquo ArteriosclerosisThrombosis and Vascular Biology vol 28 no 1 pp 18ndash26 2008
[110] G Malviya F Galli I Sonni and A Signore ldquoImaging T-lymphocytes in inflammatory diseases A nuclear medicineapproachrdquo The Quarterly Journal of Nuclear Medicine andMolecular Imaging vol 58 no 3 pp 237ndash257 2014
[111] S Gratz H J RennenO C BoermanW J Oyen and P Burmaldquo(99m)Tc-interleukin-8 for imaging acute osteomyelitisrdquo Jour-nal of Nuclear Medicine vol 42 no 8 pp 1257ndash1264 2001
[112] S Gratz H J Rennen O C Boerman W J Oyen andF H Corstens ldquoRapid imaging of experimental colitis with(99m)Tc-interleukin-8 in rabbitsrdquo Journal of Nuclear Medicnevol 42 no 6 pp 917ndash923 2001
[113] C Alkim H Alkim A R Koksal S Boga and I SenldquoAngiogenesis in inflammatory bowel diseaserdquo InternationalJournal of Inflammation vol 2015 Article ID 970890 2015
[114] I S Alam T H Witney G Tomasi et al ldquoRadiolabeled RGDtracer kinetics annotates differential 120572v1205733 integrin expressionlinked to cell intrinsic and vessel expressionrdquoMolecular Imagingand Biology vol 16 no 4 pp 558ndash566 2014
[115] J Notni K Pohle and H-J Wester ldquoBe spoilt for choice withradiolabelled RGD peptides Preclinical evaluation of 68Ga-TRAP(RGD)3rdquoNuclear Medicine and Biology vol 40 no 1 pp33ndash41 2013
[116] J Oxboel M Brandt-Larsen C Schjoeth-Eskesen et al ldquoCom-parison of two new angiogenesis PET tracers 68Ga-NODAGA-E[c(RGDyK)]2 and 64Cu-NODAGA-E[c(RGDyK)]2 in vivoimaging studies in human xenograft tumorsrdquo Nuclear Medicineand Biology vol 41 no 3 pp 259ndash267 2014
[117] J Simecek J Notni T G Kapp H Kessler and H-J WesterldquoBenefits of NOPO as chelator in gallium-68 peptides exempli-fied by preclinical characterization of 68Ga-NOPO-c(RGDfK)rdquoMolecular Pharmaceutics vol 11 no 5 pp 1687ndash1695 2014
[118] M Trajkovic-Arsic P Mohajerani A Sarantopoulos et alldquoMultimodal molecular imaging of integrin avb3 for in vivodetection of pancreatic cancerrdquo Journal of NuclearMedicine vol55 no 3 pp 446ndash451 2014
[119] H Cai and P S Conti ldquoRGD-based PET tracers for imagingreceptor integrin 120572 v1205733 expressionrdquo Journal of Labelled Com-pounds and Radiopharmaceuticals vol 56 no 5 pp 264ndash2792013
[120] I Dijkgraaf S Y A Terry W J Mcbride et al ldquoImagingintegrin alpha-v-beta-3 expression in tumors with an 18F-labeled dimeric RGD peptiderdquo Contrast Media amp MolecularImaging vol 8 no 3 pp 238ndash245 2013
[121] P A Knetsch M Petrik C Rangger et al ldquo[68Ga]NS3-RGD and [68Ga] Oxo-DO3A-RGD for imaging 120572v1205733 integrinexpression Synthesis evaluation and comparisonrdquo NuclearMedicine and Biology vol 40 no 1 pp 65ndash72 2013
[122] Z Liu and F Wang ldquoDevelopment of RGD-based radiotracersfor tumor imaging and therapy Translating from bench tobedsiderdquo Current Molecular Medicine vol 13 no 10 pp 1487ndash1505 2013
[123] H Choi J H Phi J C Paeng et al ldquoImaging of integrin 120572v1205733expression using 68Ga-RGD positron emission tomography inpediatric cerebral infarctrdquoMolecular Imaging vol 12 no 4 pp213ndash217 2013
[124] H-J Yoon K W Kang I K Chun et al ldquoCorrelation of breastcancer subtypes based on estrogen receptor progesteronereceptor and HER2 with functional imaging parameters from68Ga-RGD PETCT and 18F-FDG PETCTrdquo European Journalof Nuclear Medicine and Molecular Imaging vol 41 no 8 pp1534ndash1543 2014
[125] R P Baum H R Kulkarni D Muller et al ldquoFirst-in-human study demonstrating tumor-angiogenesis by PETCTimaging with 68Ga-NODAGA-THERANOST a high-affinitypeptidomimetic for 120572v1205733 integrin receptor targetingrdquo CancerBiotherapy andRadiopharmaceuticals vol 30 no 4 pp 152ndash1592015
[126] R Haubner A Finkenstedt A Stegmayr et alldquo[68Ga]NODAGA-RGD ndash Metabolic stability biodistributionand dosimetry data from patients with hepatocellularcarcinoma and liver cirrhosisrdquo European Journal of NuclearMedicine and Molecular Imaging vol 43 no 11 pp 2005ndash20132016
[127] V Lopez-Rodrıguez C Galindo-Sarco F O Garcıa-Perez GFerro-Flores O Arrieta and M A Avila-Rodrıguez ldquoPET-based human dosimetry of the dimeric 120572v1205733 integrin ligand68Ga-DOTA-E-[c(RGDfK)]2 a potential tracer for imagingtumor angiogenesisrdquo Journal of Nuclear Medicine vol 57 no 3pp 404ndash409 2016
[128] M V Backer Z Levashova V Patel et al ldquoMolecular imagingof VEGF receptors in angiogenic vasculature with single-chainVEGF-based probesrdquo Nature Medicine vol 13 no 4 pp 504ndash509 2007
[129] MV Backer Z Levashova R Levenson F G Blankenberg andJ M Backer ldquoCysteine-containing fusion tag for site-specificconjugation of therapeutic and imaging agents to targetingproteinsrdquoMethods in Molecular Biology (Clifton NJ) vol 494pp 275ndash294 2008
[130] M Eder A V Krivoshein M Backer J M Backer UHaberkorn and M Eisenhut ldquoScVEGF-PEG-HBED-CC andscVEGF-PEG-NOTA conjugates comparison of easy-to-labelrecombinant proteins for [68Ga]PET imaging of VEGF recep-tors in angiogenic vasculaturerdquo Nuclear Medicine and Biologyvol 37 no 4 pp 405ndash412 2010
[131] E Blom I Velikyan A Monazzam P Razifar et al ldquoSynthe-sis and characterization of scVEGF-PEG-[ 68Ga]NOTA andscVEGF-PEG-[ 68Ga]DOTA PET tracersrdquo Journal of Labelled
20 Contrast Media amp Molecular Imaging
Compounds and Radiopharmaceuticals vol 54 no 11 pp 685ndash692 2011
[132] S Gratz M Behe and O C Boerman ldquo 99119898Tc-E-selectinbinding peptide for imaging acute osteomyelitis in a novel ratmodelrdquo Nuclear Medicine Communications vol 22 no 9 pp1003ndash1013 2001
[133] S B Jensen M Kakela L Joslashdal et al ldquoExploring the radiosyn-thesis and in vitro characteristics of [68Ga]Ga-DOTA-Siglec-9rdquoJournal of Labelled Compounds and Radiopharmaceuticals vol60 no 9 pp 439ndash449 2017
[134] B A Teicher and S P Fricker ldquoCXCL12 (SDF-1)CXCR4pathway in cancerrdquo Clinical Cancer Research vol 16 no 11 pp2927ndash2931 2010
[135] O Jacobson I D Weiss D O Kiesewetter J M Farber andX Chen ldquoPET of tumor CXCR4 expression with 4-18F-T140rdquoJournal of Nuclear Medicine vol 51 no 11 pp 1796ndash1804 2010
[136] A Aghanejad A R Jalilian Y Fazaeli et al ldquoSynthesis andevaluation of [67Ga]-AMD3100 A novel imaging agent fortargeting the chemokine receptorCXCR4rdquo Scientia Pharmaceu-tica vol 82 no 1 pp 29ndash42 2014
[137] O Jacobson I D Weiss L P Szajek et al ldquoPET imaging ofCXCR4 using copper-64 labeled peptide antagonistrdquoTheranos-tics vol 1 pp 251ndash262 2011
[138] O Jacobson I D Weiss L P Szajek et al ldquoImprovement ofCXCR4 tracer specificity for PET imagingrdquo Journal of Con-trolled Release vol 157 no 2 pp 216ndash223 2012
[139] H J Wester U Keller M Schottelius et al ldquoDisclosing theCXCR4 expression in lymphoproliferative diseases by targetedmolecular imagingrdquo Theranostics vol 5 no 6 pp 618ndash6302015
[140] E Gourni O Demmer M Schottelius et al ldquoPET of CXCR4expression by a 68Ga-labeled highly specific targeted contrastagentrdquo Journal of NuclearMedicine vol 52 no 11 pp 1803ndash18102011
[141] O Demmer I Dijkgraaf U Schumacher et al ldquoDesignsynthesis and functionalization of dimeric peptides targetingchemokine receptor CXCR4rdquo Journal of Medicinal Chemistryvol 54 no 21 pp 7648ndash7662 2011
[142] O Demmer E Gourni U Schumacher H Kessler and H-JWester ldquoPET Imaging of CXCR4 Receptors in Cancer by a NewOptimized Ligandrdquo ChemMedChem vol 6 no 10 pp 1789ndash1791 2011
[143] U Hennrich L Seyler M Schafer et al ldquoSynthesis and invitro evaluation of 68Ga-DOTA-4-FBn-TN14003 a novel tracerfor the imaging of CXCR4 expressionrdquo Bioorganic amp MedicinalChemistry vol 20 no 4 pp 1502ndash1510 2012
[144] G P C George E Stevens O Aberg et al ldquoPreclinical evalua-tion of a CXCR4-specific 68Ga-labelled TN14003 derivative forcancer PET imagingrdquo Bioorganic amp Medicinal Chemistry vol22 no 2 pp 796ndash803 2014
[145] S Poty E Gourni P Desogere et al ldquoAMD3100 A VersatilePlatform for CXCR4 Targeting 68Ga-Based Radiopharmaceu-ticalsrdquo Bioconjugate Chemistry vol 27 no 3 pp 752ndash761 2016
[146] K Philipp-Abbrederis K Herrmann S Knop et al ldquoIn vivomolecular imaging of chemokine receptor CXCR4 expressionin patients with advancedmultiple myelomardquo EMBOMolecularMedicine vol 7 no 4 pp 477ndash487 2015
[147] Z Wang M Zhang L Wang et al ldquoProspective study of 68Ga-NOTA-NFB Radiation dosimetry in healthy volunteers andfirst application in glioma patientsrdquo Theranostics vol 5 no 8pp 882ndash889 2015
[148] I M Jackson P J Scott and S Thompson ldquoClinical Applica-tions of Radiolabeled Peptides for PETrdquo Seminars in NuclearMedicine vol 47 no 5 pp 493ndash523 2017
[149] C Lapa T Reiter R A Werner et al ldquo[68Ga]Pentixafor-PETCT for Imaging of Chemokine Receptor 4 Expression afterMyocardial Infarctionrdquo JACC Cardiovascular Imaging vol 8no 12 pp 1466ndash1468 2015
[150] C Rischpler S G Nekolla H Kossmann et al ldquoUpregu-lated myocardial CXCR4-expression after myocardial infarc-tion assessed by simultaneous GA-68 pentixafor PETMRIrdquoJournal of Nuclear Cardiology vol 23 no 1 pp 131ndash133 2016
[151] F Hyafil J Pelisek I Laitinen et al ldquoImaging the CytokineReceptorCXCR4 in atherosclerotic plaqueswith the radiotracer68Ga-Pentixafor for PETrdquo Journal of Nuclear Medicine vol 58no 3 pp 499ndash506 2017
[152] Y Yi ldquoFolate receptor-targeted diagnostics and therapeutics forinflammatory diseasesrdquo ImmuneNetwork vol 16 no 6 pp 337ndash343 2016
[153] C M Paulos M J Turk G J Breur and P S Low ldquoFolatereceptor-mediated targeting of therapeutic and imaging agentsto activated macrophages in rheumatoid arthritisrdquo AdvancedDrug Delivery Reviews vol 56 no 8 pp 1205ndash1217 2004
[154] W Han R Zaynagetdinov F E Yull et al ldquoMolecular imagingof folate receptor 120573-positive macrophages during acute lunginflammationrdquo American Journal of Respiratory Cell and Molec-ular Biology vol 53 no 1 pp 50ndash59 2015
[155] B Kuhle C Muller and T L Ross ldquoA Novel 68Ga-Labeledpteroic acid-based PET tracer for tumor imaging via the folatereceptorrdquo Recent Results in Cancer Research vol 194 pp 257ndash267 2013
[156] C Brand V A Longo M Groaning W A Weber and TReiner ldquoDevelopment of a New Folate-Derived Ga-68-BasedPET Imaging AgentrdquoMolecular Imaging and Biology vol 19 no5 pp 754ndash761 2017
[157] M Fani XWang G Nicolas et al ldquoDevelopment of new folate-based PET radiotracers Preclinical evaluation of 68Ga-DOTA-folate conjugatesrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 38 no 1 pp 108ndash119 2011
[158] C J Mathias M R Lewis D E Reichert et al ldquoPreparationof 66Ga- and 68Ga-labeled Ga(III)-deferoxamine-folate aspotential folate-receptor-targeted PET radiopharmaceuticalsrdquoNuclear Medicine and Biology vol 30 no 7 pp 725ndash731 2003
[159] S-M Kim N Choi S Hwang et al ldquoFolate receptor-specific positron emission tomography imaging with folic acid-conjugated tissue inhibitor of metalloproteinase-2rdquo Bulletin ofthe Korean Chemical Society vol 34 no 11 pp 3243ndash3248 2013
[160] M Fani M-L Tamma G P Nicolas et al ldquoIn vivo imagingof folate receptor positive tumor xenografts using novel 68Ga-NODAGA-folate conjugatesrdquo Molecular Pharmaceutics vol 9no 5 pp 1136ndash1145 2012
[161] C Muller and R Schibli ldquoProspects in folate receptor-targetedradionuclide therapyrdquo Frontiers in Oncology vol 3 Article IDArticle 249 2013
[162] A Jain A Mathur U Pandey et al ldquoSynthesis and evaluationof a 68Ga labeled folic acid derivative for targeting folatereceptorsrdquo Applied Radiation and Isotopes vol 116 pp 77ndash842016
[163] W Xia A R Hilgenbrink E L Matteson M B Lockwood J-X Cheng and P S Low ldquoA functional folate receptor is inducedduring macrophage activation and can be used to target drugsto activated macrophagesrdquo Blood vol 113 no 2 pp 438ndash4462009
Contrast Media amp Molecular Imaging 21
[164] E P Krenning W A P Breeman P P M Kooij et alldquoLocalisation of endocrine-related tumours with radioiodi-nated analogue of somatostatinrdquoThe Lancet vol 1 no 8632 pp242ndash244 1989
[165] E P Krenning D J KwekkeboomWH Bakker et al ldquoSomato-statin receptor scintigraphy with [111In-DTPA-d-Phe1]- and[123I-Tyr3]-octreotide the Rotterdam experience with morethan 1000 patientsrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 20 no 8 pp 716ndash731 1993
[166] A Stahl G Meisetschlager M Schottelius et al ldquo[123I]Mtr-TOCA a radioiodinated and carbohydrated analogue ofoctreotide Scintigraphic comparison with [111In]octreotiderdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 33 no 1 pp 45ndash52 2006
[167] R Lebtahi J le Cloirec C Houzard et al ldquoDetection of neu-roendocrine tumors 99mTc-P829 scintigraphy compared with111In-pentetreotide scintigraphyrdquo Journal of Nuclear Medicinevol 43 no 7 pp 889ndash895 2002
[168] C Decristoforo T Maina B Nock M Gabriel P Cordopatisand R Moncayo ldquo99mTc-demotate 1 First data in tumourpatients - Results of a pilotphase I studyrdquo European Journal ofNuclearMedicine andMolecular Imaging vol 30 no 9 pp 1211ndash1219 2003
[169] C Decristoforo S J Mather W Cholewinski E DonnemillerG Riccabona and R Moncayo ldquo(99m)Tc-EDDAHYNIC-TOC A new (99m)Tc-labelled radiopharmaceutical forimaging somatostatin receptor-positive tumours First clinicalresults and intra-patient comparison with 111In-labelledoctreotide derivativesrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 27 no 9 pp 1318ndash1325 2000
[170] A Hubalewska-Dydejczyk K Fross-Baron R Mikołajczak etal ldquo99mTc-EDDAHYNIC-octreotate scintigraphy an efficientmethod for the detection and staging of carcinoid tumoursResults of 3 yearsrsquo experiencerdquo European Journal of NuclearMedicine and Molecular Imaging vol 33 no 10 pp 1123ndash11332006
[171] M Bangard M Behe S Guhlke et al ldquoDetection of somato-statin receptor-positive tumours using the new 99mC-tricine-HYNIC-D-Phe1-Tyr3-octreotide First results in patients andcomparison with 111In-DTPA-D-Phe1-octreotiderdquo EuropeanJournal of Nuclear Medicine and Molecular Imaging vol 27 no6 pp 628ndash637 2000
[172] A Helisch G J Forster H Reber et al ldquoPre-therapeuticdosimetry and biodistribution of 86Y-DOTA- Phe1-Tyr3-octreotide versus 111In-pentetreotide in patients with advancedneuroendocrine tumoursrdquo European Journal of NuclearMedicine and Molecular Imaging vol 31 no 10 pp 1386ndash13922004
[173] M Henze J Schuhmacher P Hipp et al ldquoPET imaging ofsomatostatin receptors using [68GA]DOTA-D-Phe1-Tyr3-Octreotide First results in patients with meningiomasrdquo Journalof Nuclear Medicine vol 42 no 7 pp 1053ndash1056 2001
[174] I Kayani J B Bomanji A Groves et al ldquoFunctional imaging ofneuroendocrine tumors with combined PETCT using 68Ga-DOTATATE (Dota-DPhe1 Tyr3-octreotate) and 18F-FDGrdquoCancer vol 112 no 11 pp 2447ndash2455 2008
[175] A Al-Nahhas ldquoNuclear medicine imaging of neuroendocrinetumoursrdquo Clinical Medicine vol 12 no 4 pp 377ndash380 2012
[176] V Ambrosini S Nicolini P Caroli et al ldquoPETCT imaging indifferent types of lung cancer an overviewrdquo European Journal ofRadiology vol 81 no 5 pp 988ndash1001 2012
[177] V Ambrosini D Campana P Tomassetti and S Fanti ldquo68Ga-labelled peptides for diagnosis of gastroenteropancreatic NETrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 39 no 1 pp S52ndashS60 2012
[178] K E Oberg J-C Reubi D J Kwekkeboom and E P KrenningldquoRole of somatostatins in gastroenteropancreatic neuroen-docrine tumor development and therapyrdquoGastroenterology vol139 no 3 pp 753-753 2010
[179] K Oberg ldquoGallium-68 somatostatin receptor PETCT Is ittime to replace 111Indium DTPA octreotide for patients withneuroendocrine tumorsrdquo Endocrine Journal vol 42 no 1 pp3-4 2012
[180] R Srirajaskanthan I Kayani A M Quigley J Soh M ECaplin and J Bomanji ldquoThe role of 68Ga-DOTATATE PET inpatients with neuroendocrine tumors and negative or equivocalfindings on 111In-DTPA-octreotide scintigraphyrdquo Journal ofNuclear Medicine vol 51 no 6 pp 875ndash882 2010
[181] A Kroiss D Putzer and C Uprimny ldquoFunctional imag-ing in phaeochromocytoma and neuroblastoma with 68Ga-DOTA-Tyr3-octreotide positron emission tomography and123I-metaiodobenzylguanidinerdquo European Journal of NuclearMedicine and Molecular Imaging vol 38 no 5 pp 865ndash8732011
[182] M Naji C Zhao S J Welsh et al ldquo68Ga-DOTA-TATE PETvs 123I-MIBG in identifying malignant neural crest tumoursrdquoMolecular Imaging and Biology vol 13 no 4 pp 769ndash775 2011
[183] V Ambrosini P Tomassetti P Castellucci et al ldquoComparisonbetween 68Ga-DOTA-NOC and 18F-DOPA PET for the detec-tion of gastro-entero-pancreatic and lung neuro-endocrinetumoursrdquo European Journal of Nuclear Medicine and MolecularImaging vol 35 no 8 pp 1431ndash1438 2008
[184] D Putzer M Gabriel B Henninger et al ldquoBone metastasesin patients with neuroendocrine tumor 68Ga- DOTA-Tyr3-octreotide PET in comparison to CT and bone scintigraphyrdquoJournal of Nuclear Medicine vol 50 no 8 pp 1214ndash1221 2009
[185] L K Anzola-Fuentes M Chianelli F Galli et al ldquoSomatostatinreceptor scintigraphy in patients with rheumatoid arthritis andsecondary Sjogrenrsquos syndrome treated with Infliximab a pilotstudyrdquo EJNMMI Research vol 6 no 1 article no 49 2016
[186] T Nobashi Y Nakamoto T Kubo et al ldquoThe utility of PETCTwith 68Ga-DOTATOC in sarcoidosis comparison with 67Ga-scintigraphyrdquoAnnals ofNuclearMedicine vol 30 no 8 pp 544ndash552 2016
[187] C Boy T A Heusner T D Poeppel et al ldquo68Ga-DOTATOCPETCT and somatostatin receptor (sst1-sst5) expression innormal human tissue Correlation of sst2mRNAand SUVmaxrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 38 no 7 pp 1224ndash1236 2011
[188] P Rinne S Hellberg M Kiugel et al ldquoComparison of Somato-statin Receptor 2-Targeting PET Tracers in the Detection ofMouse Atherosclerotic Plaquesrdquo Molecular Imaging and Biol-ogy vol 18 no 1 pp 99ndash108 2016
[189] M Asti E Ferrari S Croci et al ldquoSynthesis and characteri-zation of 68Ga-labeled curcumin and curcuminoid complexesas potential radiotracers for imaging of cancer and alzheimersdiseaserdquo Inorganic Chemistry vol 53 no 10 pp 4922ndash49332014
[190] A Signore I Santino and A W J M Glaudemans ldquoIn vivoimaging of microorganismsrdquo Clinical and Translational Imag-ing vol 4 no 3 pp 161-162 2016
[191] S Auletta F Galli C Lauri D Martinelli I Santino andA Signore ldquoImaging bacteria with radiolabelled quinolones
22 Contrast Media amp Molecular Imaging
cephalosporins and siderophores for imaging infection a sys-tematic reviewrdquo Clinical and Translational Imaging vol 4 no 4pp 229ndash252 2016
[192] X Ning S Lee Z Wang et al ldquoMaltodextrin-based imagingprobes detect bacteria in vivo with high sensitivity and speci-ficityrdquo Nature Materials vol 10 no 8 pp 602ndash607 2011
[193] J Ady andY Fong ldquoImaging for infection Fromvisualization ofinflammation to visualization of microbesrdquo Surgical Infectionsvol 15 no 6 pp 700ndash707 2014
[194] J M Sierra D Rodriguez-Puig A Soriano J Mensa C Pieraand J Vila ldquoAccumulation of 99mTc-ciprofloxacin in Staphy-lococcus aureus and Pseudomonas aeruginosardquo AntimicrobialAgents and Chemotherapy vol 52 no 7 pp 2691-2692 2008
[195] D I Andersson and D Hughes ldquoMicrobiological effects ofsublethal levels of antibioticsrdquoNature ReviewsMicrobiology vol12 no 7 pp 465ndash478 2014
[196] N Dumarey D Blocklet T Appelboom L Tant and ASchoutens ldquoInfecton is not specific for bacterial osteo-articularinfective pathologyrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 29 no 4 pp 530ndash535 2002
[197] K E Britton D W Wareham S S Das et al ldquoImaging bacte-rial infection with 99mTc-ciprofloxacin (Infecton)rdquo Journal ofClinical Pathology vol 55 no 11 pp 817ndash823 2002
[198] G Ferro-Flores M A Avila-Rodrıguez and F O Garcıa-PerezldquoImaging of bacteria with radiolabeled ubiquicidin by SPECTand PET techniquesrdquo Clinical and Translational Imaging vol 4no 3 pp 175ndash182 2016
[199] P S Hiemstra M T van den Barselaar M Roest P H Nibber-ing and R van Furth ldquoUbiquicidin a novel murine microbi-cidal protein present in the cytosolic fraction of macrophagesrdquoJournal of Leukocyte Biology vol 66 no 3 pp 423ndash428 1999
[200] M S Akhtar A Qaisar J Irfanullah et al ldquoAntimicrobialpeptide 99mTc-ubiquicidin 29ndash41 as human infection-imagingagent clinical trialrdquo Journal of Nuclear Medicne vol 46 no 4pp 567ndash573 2005
[201] M Assadi K Vahdat I Nabipour et al ldquoDiagnostic value of99mTc-ubiquicidin scintigraphy for osteomyelitis and compar-isons with 99mTc-methylene diphosphonate scintigraphy andmagnetic resonance imagingrdquo Nuclear Medicine Communica-tions vol 32 no 8 pp 716ndash723 2011
[202] T Emery ldquoExchange of Iron by Gallium in SiderophoresrdquoBiochemistry vol 25 no 16 pp 4629ndash4633 1986
[203] M Petrik C Zhai H Haas and C Decristoforo ldquoSiderophoresfor molecular imaging applicationsrdquo Clinical and TranslationalImaging vol 5 no 1 pp 15ndash27 2017
[204] H J Flint E A BayerM T Rincon R Lamed and B AWhiteldquoPolysaccharide utilization by gut bacteria potential for newinsights from genomic analysisrdquo Nature Reviews Microbiologyvol 6 no 2 pp 121ndash131 2008
[205] GGowrishankarMNamavari E B Jouannot et al ldquoInvestiga-tion of 6-[18F]-fluoromaltose as a novel PET tracer for imagingbacterial infectionrdquo PLoS ONE vol 9 no 9 Article ID e1079512014
[206] N Gholipour M Akhlaghi A M Kheirabadi et al ldquoChelator-free radiolabeling of dextran with 68Ga for PET studiesrdquoJournal of Radioanalytical and Nuclear Chemistry vol 311 no3 pp 1811ndash1817 2017
[207] C Bettegowda C A Foss I Cheong et al ldquoImaging bac-terial infections with radiolabeled 1-(21015840-deoxy-21015840- fluoro-120573-D-arabinofuranosyl)-5-iodouracilrdquo Proceedings of the NationalAcadamy of Sciences of the United States of America vol 102 no4 pp 1145ndash1150 2005
[208] S A Soghomonyan M Doubrovin J Pike et al ldquoPositronemission tomography (PET) imaging of tumor-localizedSalmonella expressing HSV1-TKrdquo Cancer GeneTherapy vol 12no 1 pp 101ndash108 2005
[209] C Palestro K Nichols S Sheikh-Fayyaz S Dewey P Singhaland K Bhargava ldquoCan Gallium-68 PET differentiate acuteinterstitial nephritis from acute tubular necrosisrdquo Journal ofNuclear Medicne vol 57 Supplement 2 p 551 2016
[210] A J Morguet D L Munz V Ivancevic et al ldquoImmunoscintig-raphy using technetium-99m-labeled anti-NCA-95 antigranu-locyte antibodies as an adjunct to echocardiography in subacuteinfective endocarditisrdquo Journal of the American College ofCardiology vol 23 no 5 pp 1171ndash1178 1994
[211] C van der Laken O Boerman W Oyen et al ldquoIn Vivo Expres-sion of Interleukin-1 Receptors during Various ExperimentallyInduced Inflammatory Conditionsrdquo The Journal of InfectiousDiseases vol 177 no 5 pp 1398ndash1401 1998
[212] C J Van Der Laken O C Boerman W J G Oyen M T PVan De Ven J W M Van Der Meer and F H M CorstensldquoScintigraphic detection of infection and inflammation Newdevelopments with special emphasis on receptor interactionrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 25 no 5 pp 535ndash546 1998
[213] C J van der LakenOC BoermanW J GOyenM T P van deVen J W M van der Meer and F H M Corstens ldquoImaging ofinfection in rabbits with radioiodinated interleukin-1 (120572 and 120573)its receptor antagonist and a chemotactic peptide a comparativestudyrdquo European Journal of Nuclear Medicine and MolecularImaging vol 25 no 4 pp 347ndash352 1998
[214] C J Van Der Laken O C BoermanW J G Oyen M T P VanDe Ven F H M Corstens and J W M Ven Der Meer ldquoThekinetics of radiolabelled interleukin-8 in infection and sterileinflammationrdquo Nuclear Medicine Communications vol 19 no3 pp 271ndash282 1998
[215] E Lazzeri P Erba M Perri et al ldquoScintigraphic imaging ofvertebral osteomyelitis with 111in-biotinrdquoThe Spine Journal vol33 no 7 pp E198ndashE204 2008
[216] E Blom B Langstrom and I Velikyan ldquo68Ga-labeling of biotinanalogues and their characterizationrdquo Bioconjugate Chemistryvol 20 no 6 pp 1146ndash1151 2009
[217] O Eriksson F Carlsson E Blom et al ldquoPreclinical evaluationof a 68Ga-labeled biotin analogue for applications in islettransplantationrdquo Nuclear Medicine and Biology vol 39 no 3pp 415ndash421 2012
[218] E A Weinstein A A Ordonez V P DeMarco et alldquoImaging Enterobacteriaceae infection in vivo with 18F-fluoro-deoxysorbitol positron emission tomographyrdquo Science Transla-tional Medicine vol 6 no 259 p 259ra146 2014
[219] K M Nielsen M H Kyneb A K O Alstrup et alldquo68Ga-labeled phage-display selected peptides as tracers forpositron emission tomography imaging of Staphylococcusaureus biofilm-associated infections Selection radiolabellingand preliminary biological evaluationrdquo Nuclear Medicine andBiology vol 43 no 10 pp 593ndash605 2016
[220] T J Makinen P Lankinen T Poyhonen J Jalava H T Aroand A Roivainen ldquoComparison of 18F-FDG and 68Ga PETimaging in the assessment of experimental osteomyelitis due toStaphylococcus aureusrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 32 no 11 pp 1259ndash1268 2005
[221] JMU Silvola I LaitinenH J Sipila et al ldquoUptake of 68galliumin atherosclerotic plaques in LDLRminusminusApoB100100micerdquo EJN-MMI Research vol 1 no 1 pp 1ndash8 2011
Contrast Media amp Molecular Imaging 23
[222] T A Wynn ldquoCellular and molecular mechanisms of fibrosisrdquoThe Journal of Pathology vol 214 no 2 pp 199ndash210 2008
[223] T Derlin D Jonigk J Bauersachs and FM Bengel ldquoMolecularImaging of Chemokine Receptor CXCR4 in NonndashSmall CellLung Cancer Using 68Ga-Pentixafor PETCT ComparisonWith 18F-FDGrdquo Clinical Nuclear Medicine 2016
[224] I Velikyan U Rosenstrom T N Bulenga O Eriksson andG Antoni ldquoFeasibility of multiple examinations using68ga-labelled collagelin analogues Organ distribution in rat forextrapolation to human organ and whole-body radiationdosimetryrdquo Pharmaceuticals vol 9 no 2 article no 31 2016
[225] S Jadhav M Kakela J Makila et al ldquoSynthesis and in VivoPET Imaging of Hyaluronan Conjugates of OligonucleotidesrdquoBioconjugate Chemistry vol 27 no 2 pp 391ndash403 2016
[226] A Autio A Saraste N Kudomi et al ldquoAssessment of bloodflow with (68) Ga-DOTA PET in experimental inflammation avalidation study using (15) O-waterrdquo American Journal ofNuclear Medicine and Molecular Imaging vol 4 no 6 pp 571ndash579 2014
[227] G Davies A Rolle A Maurer et al ldquoTowards translationalimmunoPETMR imaging of invasive pulmonary aspergillosisthe Humanised Monoclonal Antibody JF5 detects in vivordquoTheranostics vol 7 no 14 pp 3398ndash3414 2017
[228] DGoodwin CMeares GDavid et al ldquoMonoclonal antibodiesas reversible equilibrium carriers of radiopharmaceuticalsrdquoInternational Journal of Radiation Applications and Instrumen-tation Part B Nuclear Medicine and Biology vol 13 no 4 pp383ndash391 1986
[229] D A Goodwin C F Mears M McTigue and G S DavidldquoMonoclonal antibody hapten radiopharmaceutical deliveryrdquoNuclear Medicine Communications vol 7 no 8 pp 569ndash5801986
[230] S E Halpern and R O Dillman ldquoProblems associated withradioimmunodetection and possibilities for future solutionsrdquo JBiol Response Mod vol 6 no 3 pp 235ndash262 1987
[231] H Hong J Sun and W Cai ldquoRadionuclide-based cancerimaging targeting the carcinoembryonic antigenrdquo BiomarkerInsights vol 3 pp 435ndash451 2008
[232] G J Forster E B Santos P M Smith-Jones P Zanzonico andS M Larson ldquoPretargeted radioimmunotherapy with a single-chain antibodystreptavidin construct and radiolabeledDOTA-biotin Strategies for reduction of the renal doserdquo Journal ofNuclear Medicine vol 47 no 1 pp 140ndash149 2006
[233] Z Yao M Zhang H Kobayashi et al ldquoImproved targeting ofradiolabeled streptavidin in tumors pretargeted with biotiny-lated monoclonal antibodies through an avidin chaserdquo Journalof Nuclear Medicine vol 36 no 5 pp 837ndash841 1995
[234] C-H Chang R M Sharkey E A Rossi et al ldquoMolecularAdvances in Pretargeting Radioimunotherapy with BispecificAntibodies 1 Supported in part by USPHS Grant R01-CA-84379from the NIH and Department of Energy Grant DE-FG01-00NE22941 (both to R M S)1rdquo Mol Cancer Ther vol 1 no 7pp 553ndash563 2002
[235] R M Sharkey E A Rossi W J McBride C-H Chang andD M Goldenberg ldquoRecombinant Bispecific Monoclonal Anti-bodies Prepared by theDock-and-Lock Strategy for PretargetedRadioimmunotherapyrdquo Seminars in Nuclear Medicine vol 40no 3 pp 190ndash203 2010
[236] R M Sharkey E A Rossi C-H Chang and D M Golden-berg ldquoImproved cancer therapy and molecular imaging withmultivalent multispecific antibodiesrdquo Cancer Biotherapy andRadiopharmaceuticals vol 25 no 1 pp 1ndash12 2010
[237] D M Goldenberg R M Sharkey G Paganelli J Barbet andJ Chatal ldquoAntibody pretargeting advances cancer radioim-munodetection and radioimmunotherapyrdquo Journal of ClinicalOncology vol 24 no 5 pp 823ndash834 2006
[238] O C Boerman F G van Schaijk W J G Oyen and FH M Corstens ldquoPretargeted radioimmunotherapy of cancerprogress step by steprdquo Journal of Nuclear Medicine vol 44 no3 pp 400ndash411 2003
[239] J Schuhmacher S Kaul G Klivenyi et al ldquoImmunoscintigra-phy with positron emission tomography Gallium-68 chelateimaging of breast cancer pretargeted with bispecific anti-MUC1anti-Ga chelate antibodiesrdquo Cancer Research vol 61 no9 pp 3712ndash3717 2001
[240] J Schuhmacher G Klivenyi S Kaul et al ldquoPretargeting ofhuman mammary carcinoma xenografts with bispecific anti-MUC1anti-Ga chelate antibodies and immunoscintigraphywith PETrdquo Nuclear Medicine and Biology vol 28 no 7 pp 821ndash828 2001
[241] C Somasundaram S Matzku J Schuhmacher and M ZollerldquoDevelopment of a bispecific monoclonal antibody against agallium-67 chelate and the human melanoma-associated anti-gen p97 for potential use in pretargeted immunoscintigraphyrdquoCancer Immunology Immunotherapy vol 36 no 5 pp 337ndash3451993
[242] E A Rossi D L Rossi R Stein D M Goldenberg and C-H Chang ldquoA bispecific antibody-IFN1205722b immunocytokine tar-geting CD20 and HLA-DR is highly toxic to human lymphomaandmultiplemyeloma cellsrdquoCancer Research vol 70 no 19 pp7600ndash7609 2010
[243] R M Sharkey H Karacay S Litwin et al ldquoImproved ther-apeutic results by pretargeted radioimmunotherapy of non-Hodgkinrsquos lymphoma with a new recombinant trivalent anti-CD20 bispecific antibodyrdquo Cancer Research vol 68 no 13 pp5282ndash5290 2008
[244] G L Griffiths C-H Chang W J McBride et al ldquoReagentsandmethods for PETusing bispecific antibody pretargeting and68Ga-radiolabeled bivalent hapten-peptide-chelate conjugatesrdquoJournal of Nuclear Medicine vol 45 no 1 pp 30ndash39 2004
[245] J Watine M Miedouge and B Friedberg ldquoCarcinoembryonicantigen as an independent prognostic factor of recurrence andsurvival in patients resected for colorectal liver metastases Asystematic reviewrdquo Diseases of the Colon amp Rectum vol 44 no12 pp 1791ndash1799 2001
[246] M J Goldstein and E P Mitchell ldquoCarcinoembryonic antigenin the staging and follow-up of patients with colorectal cancerrdquoCancer Investigation vol 23 no 4 pp 338ndash351 2005
[247] D V Gold D M Goldenberg H Karacay et al ldquoA novelbispecific trivalent antibody construct for targeting pancreaticcarcinomardquo Cancer Research vol 68 no 12 pp 4819ndash48262008
[248] J Schuhmacher G Klivenyi R Matys et al ldquoMultistep tumortargeting in nudemice using bispecific antibodies and a galliumchelate suitable for immunoscintigraphy with positron emis-sion tomographyrdquo Cancer Research vol 55 no 1 pp 115ndash1231995
[249] G Klivenyi J Schuhmacher E Patzelt et al ldquoGallium-68chelate imaging of human colon carcinoma xenografts pre-targeted with bispecific anti-CD44(V6)anti-gallium chelateantibodiesrdquo Journal ofNuclearMedicine vol 39 no 10 pp 1769ndash1776 1998
[250] M Zoller J Schuhmacher J Reed W Maier-Borst and SMatzku ldquoEstablishment and characterization of monoclonal
24 Contrast Media amp Molecular Imaging
antibodies against an octahedral gallium chelate suitable forimmunoscintigraphy with PETrdquo Journal of Nuclear Medicinevol 33 no 7 pp 1366ndash1372 1992
[251] R M Sharkey T M Cardillo E A Rossi et al ldquoSignal ampli-fication in molecular imaging by pretargeting a multivalentbispecific antibodyrdquo Nature Medicine vol 11 no 11 pp 1250ndash1255 2005
[252] D M Goldenberg and R M Sharkey ldquoNovel radiolabeledantibody conjugatesrdquo Oncogene vol 26 no 25 pp 3734ndash37442007
[253] D M Goldenberg E A Rossi R M Sharkey W J McBrideand C-H Chang ldquoMultifunctional antibodies by the dock-and-lock method for improved cancer imaging and therapy bypretargetingrdquo Journal of NuclearMedicine vol 49 no 1 pp 158ndash163 2008
[254] R Schoffelen R M Sharkey D M Goldenberg et al ldquoPre-targeted immuno-positron emission tomography imaging ofcarcinoembryonic antigen-expressing tumors with a bispecificantibody and a68Ga- And18F-labeled hapten peptide in micewith human tumor xenograftsrdquoMolecular Cancer Therapeuticsvol 9 no 4 pp 1019ndash1027 2010
[255] E S Bos W H Kuijpers M Meesters-Winters et al ldquoIn vitroevaluation of DNA-DNA hybridization as a two-step approachin radioimmunotherapy of cancerrdquoCancer Research vol 54 no13 pp 3479ndash3486 1994
[256] G Paganelli M Bartolomei M Ferrari et al ldquoPre-TargetedLocoregional Radioimmunotherapy withrdquo Cancer biotherapyand radiopharmaceuticals vol 16 no 3 pp 227ndash235 2001
[257] A Forero P L Weiden J M Vose et al ldquoPhase 1 trial of a novelanti-CD20 fusion protein in pretargeted radioimmunotherapyfor B-cell non-Hodgkin lymphomardquo Blood vol 104 no 1 pp227ndash236 2004
[258] DM Goldenberg C-H Chang E A RossiW J McBride andR M Sharkey ldquoPretargeted molecular imaging and radioim-munotherapyrdquoTheranostics vol 2 no 5 pp 523ndash540 2012
[259] H Karacay R M Sharkey W J McBride E A Rossi C-HChang and D M Goldenberg ldquoOptimization of hapten-peptide labeling for pretargeted immunoPET of bispecificantibody using generator-produced 68Gardquo Journal of NuclearMedicine vol 52 no 4 pp 555ndash559 2011
[260] J R Oh and B C Ahn ldquoFalse-positive uptake on radioiodinewhole-body scintigraphy physiologic and pathologic variantsunrelated to thyroid cancerrdquo American Journal of NuclearMedicine and Molecular Imaging vol 2 no 2 pp 141ndash150 2012
[261] E Frampas C Rousseau C Bodet-Milin J Barbet J-F Chataland F Kraeber-Bodere ldquoImprovement of radioimmunotherapyusing pretargetingrdquo Frontiers in Oncology vol 3 Article ID00159 2013
[262] C S McKay and M G Finn ldquoClick chemistry in complexmixtures Bioorthogonal bioconjugationrdquo Chemistry amp Biologyvol 21 no 9 pp 1075ndash1101 2014
[263] B L Oliveira Z Guo and G J Bernardes ldquoInverse electrondemand DielsndashAlder reactions in chemical biologyrdquo ChemicalSociety Reviews vol 46 no 16 pp 4895ndash4950 2017
[264] B Nichols Z Qin J Yang D R Vera and N K Devaraj ldquo68Gachelating bioorthogonal tetrazine polymers for the multisteplabeling of cancer biomarkersrdquo Chemical Communications vol50 no 40 pp 5215ndash5217 2014
[265] R Rossin P R Verkerk S M van den Bosch et al ldquoInvivo chemistry for pretargeted tumor imaging in live micerdquoAngewandte Chemie International Edition vol 49 no 19 pp3375ndash3378 2010
[266] B M Zeglis K K Sevak T Reiner et al ldquoA pretargetedPET imaging strategy based on bioorthogonal diels-alder clickchemistryrdquo Journal of Nuclear Medicine vol 54 no 8 pp 1389ndash1396 2013
[267] J L Houghton R Membreno D Abdel-Atti et al ldquoEstablish-ment of the invivo efficacy of pretargeted radioimmunotherapyutilizing inverse electron demand diels-alder click chemistryrdquoMolecular Cancer Therapeutics vol 16 no 1 pp 124ndash133 2017
[268] J Funkhouser ldquoReinventing pharma the theranostic revolu-tionrdquo Current Drug Discovery pp 17ndash19 2002
[269] J Sorensen I Velikyan A Wennborg et al ldquoMeasuring HER2-expression in metastatic breast cancer using 68Ga-ABY025PETCTrdquo European Journal of Nuclear Medicine and MolecularImaging vol 41 pp S226ndashS226 2014
[270] I Velikyan A Wennborg J Feldwisch et al ldquoGMP compliantpreparation of a 68Gallium-labeled Affibody analogue forbreast cancer patient examination first-in-manrdquoEur JNuclMedMol Imaging vol 41 pp S228ndashS229 2014
[271] K Oberg ldquoMolecular imaging radiotherapy Theranostics forpersonalized patient management of neuroendocrine tumors(NETs)rdquoTheranostics vol 2 no 5 pp 448ndash458 2012
[272] I Velikyan AWennborg J FeldwischH Lindman J Carlssonand J Sorensen ldquoGood manufacturing practice production of [(68) Ga]Ga-ABY-025 for HER2 specific breast cancer imagingrdquoAmerican Journal of Nuclear Medicine and Molecular Imagingvol 6 no 2 pp 135ndash153 2016
[273] M Sandstrom K Lindskog I Velikyan et al ldquoBiodistributionand radiation dosimetry of the anti-HER2 Affibody molecule68Ga-ABY-025 in breast cancer patientsrdquo Journal of NuclearMedicine vol 57 no 6 pp 867ndash871 2016
[274] D Sandberg V Tolmachev I Velikyan et al ldquoIntra-imagereferencing for simplified assessment of HER2-expression inbreast cancer metastases using the Affibody molecule ABY-025with PET and SPECTrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 44 no 8 pp 1337ndash1346 2017
[275] H ZhangM AMoroz I Serganova et al ldquoImaging expressionof the human somatostatin receptor subtype-2 reporter genewith 68Ga-DOTATOCrdquo Journal ofNuclearMedicine vol 52 no1 pp 123ndash131 2011
[276] M Naji and A Al-Nahhas ldquo68Ga-labelled peptides in themanagement of neuroectodermal tumoursrdquo European Journalof Nuclear Medicine and Molecular Imaging vol 39 no 1 ppS61ndashS67 2012
[277] I Velikyan ldquoThe diversity of 68Ga-Based imaging agentsrdquoRecent Results in Cancer Research vol 194 pp 101ndash131 2013
[278] K Ferreira H-Y Hu V Fetz et al ldquoMultivalent siderophore-dotam conjugates as theranostics for imaging and treatment ofbacterial infectionsrdquo Angewandte Chemie International Editionvol 56 no 28 pp 8272ndash8276 2017
Computational and Mathematical Methods in Medicine
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Diabetes ResearchJournal of
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Research and TreatmentAIDS
Hindawiwwwhindawicom Volume 2018
Gastroenterology Research and Practice
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Parkinsonrsquos Disease
Evidence-Based Complementary andAlternative Medicine
Volume 2018Hindawiwwwhindawicom
Submit your manuscripts atwwwhindawicom
Contrast Media amp Molecular Imaging 13
tissue and blood and binding specificity [89] Dosimetrycalculations demonstrated possibility of six examinations peryear in humans assuring disease monitoring in longitudinalstudies and routine clinical setup [224]
Several hyaluronan conjugates of oligonucleotides target-ing CD44 positive cells were developed and tested in healthyrats sham-operated rats and rats with myocardial infarction[225]The uptake of the agents was higher for the latter groupand varied dependent on the difference in the oligonucleotidestructure
TLR2 and TLR4 expression levels in neutrophils werefound higher in individuals with bacterial and viral infectionsthan those in control samples There is a possibility that IL-4IL-8 IL-10 IL-12 and TNF-a might serve as biomarkers forinfections and that IL-2 IL-8 or IL-10 is potentially able todistinguish between bacterial and viral infections [22]
Mannosylated human serum albumin labelled with 68Gavia NOTA chelator moiety ([68Ga]Ga-NOTA-MSA) wastested in a rat model of myocarditis targetingmannose recep-tors expressed onmacrophages infiltratingmyocardium [66]The uptake in the diseased myocardium was considerablyhigher than that of the normal one and it was precludedby administration of excess of nonlabelled MSA indicatingbinding specificity The tracer build-up was also observed inthe organs of macrophage accumulation
[68Ga]Ga-DOTA was investigated for the quantificationof increased blood flow which is one of the key events ininflammation [226] The uptake kinetics of [68Ga]Ga-DOTAin the site of inflammation in rats with induced inflamma-tion correlated well with that of 15O-water suggesting highrelevance [68Ga]Ga-DOTA
9 Pretargeted Imaging
The half-life of 68Ga is shorter than that of 64Cu 67Ga 99mTc89Zr 111In and 123124125I and thus in contrast to the latterit is not compatible with slow pharmacokinetics of largemolecules such as antibodies and glycoproteins The rangeof antigen-specific antibodies relevant to inflammation andinfection is broad and a number of 99mTc-labelled antibodieswere used clinically [20 21 227] The respective range of68Ga-based agents could be similarThe solution to overcomethe incompatibility of half-life time frames could be eitherthe reduction of the antibody size or the application of thepretargeting concept
The history of the pretargeting concept spans threedecades predominantly in the field of oncology [228ndash230]It was developed to improve image contrast and dosimetryin immunoimaging and radioimmunotherapy when usingradiolabelled antibody ligands with slow pharmacokinetics[231] The arsenal of antibodies is vast and diverse encourag-ing extensive investment into development of techniques thatwould allow their exploration to the fullest Pretargeting con-siders at least two major steps wherein a functionalized anti-body is first administered for target localization and clearancefrom blood and normal tissue and thereafter a radiolabelledsmall molecule capable of binding to the functionalized
antibody due to high affinity or covalent interaction is admin-istered The key properties of the radiolabelled molecules arefast pharmacokinetic and clearance Several techniques havebeen developed for the realization of pretargeting conceptincluding avidinstreptavidin-biotin systems [216 217 232233] bispecific antibodies (bsmAb) with haptens [232 234ndash254] antibody-oligonucleotide conjugates with complemen-tary oligonucleotides [255] biorthogonal systems allowingcovalent chemical reactions in vivo (Figure 8)
The high affinity of biotin to avidin and streptavidinproteins was utilized clinically and preclinically in pretar-geting approach for the imaging and therapy of pancreaticadenocarcinoma [232] glioblastoma [256] and lymphoma[257] However this pretargeting technique may requirethree steps in order to eliminate the excess of antibody-(strept)avidin conjugate circulating in the blood and notbound to the target by adding clearing agent Anotherapplication of the technique was monitoring transplantationof islets of Langerhans in the treatment for type 1 diabetesmellitus wherein the cells or cellmimetics were conjugated to(strept)avidin prior to the transplantation [216 217] Severalanalogues of biotin comprising DOTA chelate moiety forlabelling with 68Ga and ethylene glycol linker of variouslength demonstrated the influence of the latter on the affinitytowards avidin
Particular example of hapten molecules is the ones com-prising histamine-succinyl-glycine (HSG) motif and chelatemoiety [251ndash253 258] for the complexationwith 68Ga Severalanalogues were developed for the imaging of carcinoem-bryonic antigen (CEA) pretargeted with anti-CEA bsmAb[254 259 260] and two clinical studies of medullary thyroidcarcinoma and breast carcinoma positive for CEA using68Ga-labelled hapten molecules and bsmAb were initiated[261]
Bioorthogonal reactions are fast regioselective requiringsmall reagent concentration and occurring under mild con-ditions often in aqueous solution and temperature below 37∘C[262 263] Amongst various biorthogonal reaction types thecycloaddition of tetrazines and various dienophiles referredto as inverse-electron-demandDiels-Alder (IEDDA) reactionis themost successful in the context of pretargeting Antibod-ies functionalized with trans-cyclooctene (TCO) and a radi-olabelled tetrazine that can interact in vivo based on IEDDAreaction were studied [264ndash267] In particular 68Ga-labelledtetrazine dextran demonstrated favorable pharmacokineticsin a healthy mouse [264] However the proof of concept is tobe performed in a xenografted animal Accumulation of anti-TAG72 [265] and anti-A33 [266] antibodies functionalizedwith TCO in mouse xenografts was visualized respectivelyby an 111In and 64Cu-labelled tetrazine analogues Anti-CA199 antibody-TCO in combination with 177Lu-labelledtetrazine demonstrated radiotherapeutic effect in pancreaticcancer murine model [267]
Thepretargeted imaging techniquesmay contribute to theexpansion of immuno-PET with 68Ga providing the intrinsicadvantages of 68Ga and PET As mentioned above mostof the developed radiolabelled counterparts of pretargetingtechniques have demonstrated promising results There are
14 Contrast Media amp Molecular Imaging
H
ON
NN
O
OO
OO
NH
NS
NH
ONH
O
HO
ONH
O
Ga
HN
NH
NH
O
OO
HNN
HN
NH
NH
O
OO
HNN
（2
(a)
NH
O
O
NH
N
NNGa
O O
O O
O
O
O
N N
NN
OO
（2
(b)
N
N
O
O
N
N
O
O
O
NH
O
O
ONH
NHS
O
H
HO
NH
+
minus
(c)
Figure 8 Schematic presentation of pretargeting techniques (a) bispecific antibodies engineered to specifically bind with radiolabelledhapten molecules (b) bioorthogonal click chemistry for fast and specific covalent binding between for example a trans-cyclooctenefunctionalized antibody and a radiolabelled tetrazine (c) interaction between antibody-(strept)avidin conjugate and radiolabelled biotinutilizing extremely high affinity of (strept)avidin and biotin
Contrast Media amp Molecular Imaging 15
a considerable number of potential antibody biomarkersthat could be considered for the imaging of infection andinflammation
10 Theranostics Potential
Theranostics [268] embraces realization of personalizedmedicine by conducting diagnosis on individual basis andproviding possibility of predicting the efficacy of a specifictreatment and following up the response to the treatmentenabling adjustment of the latter very early in the processIn the context of nuclear medicine wherein the radiophar-maceuticals targeted at biomarkers specific to a disease cancarry either diagnostic radionuclides or therapeutic ones theconcept can be denoted as radiotheranostics [28] The tar-geted molecular imaging such as PET can offer noninvasivediagnosis specific to the disease for example tumour-typespecific and provide accurate localization of the lesions Thestrongest advantage of PET is the potential for quantificationof the target for example receptor expression investigationof the uptake kinetics and estimation of the dosimetryThesecharacteristics of PET allow for individualized treatmentselection and planning monitoring of treatment responseand detection of recurrent diseaseThe individualized patientmanagement provides such advantages as optimization ofthe treatment regimen for the improved response and exclu-sion of futile treatments minimization of risks and toxicitywith overall outcome of reduced cost and patient distressThe importance of individualized patient management wasdemonstrated by clinical studies wherein the influence ofdose of the administered radiopharmaceutical targeted atreceptors overexpressed in cancer lesions on the diagnosticoutcome was investigated in the same patient [85 269270] 68Ga-labelled SST analogues [26ndash28 271] and Affibodymolecules [5 272ndash274] used respectively in NENs andbreast cancer patients are the most prominent examplesof (radio)theranostics involving 68GaPET wherein 68Ga-labelled analogues were used not only for localization of thelesions but also for staging patient stratification prognosistherapy selection and monitoring of the response to thetreatment of NETs and other cancer types [2ndash4 6 85 176275ndash277]
The methodology can be translated to inflammationand infection allowing for accurate and specific selection oftreatment regimen and for follow-up and evaluation of theresponse to therapy resulting in improved treatment efficacyand decreased cost and side effects The accommodation ofboth imaging function and antibiotic function in the samemolecule is a novel example of a theranostic agent [278]A series of siderophores conjugated with DOTA moiety forthe radiolabelling and with antibiotics for the treatmentof bacterial infection were investigated preclinically Theaccumulation of the intravenously administered ampicillinconjugate in the site of subcutaneously injected P aeruginosain mice was clearly and focally visualized within 06 h withretention for at least 24 h These results obtained usinganalogues carrying dye for optical imaging can be translatedto 68Ga-labelled counterparts for PET
11 Conclusions
The medical need for specific agents for noninvasive quan-titative and whole-body imaging of inflammation and infec-tion has not been met yet despite decades of research How-ever the prerequisites in terms of identification of potentialtargets design and synthesis of the respective ligands andimaging technologies are evolving very fast The potentialof accurate and quantitative lesion localization as well asmonitoring of the treatment response promises personalizedpatient management
The use of 68Ga in oncology is established proving thestrong potential of 68Ga for the promotion of PET technol-ogy for effective and efficient diagnostics and personalizedmedicineThe experience of oncological 68Ga-based agents isgetting translated to inflammation and infection Pretargetedimaging technology opens wide possibilities based on anti-body biomarkers
Conflicts of Interest
The author declares that there are no conflicts of interestregarding the publication of this article
References
[1] I Velikyan ldquoContinued rapid growth inGa applications update2013 to June 2014rdquo Journal of Labelled CompoundsampRadiophar-maceuticals pp 99ndash121 2015
[2] I Velikyan ldquo 68Ga-based radiopharmaceuticals Production andapplication relationshiprdquo Molecules vol 20 no 7 pp 12913ndash12943 2015
[3] M Fani P Peitl and I Velikyan ldquoCurrent status of radiophar-maceuticals for the theranostics of neuroendocrine neoplasmsrdquoPharmaceuticals vol 10 no 1 article no 30 2017
[4] I Velikyan ldquoPositron emitting [68Ga]Ga-based imaging agentsChemistry and diversityrdquoMedicinal Chemistry vol 7 no 5 pp345ndash379 2011
[5] J Sorensen I Velikyan D Sandberg et al ldquoMeasuringHER2-receptor expression in metastatic breast cancer using[68Ga]ABY-025 Affibody PETCTrdquo Theranostics vol 6 no 2pp 262ndash271 2016
[6] I Velikyan ldquoProspective of 68Ga-Radiopharmaceutical devel-opmentrdquoTheranostics vol 4 no 1 pp 47ndash80 2014
[7] P Lankinen T J Makinen T A Poyhonen et al ldquo68Ga-DOTAVAP-P1 PET imaging capable of demonstrating the phaseof inflammation in healing bones and the progress of infectionin osteomyelitic bonesrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 35 no 2 pp 352ndash364 2008
[8] T UjulaMHuttunen P Luoto et al ldquoMatrixmetalloproteinase9 targeting peptides Syntheses 68Ga-labeling and preliminaryevaluation in a rat melanoma xenograft modelrdquo BioconjugateChemistry vol 21 no 9 pp 1612ndash1621 2010
[9] A Autio T Ujula P Luoto S Salomaki S Jalkanen and ARoivainen ldquoPET imaging of inflammation and adenocarcinomaxenografts using vascular adhesion protein 1 targeting peptide68Ga-DOTAVAP-P1 Comparison with 18F-FDGrdquo EuropeanJournal of Nuclear Medicine and Molecular Imaging vol 37 no10 pp 1918ndash1925 2010
16 Contrast Media amp Molecular Imaging
[10] J Silvola A Autio P Luoto S Jalkanen andA Roivainen ldquoPre-liminary evaluation of novel 68Ga-DOTAVAP-PEG-P2 peptidetargeting vascular adhesion protein-1rdquo Clinical Physiology andFunctional Imaging vol 30 no 1 pp 75ndash78 2010
[11] T Ujula S Salomaki P Virsu et al ldquoSynthesis 68Ga labelingand preliminary evaluation of DOTA peptide binding vascularadhesion protein-1 a potential PET imaging agent for diagnos-ing osteomyelitisrdquo Nuclear Medicine and Biology vol 36 no 6pp 631ndash641 2009
[12] A Autio T Henttinen H J Sipila S Jalkanen and ARoivainen ldquoMini-PEG spacering of VAP-1-targeting 68Ga-DOTAVAP-P1 peptide improves PET imaging of inflamma-tionrdquo EJNMMI Research vol 1 no 1 pp 1ndash7 2011
[13] K Aalto A Autio E A Kiss et al ldquoSiglec-9 is a novel leukocyteligand for vascular adhesion protein-1 and can be used in PETimaging of inflammation and cancerrdquo Blood vol 118 no 13 pp3725ndash3733 2011
[14] V Kumar D K Boddeti S G Evans F Roesch and RHowman-Giles ldquoPotential use of 68Ga-apo-transferrin as a PETimaging agent for detecting Staphylococcus aureus infectionrdquoNuclear Medicine and Biology vol 38 no 3 pp 393ndash398 2011
[15] M Petrik H Haas G Dobrozemsky et al ldquo68Ga-siderophoresfor PET imaging of invasive pulmonary aspergillosis Proof ofprinciplerdquo Journal of Nuclear Medicine vol 51 no 4 pp 639ndash645 2010
[16] M Petrik H Haas M Schrettl A Helbok M Blatzer and CDecristoforo ldquoIn vitro and in vivo evaluation of selected 68Ga-siderophores for infection imagingrdquo Nuclear Medicine andBiology vol 39 no 3 pp 361ndash369 2012
[17] M Petrik GM Franssen H Haas et al ldquoPreclinical evaluationof two 68Ga-siderophores as potential radiopharmaceuticals forAspergillus fumigatus infection imagingrdquo European Journal ofNuclearMedicine andMolecular Imaging vol 39 no 7 pp 1175ndash1183 2012
[18] A Rizzello D Di Pierro F Lodi et al ldquoSynthesis and qualitycontrol of 68Ga citrate for routine clinical PETrdquo NuclearMedicine Communications vol 30 no 7 pp 542ndash545 2009
[19] C Nanni C Errani and L Boriani ldquo 68Ga-citrate PETCT forevaluating patients with infections of the bone preliminaryresultsrdquo Journal of Nuclear Medicine vol 51 no 12 pp 1932ndash1936 2010
[20] S S Das A V Hall D W Wareham and K E Britton ldquoInfec-tion imaging with radiopharmaceuticals in the 21st centuryrdquoBrazilian Archives of Biology and Technology vol 45 no spepp 25ndash37 2002
[21] A Signore and A W J M Glaudemans ldquoThe molecularimaging approach to image infections and inflammation bynuclear medicine techniquesrdquo Annals of Nuclear Medicine vol25 no 10 pp 681ndash700 2011
[22] T Yusa K Tateda A Ohara and S Miyazaki ldquoNew possiblebiomarkers for diagnosis of infections and diagnostic distinc-tion between bacterial and viral infections in childrenrdquo Journalof Infection and Chemotherapy vol 23 no 2 pp 96ndash100 2017
[23] A Signore A W J M Glaudemans O Gheysens C Lauriand O A Catalano ldquoNuclear Medicine Imaging in PediatricInfection or Chronic Inflammatory Diseasesrdquo Seminars inNuclear Medicine vol 47 no 3 pp 286ndash303 2017
[24] I Velikyan ldquoMolecular imaging and radiotherapyTheranosticsfor personalized patient managementrdquo Theranostics vol 2 no5 pp 424ndash426 2012
[25] F Rosch and R P Baum ldquoGenerator-based PET radiophar-maceuticals for molecular imaging of tumours On the way
to THERANOSTICSrdquo Dalton Transactions vol 40 no 23 pp6104ndash6111 2011
[26] R P Baum H R Kulkarni and C Carreras ldquoPeptides andreceptors in image-guided therapy Theranostics for neuroen-docrine neoplasmsrdquo Seminars in Nuclear Medicine vol 42 no3 pp 190ndash207 2012
[27] R P Baum and H R Kulkarni ldquoTheranostics From molecularimaging using Ga-68 labeled tracers and PETCT to per-sonalized radionuclide therapy - the bad berka experiencerdquoTheranostics vol 2 no 5 pp 437ndash447 2012
[28] I Velikyan ldquoRadionuclides for Imaging andTherapy in Oncol-ogyrdquo Cancer Theranostics pp 285ndash325 2014
[29] J Czernin andWAWeber ldquoIssues and controversies in nuclearmedicine Introductionrdquo Journal of Nuclear Medicine vol 52no Supplement 2 pp 1Sndash2S 2011
[30] S J Goldsmith and S Vallabhajosula ldquoClinically proven radio-pharmaceuticals for infection imaging mechanisms and appli-cationsrdquo Seminars in Nuclear Medicine vol 39 no 1 pp 2ndash102009
[31] M F Tsan ldquoMechanism of gallium-67 accumulation in inflam-matory lesionsrdquo Journal of Nuclear Medicine vol 26 no 1 pp88ndash92 1985
[32] S L Kipper ldquoRadiolabelled leukocyte imaging of the abdomenrdquoin Nuclear Medicine Annual J Freeman Ed pp 81ndash126 RavenPress New York NY USA 1995
[33] F Jamar J Buscombe A Chiti et al ldquoEANMSNMMI guidelinefor 18F-FDG use in inflammation and infectionrdquo Journal ofNuclear Medicine vol 54 no 4 pp 647ndash658 2013
[34] C J Palestro ldquoThe current role of gallium imaging in infectionrdquoSeminars in Nuclear Medicine vol 24 no 2 pp 128ndash141 1994
[35] M S Akhtar M B Imran M A Nadeem and A ShahidldquoAntimicrobial peptides as infection imaging agents better thanradiolabeled antibioticsrdquo International Journal of Peptides vol2012 Article ID 965238 19 pages 2012
[36] D Delbeke and G M Segall ldquoStatus of and trends in nuclearmedicine in the United Statesrdquo Journal of Nuclear Medicine vol52 no 2 2011
[37] S S Gambhir J Czernin J Schwimmer D H Silverman R EColeman and M E Phelps ldquoA tabulated summary of the FDGPET literaturerdquo Journal of Nuclear Medicine vol 42 pp 1Sndash93S2001
[38] M J Lindsay B A Siegel S R Tunis et al ldquoThe NationalOncologic PET Registry ExpandedMedicare coverage for PETunder coverage with evidence developmentrdquo American Journalof Roentgenology vol 188 no 4 pp 1109ndash1113 2007
[39] F Gemmel H Van Den Wyngaert C Love M M Welling PGemmel and C J Palestro ldquoProsthetic joint infectionsradionuclide state-of-the-art imagingrdquo European Journal ofNuclearMedicine andMolecular Imaging vol 39 no 5 pp 892ndash909 2012
[40] J Sorensen ldquoHow does the patient benefit from clinical PETrdquoTheranostics vol 2 no 5 pp 427ndash436 2012
[41] S L Rice C A Roney P Daumar and J S Lewis ldquoThe nextgeneration of positron emission tomography radiopharmaceu-ticals in oncologyrdquo Seminars in Nuclear Medicine vol 41 no 4pp 265ndash282 2011
[42] R LWahl JMHerman and E Ford ldquoThePromise and Pitfallsof Positron Emission Tomography and Single-Photon EmissionComputed Tomography Molecular Imaging-Guided RadiationTherapyrdquo Seminars in Radiation Oncology vol 21 no 2 pp 88ndash100 2011
Contrast Media amp Molecular Imaging 17
[43] A W J M Glaudemans R H J A Slart J M Van Dijl MVan Oosten and G M Van Dam ldquoMolecular imaging of infec-tious and inflammatory diseases A terra incognitardquo Journal ofNuclear Medicine vol 56 no 5 pp 659ndash661 2015
[44] X Li W Bauer I Israel et al ldquoTargeting p-selectin by gallium-68-labeled fucoidan positron emission tomography for nonin-vasive characterization of vulnerable plaques Correlation within vivo 176t mrirdquo Arteriosclerosis Thrombosis and VascularBiology vol 34 no 8 pp 1661ndash1667 2014
[45] S Eichendorff P Svendsen D Bender et al ldquoBiodistributionand PET Imaging of a Novel [68Ga]-Anti-CD163-AntibodyConjugate in Rats with Collagen-Induced Arthritis and inControlsrdquoMolecular Imaging and Biology vol 17 no 1 pp 87ndash93 2014
[46] Z Zhu Y Yin K Zheng et al ldquoEvaluation of synovial angiogen-esis in patients with rheumatoid arthritis using 68Ga-PRGD2PETCT A prospective proof-of-concept cohort studyrdquo Annalsof the Rheumatic Diseases vol 73 no 6 pp 1269ndash1272 2014
[47] J S Eo J C Paeng S Lee et al ldquoAngiogenesis imaging inmyocardial infarction using 68Ga-NOTA- RGD PET Charac-terization and application to therapeutic efficacy monitoring inratsrdquo Coronary Artery Disease vol 24 no 4 pp 303ndash311 2013
[48] J H Kim Y-H Kim Y J Kim et al ldquoQuantitative positronemission tomography imaging of angiogenesis in rats with fore-limb ischemia using 68Ga-NOTA-c(RGDyK)rdquo Angiogenesisvol 16 no 4 pp 837ndash846 2013
[49] I Laitinen J Notni K Pohle et al ldquoComparison of cyclicRGD peptides for 120572v1205733 integrin detection in a rat model ofmyocardial infarctionrdquo EJNMMI Research vol 3 no 1 pp 1ndash9 2013
[50] M Kiugel I Dijkgraaf V Kyto et al ldquoDimeric [68Ga]DOTA-RGD Peptide Targeting 120572 ltinfgtvltinfgt 120573 ltinfgt3ltinfgt Inte-grin Reveals Extracellular Matrix Alterations after MyocardialInfarctionrdquo Molecular Imaging and Biology vol 16 no 6 pp793ndash801 2014
[51] M Gronman M Tarkia T Kiviniemi et al ldquoImaging of 120572v1205733integrin expression in experimental myocardial ischemia with[68Ga]NODAGA-RGD positron emission tomographyrdquo Jour-nal of Translational Medicine vol 15 no 1 p 144 2017
[52] J Haukkala I Laitinen P Luoto et al ldquo68Ga-DOTA-RGDpep-tide Biodistribution and binding into atherosclerotic plaquesin micerdquo European Journal of Nuclear Medicine and MolecularImaging vol 36 no 12 pp 2058ndash2067 2009
[53] H Virtanen A Autio R Siitonen et al ldquo68Ga-DOTA-Siglec-9- a new imaging tool to detect synovitisrdquo Arthritis Research ampTherapy vol 17 no 1 article no 308 2015
[54] J Retamal J Sorensen M Lubberink et al ldquoFeasibility of(68) Ga-labeled Siglec-9 peptide for the imaging of acutelung inflammation a pilot study in a porcine model of acuterespiratory distress syndromerdquoAm JNuclMedMol Imaging vol6 no 1 pp 18ndash31 2016
[55] J M U Silvola H Virtanen R Siitonen et al ldquoLeukocytetrafficking-associated vascular adhesion protein 1 is expressedand functionally active in atherosclerotic plaquesrdquo ScientificReports vol 6 Article ID 35089 2016
[56] H Ahtinen J Kulkova L Lindholm et al ldquo68Ga-DOTA-Siglec-9 PETCT imaging of peri-implant tissue responses andstaphylococcal infectionsrdquo EJNMMI Research vol 4 no 1article no 45 pp 1ndash11 2014
[57] A Autio S Jalkanen and A Roivainen ldquoNuclear imaging ofinflammation Homing-associated molecules as targetsrdquo EJN-MMI Research vol 3 no 1 pp 1ndash7 2013
[58] J TThackeray T Derlin AHaghikia et al ldquoMolecular Imagingof the Chemokine Receptor CXCR4 after Acute MyocardialInfarctionrdquo JACC Cardiovascular Imaging vol 8 no 12 pp1417ndash1426 2015
[59] J S Schmid A Schirbel A K Buck S Kropf H-J Westerand C Lapa ldquoPentixafor-Positron Emission TomographyComputed Tomography Detects Chemokine Receptor CXCR4Expression after Ischemic Strokerdquo Circulation CardiovascularImaging vol 9 no 9 Article ID e005217 2016
[60] J Zhou G Hao H Weng et al ldquoIn vivo evaluation ofmedical device-associated inflammation using a macrophage-specific positron emission tomography (PET) imaging proberdquoBioorganic amp Medicinal Chemistry Letters vol 23 no 7 pp2044ndash2047 2013
[61] S A Kularatne M-J Belanger X Meng et al ldquoComparativeanalysis of folate derived PET imaging agents with [ 18F]-2-fluoro-2-deoxy-d-glucose using a rodent inflammatory pawmodelrdquo Molecular Pharmaceutics vol 10 no 8 pp 3103ndash31112013
[62] V Ambrosini M Zompatori F De Luca et al ldquo68Ga-DOTANOCPETCTAllows Somatostatin Receptor Imaging inIdiopathic Pulmonary Fibrosis Preliminary Resultsrdquo Journal ofNuclear Medicine vol 51 no 12 pp 1950ndash1955 2010
[63] T Lincke J Singer R Kluge O Sabri and R Paschke ldquoRela-tive quantification of indium-111 pentetreotide and gallium-68DOTATOC uptake in the thyroid gland and association withthyroid pathologiesrdquoThyroid vol 19 no 4 pp 381ndash389 2009
[64] A Rominger T Saam E Vogl et al ldquoIn vivo imaging ofmacrophage activity in the coronary arteries using 68Ga-DOTATATE PETCT correlation with coronary calcium bur-den and risk factorsrdquo Journal of Nuclear Medicine vol 51 no 2pp 193ndash197 2010
[65] J M Tarkin F R Joshi N R Evans et al ldquoDetection ofAtherosclerotic Inflammation by 68Ga-DOTATATE PET Com-pared to [18F]FDG PET Imagingrdquo Journal of the AmericanCollege of Cardiology vol 69 no 14 pp 1774ndash1791 2017
[66] S-P Lee H-J Im S Kang et al ldquoNoninvasive imaging ofmyocardial inflammation in myocarditis using 68Ga-taggedmannosylated human serum albumin positron emissiontomographyrdquoTheranostics vol 7 no 2 pp 413ndash424 2017
[67] Z Zha J Song S R Choi et al ldquo68Ga-Bivalent PolypegylatedStyrylpyridine Conjugates for Imaging A120573 Plaques in CerebralAmyloid Angiopathyrdquo Bioconjugate Chemistry vol 27 no 5 pp1314ndash1323 2016
[68] H Watanabe M Ono S Iikuni et al ldquoA 68Ga complex basedon benzofuran scaffold for the detection of 120573-amyloid plaquesrdquoBioorganic amp Medicinal Chemistry Letters vol 24 no 20 pp4834ndash4837 2014
[69] D Cressier M Dhilly T T Cao Pham et al ldquoGallium-68 Com-plexes Conjugated to Pittsburgh Compound B Radiolabelingand Biological EvaluationrdquoMolecular Imaging and Biology vol18 no 3 pp 334ndash343 2016
[70] D Satpati CArjun R KrishnamohanG Samuel and S Baner-jee ldquo68Ga-labeledCiprofloxacinConjugates as Radiotracers forTargeting Bacterial InfectionrdquoChemical Biology ampDrug Designvol 87 no 5 pp 680ndash686 2016
[71] T Ebenhan N Chadwick and M M Sathekge ldquoPeptidesynthesis characterization and 68Ga-radiolabeling of NOTA-conjugated ubiquicidin fragments for prospective infectionimaging with PETCTrdquo Nuclear Medicine and Biology vol 41no 5 pp 390ndash400 2014
18 Contrast Media amp Molecular Imaging
[72] T Ebenhan J R Zeevaart and J D Venter ldquoPreclinicalevaluation of 68Ga-labeled 1 4 7-triazacyclononane-1 4 7-triacetic acid-ubiquicidin as a radioligand for PET infectionimagingrdquo Journal of Nuclear Medicine vol 55 no 2 pp 308ndash314 2014
[73] B B Mokaleng T Ebenhan S Ramesh et al ldquoSynthesis 68Ga-radiolabeling and preliminary in vivo assessment of adepsipeptide-derived compound as a potential PETCTinfection imaging agentrdquo BioMed Research International vol2015 Article ID 284354 2015
[74] T Ebenhan B Mokaleng J Venter H Kruger J Zeevaart andM Sathekge ldquoPreclinical Assessment of a 68Ga-DOTA-Functionalized Depsipeptide as a Radiodiagnostic InfectionImaging AgentrdquoMolecules vol 22 no 9 p 1403 2017
[75] S Chopra B Singh A Koul A Mishra and H Wester ldquoSyn-thesis of DOTA conjugated GF-17 and RAWVAWR-NH2 andradiolabeling with 68Ga as a potential PET tracer for infectionimagingrdquo J Nucl Med vol 57 Supplement 2 p 1115 2016
[76] M Petrik HHaas P Laverman et al ldquo 68Ga-triacetylfusarinineC and 68Ga-ferrioxamine e for aspergillus infection imaginguptake specificity in various microorganismsrdquoMolecular Imag-ing and Biology vol 16 no 1 pp 102ndash108 2014
[77] V Kumar and D K Boddeti ldquo 68Ga-radiopharmaceuticals forPET imaging of infection and inflammationrdquo Recent Results inCancer Research vol 194 pp 189ndash219 2013
[78] M Vorster A Maes A Jacobs et al ldquoEvaluating the possiblerole of 68Ga-citrate PETCT in the characterization of indeter-minate lung lesionsrdquo Annals of Nuclear Medicine vol 28 no 6pp 523ndash530 2014
[79] M Vorster B Mokaleng M M Sathekge and T Ebenhan ldquoAmodified technique for efficient radiolabeling of 68Ga-citratefrom a SnO2-based 68Ge68Ga generator for better infectionimagingrdquoHellenic Journal of Nuclear Medicine vol 16 no 3 pp193ndash198 2013
[80] S Salomaeki J Kemppainen U Hohenthal et al ldquoHead-to-head comparison of 68Ga-Citrate and 18F-FDG PETCT fordetection of infectious foci in patients with staphylococcusaureus bacteraemiardquo Contrast Media amp Molecular Imaging vol2017 p 8 2017
[81] L Fass ldquoImaging and cancer a reviewrdquoMolecular Oncology vol2 no 2 pp 115ndash152 2008
[82] A Chopra L Shan W C Eckelman et al ldquoMolecular imagingand contrast agent database (MICAD) Evolution and progressrdquoMolecular Imaging and Biology vol 14 no 1 pp 4ndash13 2012
[83] A Sanchez-Crespo P Andreo and S A Larsson ldquoPositronflight in human tissues and its influence on PET image spatialresolutionrdquo European Journal of Nuclear Medicine and Molecu-lar Imaging vol 31 no 1 pp 44ndash51 2004
[84] H W A M De Jong L Perk G W M Visser R Boellaard GAM S Van Dongen and A A Lammertsma ldquoHigh resolutionPET imaging characteristics of68Ga 124i and89Zr comparedto18Frdquo in Proceedings of the Nuclear Science Symposium Con-ference Record 2005 IEEE pp 1624ndash1627 Puerto Rico October2005
[85] I Velikyan A Sundin B Eriksson et al ldquoIn vivo bindingof [68Ga]-DOTATOC to somatostatin receptors in neuroen-docrine tumours - impact of peptide massrdquo Nuclear Medicineand Biology vol 37 no 3 pp 265ndash275 2010
[86] U Eberlein and M Lassmann ldquoDosimetry of [68Ga]-labeledcompoundsrdquo Applied Radiation and Isotopes vol 76 pp 70ndash742013
[87] C PettinatoA SarnelliMDiDonna et al ldquo68Ga-DOTANOCBiodistribution and dosimetry in patients affected by neuroen-docrine tumorsrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 35 no 1 pp 72ndash79 2008
[88] B P Burke G S Clemente and S J Archibald ldquoRecentadvances in chelator design and labelling methodology for68Ga radiopharmaceuticalsrdquo Journal of Labelled Compoundsand Radiopharmaceuticals vol 57 no 4 pp 239ndash243 2014
[89] I Velikyan U Rosenstrom S Estrada et al ldquoSynthesis andpreclinical evaluation of 68Ga-labeled collagelin analogs forimaging and quantification of fibrosisrdquo Nuclear Medicine andBiology vol 41 no 9 pp 728ndash736 2014
[90] M F Ferreira G Pereira J P Andre and etal C ldquoGa[NO2A-N-(120572-amino)propionate] chelates Synthesis and evaluation aspotential tracers for 68Ga PETrdquoDalton Transactions vol 43 no21 pp 8037ndash8047 2014
[91] J Notni J Simecek and H-J Wester ldquoPhosphinic acid func-tionalized polyazacycloalkane chelators for radiodiagnosticsand radiotherapeutics Unique characteristics and applicationsrdquoChemMedChem vol 9 no 6 pp 1107ndash1115 2014
[92] J Simecek O Zemek P Hermann J Notni and H J WesterldquoTailored gallium( III) chelator NOPO synthesis characteriza-tion bioconjugation and application in preclinical Ga-68-PETimagingrdquoMolecular Pharmaceutics 2013
[93] D Parker B P Waldron and D S Yufit ldquoCrystallographicand solution NMR structural analyses of four hexacoordinatedgallium(iii) complexes based on ligands derived from 6-amino-perhydro-14-diazepinerdquo Dalton Transactions vol 42 no 22pp 8001ndash8008 2013
[94] B P Waldron D Parker C Burchardt D S Yufit M ZimnyandF Roesch ldquoStructure and stability of hexadentate complexesof ligands based on AAZTA for efficient PET labelling withgallium-68rdquo Chemical Communications vol 49 no 6 pp 579ndash581 2013
[95] D Parker and B PWaldron ldquoConformational analysis and syn-thetic approaches to polydentate perhydro-diazepine ligandsfor the complexation of gallium(iii)rdquo Organic amp BiomolecularChemistry vol 11 no 17 pp 2827ndash2838 2013
[96] I Velikyan H Maecke and B Langstrom ldquoConvenient prepa-ration of 68Ga-based PET-radiopharmaceuticals at room tem-peraturerdquo Bioconjugate Chemistry vol 19 no 2 pp 569ndash5732008
[97] J Erchegyi R Cescato B Waser J E Rivier and J C ReubildquoN-Imidazolebenzyl-histidine substitution in somatostatin andin its octapeptide analogue modulates receptor selectivity andfunctionrdquo Journal of Medicinal Chemistry vol 54 no 17 pp5981ndash5987 2011
[98] R Saha N Saha R S Donofrio and L L Bestervelt ldquoMicrobialsiderophores Amini reviewrdquo Journal of Basic Microbiology vol53 no 4 pp 303ndash317 2013
[99] V Nikolova S Angelova N Markova and T Dudev ldquoGalliumas a Therapeutic Agent A Thermodynamic Evaluation of theCompetition between Ga3+ and Fe3+ Ions in MetalloproteinsrdquoThe Journal of Physical Chemistry B vol 120 no 9 pp 2241ndash2248 2016
[100] C R Chitambar ldquoGallium and its competing roles with ironin biological systemsrdquo Biochimica et Biophysica Acta (BBA) -Molecular Cell Research vol 1863 no 8 pp 2044ndash2053 2016
[101] J A Lessa M A Soares and R G dos Santos ldquoGallium(III)complexes with 2-acetylpyridine-derived thiosemicarbazonesantimicrobial and cytotoxic effects and investigation on theinteractions with tubulinrdquo BioMetals vol 26 pp 151ndash165 2013
Contrast Media amp Molecular Imaging 19
[102] M van Oosten M Hahn L M A Crane et al ldquoTargetedimaging of bacterial infections Advances hurdles and hopesrdquoFEMS Microbiology Reviews vol 39 no 6 pp 892ndash916 2015
[103] M Vorster AMaes C V DWiele andM Sathekge ldquoGallium-68 PET A Powerful Generator-based Alternative to Infectionand Inflammation Imagingrdquo Seminars in Nuclear Medicine vol46 no 5 pp 436ndash447 2016
[104] M Kircher and C Lapa ldquoNovel Noninvasive Nuclear MedicineImaging Techniques for Cardiac Inflammationrdquo Current Car-diovascular Imaging Reports vol 10 no 2 article no 6 2017
[105] D AHammoud ldquoMolecular imaging of inflammation Currentstatusrdquo Journal of Nuclear Medicine vol 57 no 8 pp 1161ndash11652016
[106] D R Brenner D Scherer K Muir et al ldquoA review of the appli-cation of inflammatory biomarkers in epidemiologic cancerresearchrdquo Cancer Epidemiology Biomarkers amp Prevention vol23 no 9 pp 1729ndash1751 2014
[107] M D Turner B Nedjai T Hurst and D J PenningtonldquoCytokines and chemokines at the crossroads of cell signallingand inflammatory diseaserdquo Biochimica et Biophysica Acta (BBA)- Molecular Cell Research vol 1843 no 11 pp 2563ndash2582 2014
[108] L Werner H Guzner-Gur and I Dotan ldquoInvolvement ofCXCR4CXCR7CXCL12 interactions in inflammatory boweldiseaserdquoTheranostics vol 3 no 1 pp 40ndash46 2013
[109] S Jalkanen and M Salmi ldquoVAP-1 and CD73 endothelial cellsurface enzymes in leukocyte extravasationrdquo ArteriosclerosisThrombosis and Vascular Biology vol 28 no 1 pp 18ndash26 2008
[110] G Malviya F Galli I Sonni and A Signore ldquoImaging T-lymphocytes in inflammatory diseases A nuclear medicineapproachrdquo The Quarterly Journal of Nuclear Medicine andMolecular Imaging vol 58 no 3 pp 237ndash257 2014
[111] S Gratz H J RennenO C BoermanW J Oyen and P Burmaldquo(99m)Tc-interleukin-8 for imaging acute osteomyelitisrdquo Jour-nal of Nuclear Medicine vol 42 no 8 pp 1257ndash1264 2001
[112] S Gratz H J Rennen O C Boerman W J Oyen andF H Corstens ldquoRapid imaging of experimental colitis with(99m)Tc-interleukin-8 in rabbitsrdquo Journal of Nuclear Medicnevol 42 no 6 pp 917ndash923 2001
[113] C Alkim H Alkim A R Koksal S Boga and I SenldquoAngiogenesis in inflammatory bowel diseaserdquo InternationalJournal of Inflammation vol 2015 Article ID 970890 2015
[114] I S Alam T H Witney G Tomasi et al ldquoRadiolabeled RGDtracer kinetics annotates differential 120572v1205733 integrin expressionlinked to cell intrinsic and vessel expressionrdquoMolecular Imagingand Biology vol 16 no 4 pp 558ndash566 2014
[115] J Notni K Pohle and H-J Wester ldquoBe spoilt for choice withradiolabelled RGD peptides Preclinical evaluation of 68Ga-TRAP(RGD)3rdquoNuclear Medicine and Biology vol 40 no 1 pp33ndash41 2013
[116] J Oxboel M Brandt-Larsen C Schjoeth-Eskesen et al ldquoCom-parison of two new angiogenesis PET tracers 68Ga-NODAGA-E[c(RGDyK)]2 and 64Cu-NODAGA-E[c(RGDyK)]2 in vivoimaging studies in human xenograft tumorsrdquo Nuclear Medicineand Biology vol 41 no 3 pp 259ndash267 2014
[117] J Simecek J Notni T G Kapp H Kessler and H-J WesterldquoBenefits of NOPO as chelator in gallium-68 peptides exempli-fied by preclinical characterization of 68Ga-NOPO-c(RGDfK)rdquoMolecular Pharmaceutics vol 11 no 5 pp 1687ndash1695 2014
[118] M Trajkovic-Arsic P Mohajerani A Sarantopoulos et alldquoMultimodal molecular imaging of integrin avb3 for in vivodetection of pancreatic cancerrdquo Journal of NuclearMedicine vol55 no 3 pp 446ndash451 2014
[119] H Cai and P S Conti ldquoRGD-based PET tracers for imagingreceptor integrin 120572 v1205733 expressionrdquo Journal of Labelled Com-pounds and Radiopharmaceuticals vol 56 no 5 pp 264ndash2792013
[120] I Dijkgraaf S Y A Terry W J Mcbride et al ldquoImagingintegrin alpha-v-beta-3 expression in tumors with an 18F-labeled dimeric RGD peptiderdquo Contrast Media amp MolecularImaging vol 8 no 3 pp 238ndash245 2013
[121] P A Knetsch M Petrik C Rangger et al ldquo[68Ga]NS3-RGD and [68Ga] Oxo-DO3A-RGD for imaging 120572v1205733 integrinexpression Synthesis evaluation and comparisonrdquo NuclearMedicine and Biology vol 40 no 1 pp 65ndash72 2013
[122] Z Liu and F Wang ldquoDevelopment of RGD-based radiotracersfor tumor imaging and therapy Translating from bench tobedsiderdquo Current Molecular Medicine vol 13 no 10 pp 1487ndash1505 2013
[123] H Choi J H Phi J C Paeng et al ldquoImaging of integrin 120572v1205733expression using 68Ga-RGD positron emission tomography inpediatric cerebral infarctrdquoMolecular Imaging vol 12 no 4 pp213ndash217 2013
[124] H-J Yoon K W Kang I K Chun et al ldquoCorrelation of breastcancer subtypes based on estrogen receptor progesteronereceptor and HER2 with functional imaging parameters from68Ga-RGD PETCT and 18F-FDG PETCTrdquo European Journalof Nuclear Medicine and Molecular Imaging vol 41 no 8 pp1534ndash1543 2014
[125] R P Baum H R Kulkarni D Muller et al ldquoFirst-in-human study demonstrating tumor-angiogenesis by PETCTimaging with 68Ga-NODAGA-THERANOST a high-affinitypeptidomimetic for 120572v1205733 integrin receptor targetingrdquo CancerBiotherapy andRadiopharmaceuticals vol 30 no 4 pp 152ndash1592015
[126] R Haubner A Finkenstedt A Stegmayr et alldquo[68Ga]NODAGA-RGD ndash Metabolic stability biodistributionand dosimetry data from patients with hepatocellularcarcinoma and liver cirrhosisrdquo European Journal of NuclearMedicine and Molecular Imaging vol 43 no 11 pp 2005ndash20132016
[127] V Lopez-Rodrıguez C Galindo-Sarco F O Garcıa-Perez GFerro-Flores O Arrieta and M A Avila-Rodrıguez ldquoPET-based human dosimetry of the dimeric 120572v1205733 integrin ligand68Ga-DOTA-E-[c(RGDfK)]2 a potential tracer for imagingtumor angiogenesisrdquo Journal of Nuclear Medicine vol 57 no 3pp 404ndash409 2016
[128] M V Backer Z Levashova V Patel et al ldquoMolecular imagingof VEGF receptors in angiogenic vasculature with single-chainVEGF-based probesrdquo Nature Medicine vol 13 no 4 pp 504ndash509 2007
[129] MV Backer Z Levashova R Levenson F G Blankenberg andJ M Backer ldquoCysteine-containing fusion tag for site-specificconjugation of therapeutic and imaging agents to targetingproteinsrdquoMethods in Molecular Biology (Clifton NJ) vol 494pp 275ndash294 2008
[130] M Eder A V Krivoshein M Backer J M Backer UHaberkorn and M Eisenhut ldquoScVEGF-PEG-HBED-CC andscVEGF-PEG-NOTA conjugates comparison of easy-to-labelrecombinant proteins for [68Ga]PET imaging of VEGF recep-tors in angiogenic vasculaturerdquo Nuclear Medicine and Biologyvol 37 no 4 pp 405ndash412 2010
[131] E Blom I Velikyan A Monazzam P Razifar et al ldquoSynthe-sis and characterization of scVEGF-PEG-[ 68Ga]NOTA andscVEGF-PEG-[ 68Ga]DOTA PET tracersrdquo Journal of Labelled
20 Contrast Media amp Molecular Imaging
Compounds and Radiopharmaceuticals vol 54 no 11 pp 685ndash692 2011
[132] S Gratz M Behe and O C Boerman ldquo 99119898Tc-E-selectinbinding peptide for imaging acute osteomyelitis in a novel ratmodelrdquo Nuclear Medicine Communications vol 22 no 9 pp1003ndash1013 2001
[133] S B Jensen M Kakela L Joslashdal et al ldquoExploring the radiosyn-thesis and in vitro characteristics of [68Ga]Ga-DOTA-Siglec-9rdquoJournal of Labelled Compounds and Radiopharmaceuticals vol60 no 9 pp 439ndash449 2017
[134] B A Teicher and S P Fricker ldquoCXCL12 (SDF-1)CXCR4pathway in cancerrdquo Clinical Cancer Research vol 16 no 11 pp2927ndash2931 2010
[135] O Jacobson I D Weiss D O Kiesewetter J M Farber andX Chen ldquoPET of tumor CXCR4 expression with 4-18F-T140rdquoJournal of Nuclear Medicine vol 51 no 11 pp 1796ndash1804 2010
[136] A Aghanejad A R Jalilian Y Fazaeli et al ldquoSynthesis andevaluation of [67Ga]-AMD3100 A novel imaging agent fortargeting the chemokine receptorCXCR4rdquo Scientia Pharmaceu-tica vol 82 no 1 pp 29ndash42 2014
[137] O Jacobson I D Weiss L P Szajek et al ldquoPET imaging ofCXCR4 using copper-64 labeled peptide antagonistrdquoTheranos-tics vol 1 pp 251ndash262 2011
[138] O Jacobson I D Weiss L P Szajek et al ldquoImprovement ofCXCR4 tracer specificity for PET imagingrdquo Journal of Con-trolled Release vol 157 no 2 pp 216ndash223 2012
[139] H J Wester U Keller M Schottelius et al ldquoDisclosing theCXCR4 expression in lymphoproliferative diseases by targetedmolecular imagingrdquo Theranostics vol 5 no 6 pp 618ndash6302015
[140] E Gourni O Demmer M Schottelius et al ldquoPET of CXCR4expression by a 68Ga-labeled highly specific targeted contrastagentrdquo Journal of NuclearMedicine vol 52 no 11 pp 1803ndash18102011
[141] O Demmer I Dijkgraaf U Schumacher et al ldquoDesignsynthesis and functionalization of dimeric peptides targetingchemokine receptor CXCR4rdquo Journal of Medicinal Chemistryvol 54 no 21 pp 7648ndash7662 2011
[142] O Demmer E Gourni U Schumacher H Kessler and H-JWester ldquoPET Imaging of CXCR4 Receptors in Cancer by a NewOptimized Ligandrdquo ChemMedChem vol 6 no 10 pp 1789ndash1791 2011
[143] U Hennrich L Seyler M Schafer et al ldquoSynthesis and invitro evaluation of 68Ga-DOTA-4-FBn-TN14003 a novel tracerfor the imaging of CXCR4 expressionrdquo Bioorganic amp MedicinalChemistry vol 20 no 4 pp 1502ndash1510 2012
[144] G P C George E Stevens O Aberg et al ldquoPreclinical evalua-tion of a CXCR4-specific 68Ga-labelled TN14003 derivative forcancer PET imagingrdquo Bioorganic amp Medicinal Chemistry vol22 no 2 pp 796ndash803 2014
[145] S Poty E Gourni P Desogere et al ldquoAMD3100 A VersatilePlatform for CXCR4 Targeting 68Ga-Based Radiopharmaceu-ticalsrdquo Bioconjugate Chemistry vol 27 no 3 pp 752ndash761 2016
[146] K Philipp-Abbrederis K Herrmann S Knop et al ldquoIn vivomolecular imaging of chemokine receptor CXCR4 expressionin patients with advancedmultiple myelomardquo EMBOMolecularMedicine vol 7 no 4 pp 477ndash487 2015
[147] Z Wang M Zhang L Wang et al ldquoProspective study of 68Ga-NOTA-NFB Radiation dosimetry in healthy volunteers andfirst application in glioma patientsrdquo Theranostics vol 5 no 8pp 882ndash889 2015
[148] I M Jackson P J Scott and S Thompson ldquoClinical Applica-tions of Radiolabeled Peptides for PETrdquo Seminars in NuclearMedicine vol 47 no 5 pp 493ndash523 2017
[149] C Lapa T Reiter R A Werner et al ldquo[68Ga]Pentixafor-PETCT for Imaging of Chemokine Receptor 4 Expression afterMyocardial Infarctionrdquo JACC Cardiovascular Imaging vol 8no 12 pp 1466ndash1468 2015
[150] C Rischpler S G Nekolla H Kossmann et al ldquoUpregu-lated myocardial CXCR4-expression after myocardial infarc-tion assessed by simultaneous GA-68 pentixafor PETMRIrdquoJournal of Nuclear Cardiology vol 23 no 1 pp 131ndash133 2016
[151] F Hyafil J Pelisek I Laitinen et al ldquoImaging the CytokineReceptorCXCR4 in atherosclerotic plaqueswith the radiotracer68Ga-Pentixafor for PETrdquo Journal of Nuclear Medicine vol 58no 3 pp 499ndash506 2017
[152] Y Yi ldquoFolate receptor-targeted diagnostics and therapeutics forinflammatory diseasesrdquo ImmuneNetwork vol 16 no 6 pp 337ndash343 2016
[153] C M Paulos M J Turk G J Breur and P S Low ldquoFolatereceptor-mediated targeting of therapeutic and imaging agentsto activated macrophages in rheumatoid arthritisrdquo AdvancedDrug Delivery Reviews vol 56 no 8 pp 1205ndash1217 2004
[154] W Han R Zaynagetdinov F E Yull et al ldquoMolecular imagingof folate receptor 120573-positive macrophages during acute lunginflammationrdquo American Journal of Respiratory Cell and Molec-ular Biology vol 53 no 1 pp 50ndash59 2015
[155] B Kuhle C Muller and T L Ross ldquoA Novel 68Ga-Labeledpteroic acid-based PET tracer for tumor imaging via the folatereceptorrdquo Recent Results in Cancer Research vol 194 pp 257ndash267 2013
[156] C Brand V A Longo M Groaning W A Weber and TReiner ldquoDevelopment of a New Folate-Derived Ga-68-BasedPET Imaging AgentrdquoMolecular Imaging and Biology vol 19 no5 pp 754ndash761 2017
[157] M Fani XWang G Nicolas et al ldquoDevelopment of new folate-based PET radiotracers Preclinical evaluation of 68Ga-DOTA-folate conjugatesrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 38 no 1 pp 108ndash119 2011
[158] C J Mathias M R Lewis D E Reichert et al ldquoPreparationof 66Ga- and 68Ga-labeled Ga(III)-deferoxamine-folate aspotential folate-receptor-targeted PET radiopharmaceuticalsrdquoNuclear Medicine and Biology vol 30 no 7 pp 725ndash731 2003
[159] S-M Kim N Choi S Hwang et al ldquoFolate receptor-specific positron emission tomography imaging with folic acid-conjugated tissue inhibitor of metalloproteinase-2rdquo Bulletin ofthe Korean Chemical Society vol 34 no 11 pp 3243ndash3248 2013
[160] M Fani M-L Tamma G P Nicolas et al ldquoIn vivo imagingof folate receptor positive tumor xenografts using novel 68Ga-NODAGA-folate conjugatesrdquo Molecular Pharmaceutics vol 9no 5 pp 1136ndash1145 2012
[161] C Muller and R Schibli ldquoProspects in folate receptor-targetedradionuclide therapyrdquo Frontiers in Oncology vol 3 Article IDArticle 249 2013
[162] A Jain A Mathur U Pandey et al ldquoSynthesis and evaluationof a 68Ga labeled folic acid derivative for targeting folatereceptorsrdquo Applied Radiation and Isotopes vol 116 pp 77ndash842016
[163] W Xia A R Hilgenbrink E L Matteson M B Lockwood J-X Cheng and P S Low ldquoA functional folate receptor is inducedduring macrophage activation and can be used to target drugsto activated macrophagesrdquo Blood vol 113 no 2 pp 438ndash4462009
Contrast Media amp Molecular Imaging 21
[164] E P Krenning W A P Breeman P P M Kooij et alldquoLocalisation of endocrine-related tumours with radioiodi-nated analogue of somatostatinrdquoThe Lancet vol 1 no 8632 pp242ndash244 1989
[165] E P Krenning D J KwekkeboomWH Bakker et al ldquoSomato-statin receptor scintigraphy with [111In-DTPA-d-Phe1]- and[123I-Tyr3]-octreotide the Rotterdam experience with morethan 1000 patientsrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 20 no 8 pp 716ndash731 1993
[166] A Stahl G Meisetschlager M Schottelius et al ldquo[123I]Mtr-TOCA a radioiodinated and carbohydrated analogue ofoctreotide Scintigraphic comparison with [111In]octreotiderdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 33 no 1 pp 45ndash52 2006
[167] R Lebtahi J le Cloirec C Houzard et al ldquoDetection of neu-roendocrine tumors 99mTc-P829 scintigraphy compared with111In-pentetreotide scintigraphyrdquo Journal of Nuclear Medicinevol 43 no 7 pp 889ndash895 2002
[168] C Decristoforo T Maina B Nock M Gabriel P Cordopatisand R Moncayo ldquo99mTc-demotate 1 First data in tumourpatients - Results of a pilotphase I studyrdquo European Journal ofNuclearMedicine andMolecular Imaging vol 30 no 9 pp 1211ndash1219 2003
[169] C Decristoforo S J Mather W Cholewinski E DonnemillerG Riccabona and R Moncayo ldquo(99m)Tc-EDDAHYNIC-TOC A new (99m)Tc-labelled radiopharmaceutical forimaging somatostatin receptor-positive tumours First clinicalresults and intra-patient comparison with 111In-labelledoctreotide derivativesrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 27 no 9 pp 1318ndash1325 2000
[170] A Hubalewska-Dydejczyk K Fross-Baron R Mikołajczak etal ldquo99mTc-EDDAHYNIC-octreotate scintigraphy an efficientmethod for the detection and staging of carcinoid tumoursResults of 3 yearsrsquo experiencerdquo European Journal of NuclearMedicine and Molecular Imaging vol 33 no 10 pp 1123ndash11332006
[171] M Bangard M Behe S Guhlke et al ldquoDetection of somato-statin receptor-positive tumours using the new 99mC-tricine-HYNIC-D-Phe1-Tyr3-octreotide First results in patients andcomparison with 111In-DTPA-D-Phe1-octreotiderdquo EuropeanJournal of Nuclear Medicine and Molecular Imaging vol 27 no6 pp 628ndash637 2000
[172] A Helisch G J Forster H Reber et al ldquoPre-therapeuticdosimetry and biodistribution of 86Y-DOTA- Phe1-Tyr3-octreotide versus 111In-pentetreotide in patients with advancedneuroendocrine tumoursrdquo European Journal of NuclearMedicine and Molecular Imaging vol 31 no 10 pp 1386ndash13922004
[173] M Henze J Schuhmacher P Hipp et al ldquoPET imaging ofsomatostatin receptors using [68GA]DOTA-D-Phe1-Tyr3-Octreotide First results in patients with meningiomasrdquo Journalof Nuclear Medicine vol 42 no 7 pp 1053ndash1056 2001
[174] I Kayani J B Bomanji A Groves et al ldquoFunctional imaging ofneuroendocrine tumors with combined PETCT using 68Ga-DOTATATE (Dota-DPhe1 Tyr3-octreotate) and 18F-FDGrdquoCancer vol 112 no 11 pp 2447ndash2455 2008
[175] A Al-Nahhas ldquoNuclear medicine imaging of neuroendocrinetumoursrdquo Clinical Medicine vol 12 no 4 pp 377ndash380 2012
[176] V Ambrosini S Nicolini P Caroli et al ldquoPETCT imaging indifferent types of lung cancer an overviewrdquo European Journal ofRadiology vol 81 no 5 pp 988ndash1001 2012
[177] V Ambrosini D Campana P Tomassetti and S Fanti ldquo68Ga-labelled peptides for diagnosis of gastroenteropancreatic NETrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 39 no 1 pp S52ndashS60 2012
[178] K E Oberg J-C Reubi D J Kwekkeboom and E P KrenningldquoRole of somatostatins in gastroenteropancreatic neuroen-docrine tumor development and therapyrdquoGastroenterology vol139 no 3 pp 753-753 2010
[179] K Oberg ldquoGallium-68 somatostatin receptor PETCT Is ittime to replace 111Indium DTPA octreotide for patients withneuroendocrine tumorsrdquo Endocrine Journal vol 42 no 1 pp3-4 2012
[180] R Srirajaskanthan I Kayani A M Quigley J Soh M ECaplin and J Bomanji ldquoThe role of 68Ga-DOTATATE PET inpatients with neuroendocrine tumors and negative or equivocalfindings on 111In-DTPA-octreotide scintigraphyrdquo Journal ofNuclear Medicine vol 51 no 6 pp 875ndash882 2010
[181] A Kroiss D Putzer and C Uprimny ldquoFunctional imag-ing in phaeochromocytoma and neuroblastoma with 68Ga-DOTA-Tyr3-octreotide positron emission tomography and123I-metaiodobenzylguanidinerdquo European Journal of NuclearMedicine and Molecular Imaging vol 38 no 5 pp 865ndash8732011
[182] M Naji C Zhao S J Welsh et al ldquo68Ga-DOTA-TATE PETvs 123I-MIBG in identifying malignant neural crest tumoursrdquoMolecular Imaging and Biology vol 13 no 4 pp 769ndash775 2011
[183] V Ambrosini P Tomassetti P Castellucci et al ldquoComparisonbetween 68Ga-DOTA-NOC and 18F-DOPA PET for the detec-tion of gastro-entero-pancreatic and lung neuro-endocrinetumoursrdquo European Journal of Nuclear Medicine and MolecularImaging vol 35 no 8 pp 1431ndash1438 2008
[184] D Putzer M Gabriel B Henninger et al ldquoBone metastasesin patients with neuroendocrine tumor 68Ga- DOTA-Tyr3-octreotide PET in comparison to CT and bone scintigraphyrdquoJournal of Nuclear Medicine vol 50 no 8 pp 1214ndash1221 2009
[185] L K Anzola-Fuentes M Chianelli F Galli et al ldquoSomatostatinreceptor scintigraphy in patients with rheumatoid arthritis andsecondary Sjogrenrsquos syndrome treated with Infliximab a pilotstudyrdquo EJNMMI Research vol 6 no 1 article no 49 2016
[186] T Nobashi Y Nakamoto T Kubo et al ldquoThe utility of PETCTwith 68Ga-DOTATOC in sarcoidosis comparison with 67Ga-scintigraphyrdquoAnnals ofNuclearMedicine vol 30 no 8 pp 544ndash552 2016
[187] C Boy T A Heusner T D Poeppel et al ldquo68Ga-DOTATOCPETCT and somatostatin receptor (sst1-sst5) expression innormal human tissue Correlation of sst2mRNAand SUVmaxrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 38 no 7 pp 1224ndash1236 2011
[188] P Rinne S Hellberg M Kiugel et al ldquoComparison of Somato-statin Receptor 2-Targeting PET Tracers in the Detection ofMouse Atherosclerotic Plaquesrdquo Molecular Imaging and Biol-ogy vol 18 no 1 pp 99ndash108 2016
[189] M Asti E Ferrari S Croci et al ldquoSynthesis and characteri-zation of 68Ga-labeled curcumin and curcuminoid complexesas potential radiotracers for imaging of cancer and alzheimersdiseaserdquo Inorganic Chemistry vol 53 no 10 pp 4922ndash49332014
[190] A Signore I Santino and A W J M Glaudemans ldquoIn vivoimaging of microorganismsrdquo Clinical and Translational Imag-ing vol 4 no 3 pp 161-162 2016
[191] S Auletta F Galli C Lauri D Martinelli I Santino andA Signore ldquoImaging bacteria with radiolabelled quinolones
22 Contrast Media amp Molecular Imaging
cephalosporins and siderophores for imaging infection a sys-tematic reviewrdquo Clinical and Translational Imaging vol 4 no 4pp 229ndash252 2016
[192] X Ning S Lee Z Wang et al ldquoMaltodextrin-based imagingprobes detect bacteria in vivo with high sensitivity and speci-ficityrdquo Nature Materials vol 10 no 8 pp 602ndash607 2011
[193] J Ady andY Fong ldquoImaging for infection Fromvisualization ofinflammation to visualization of microbesrdquo Surgical Infectionsvol 15 no 6 pp 700ndash707 2014
[194] J M Sierra D Rodriguez-Puig A Soriano J Mensa C Pieraand J Vila ldquoAccumulation of 99mTc-ciprofloxacin in Staphy-lococcus aureus and Pseudomonas aeruginosardquo AntimicrobialAgents and Chemotherapy vol 52 no 7 pp 2691-2692 2008
[195] D I Andersson and D Hughes ldquoMicrobiological effects ofsublethal levels of antibioticsrdquoNature ReviewsMicrobiology vol12 no 7 pp 465ndash478 2014
[196] N Dumarey D Blocklet T Appelboom L Tant and ASchoutens ldquoInfecton is not specific for bacterial osteo-articularinfective pathologyrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 29 no 4 pp 530ndash535 2002
[197] K E Britton D W Wareham S S Das et al ldquoImaging bacte-rial infection with 99mTc-ciprofloxacin (Infecton)rdquo Journal ofClinical Pathology vol 55 no 11 pp 817ndash823 2002
[198] G Ferro-Flores M A Avila-Rodrıguez and F O Garcıa-PerezldquoImaging of bacteria with radiolabeled ubiquicidin by SPECTand PET techniquesrdquo Clinical and Translational Imaging vol 4no 3 pp 175ndash182 2016
[199] P S Hiemstra M T van den Barselaar M Roest P H Nibber-ing and R van Furth ldquoUbiquicidin a novel murine microbi-cidal protein present in the cytosolic fraction of macrophagesrdquoJournal of Leukocyte Biology vol 66 no 3 pp 423ndash428 1999
[200] M S Akhtar A Qaisar J Irfanullah et al ldquoAntimicrobialpeptide 99mTc-ubiquicidin 29ndash41 as human infection-imagingagent clinical trialrdquo Journal of Nuclear Medicne vol 46 no 4pp 567ndash573 2005
[201] M Assadi K Vahdat I Nabipour et al ldquoDiagnostic value of99mTc-ubiquicidin scintigraphy for osteomyelitis and compar-isons with 99mTc-methylene diphosphonate scintigraphy andmagnetic resonance imagingrdquo Nuclear Medicine Communica-tions vol 32 no 8 pp 716ndash723 2011
[202] T Emery ldquoExchange of Iron by Gallium in SiderophoresrdquoBiochemistry vol 25 no 16 pp 4629ndash4633 1986
[203] M Petrik C Zhai H Haas and C Decristoforo ldquoSiderophoresfor molecular imaging applicationsrdquo Clinical and TranslationalImaging vol 5 no 1 pp 15ndash27 2017
[204] H J Flint E A BayerM T Rincon R Lamed and B AWhiteldquoPolysaccharide utilization by gut bacteria potential for newinsights from genomic analysisrdquo Nature Reviews Microbiologyvol 6 no 2 pp 121ndash131 2008
[205] GGowrishankarMNamavari E B Jouannot et al ldquoInvestiga-tion of 6-[18F]-fluoromaltose as a novel PET tracer for imagingbacterial infectionrdquo PLoS ONE vol 9 no 9 Article ID e1079512014
[206] N Gholipour M Akhlaghi A M Kheirabadi et al ldquoChelator-free radiolabeling of dextran with 68Ga for PET studiesrdquoJournal of Radioanalytical and Nuclear Chemistry vol 311 no3 pp 1811ndash1817 2017
[207] C Bettegowda C A Foss I Cheong et al ldquoImaging bac-terial infections with radiolabeled 1-(21015840-deoxy-21015840- fluoro-120573-D-arabinofuranosyl)-5-iodouracilrdquo Proceedings of the NationalAcadamy of Sciences of the United States of America vol 102 no4 pp 1145ndash1150 2005
[208] S A Soghomonyan M Doubrovin J Pike et al ldquoPositronemission tomography (PET) imaging of tumor-localizedSalmonella expressing HSV1-TKrdquo Cancer GeneTherapy vol 12no 1 pp 101ndash108 2005
[209] C Palestro K Nichols S Sheikh-Fayyaz S Dewey P Singhaland K Bhargava ldquoCan Gallium-68 PET differentiate acuteinterstitial nephritis from acute tubular necrosisrdquo Journal ofNuclear Medicne vol 57 Supplement 2 p 551 2016
[210] A J Morguet D L Munz V Ivancevic et al ldquoImmunoscintig-raphy using technetium-99m-labeled anti-NCA-95 antigranu-locyte antibodies as an adjunct to echocardiography in subacuteinfective endocarditisrdquo Journal of the American College ofCardiology vol 23 no 5 pp 1171ndash1178 1994
[211] C van der Laken O Boerman W Oyen et al ldquoIn Vivo Expres-sion of Interleukin-1 Receptors during Various ExperimentallyInduced Inflammatory Conditionsrdquo The Journal of InfectiousDiseases vol 177 no 5 pp 1398ndash1401 1998
[212] C J Van Der Laken O C Boerman W J G Oyen M T PVan De Ven J W M Van Der Meer and F H M CorstensldquoScintigraphic detection of infection and inflammation Newdevelopments with special emphasis on receptor interactionrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 25 no 5 pp 535ndash546 1998
[213] C J van der LakenOC BoermanW J GOyenM T P van deVen J W M van der Meer and F H M Corstens ldquoImaging ofinfection in rabbits with radioiodinated interleukin-1 (120572 and 120573)its receptor antagonist and a chemotactic peptide a comparativestudyrdquo European Journal of Nuclear Medicine and MolecularImaging vol 25 no 4 pp 347ndash352 1998
[214] C J Van Der Laken O C BoermanW J G Oyen M T P VanDe Ven F H M Corstens and J W M Ven Der Meer ldquoThekinetics of radiolabelled interleukin-8 in infection and sterileinflammationrdquo Nuclear Medicine Communications vol 19 no3 pp 271ndash282 1998
[215] E Lazzeri P Erba M Perri et al ldquoScintigraphic imaging ofvertebral osteomyelitis with 111in-biotinrdquoThe Spine Journal vol33 no 7 pp E198ndashE204 2008
[216] E Blom B Langstrom and I Velikyan ldquo68Ga-labeling of biotinanalogues and their characterizationrdquo Bioconjugate Chemistryvol 20 no 6 pp 1146ndash1151 2009
[217] O Eriksson F Carlsson E Blom et al ldquoPreclinical evaluationof a 68Ga-labeled biotin analogue for applications in islettransplantationrdquo Nuclear Medicine and Biology vol 39 no 3pp 415ndash421 2012
[218] E A Weinstein A A Ordonez V P DeMarco et alldquoImaging Enterobacteriaceae infection in vivo with 18F-fluoro-deoxysorbitol positron emission tomographyrdquo Science Transla-tional Medicine vol 6 no 259 p 259ra146 2014
[219] K M Nielsen M H Kyneb A K O Alstrup et alldquo68Ga-labeled phage-display selected peptides as tracers forpositron emission tomography imaging of Staphylococcusaureus biofilm-associated infections Selection radiolabellingand preliminary biological evaluationrdquo Nuclear Medicine andBiology vol 43 no 10 pp 593ndash605 2016
[220] T J Makinen P Lankinen T Poyhonen J Jalava H T Aroand A Roivainen ldquoComparison of 18F-FDG and 68Ga PETimaging in the assessment of experimental osteomyelitis due toStaphylococcus aureusrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 32 no 11 pp 1259ndash1268 2005
[221] JMU Silvola I LaitinenH J Sipila et al ldquoUptake of 68galliumin atherosclerotic plaques in LDLRminusminusApoB100100micerdquo EJN-MMI Research vol 1 no 1 pp 1ndash8 2011
Contrast Media amp Molecular Imaging 23
[222] T A Wynn ldquoCellular and molecular mechanisms of fibrosisrdquoThe Journal of Pathology vol 214 no 2 pp 199ndash210 2008
[223] T Derlin D Jonigk J Bauersachs and FM Bengel ldquoMolecularImaging of Chemokine Receptor CXCR4 in NonndashSmall CellLung Cancer Using 68Ga-Pentixafor PETCT ComparisonWith 18F-FDGrdquo Clinical Nuclear Medicine 2016
[224] I Velikyan U Rosenstrom T N Bulenga O Eriksson andG Antoni ldquoFeasibility of multiple examinations using68ga-labelled collagelin analogues Organ distribution in rat forextrapolation to human organ and whole-body radiationdosimetryrdquo Pharmaceuticals vol 9 no 2 article no 31 2016
[225] S Jadhav M Kakela J Makila et al ldquoSynthesis and in VivoPET Imaging of Hyaluronan Conjugates of OligonucleotidesrdquoBioconjugate Chemistry vol 27 no 2 pp 391ndash403 2016
[226] A Autio A Saraste N Kudomi et al ldquoAssessment of bloodflow with (68) Ga-DOTA PET in experimental inflammation avalidation study using (15) O-waterrdquo American Journal ofNuclear Medicine and Molecular Imaging vol 4 no 6 pp 571ndash579 2014
[227] G Davies A Rolle A Maurer et al ldquoTowards translationalimmunoPETMR imaging of invasive pulmonary aspergillosisthe Humanised Monoclonal Antibody JF5 detects in vivordquoTheranostics vol 7 no 14 pp 3398ndash3414 2017
[228] DGoodwin CMeares GDavid et al ldquoMonoclonal antibodiesas reversible equilibrium carriers of radiopharmaceuticalsrdquoInternational Journal of Radiation Applications and Instrumen-tation Part B Nuclear Medicine and Biology vol 13 no 4 pp383ndash391 1986
[229] D A Goodwin C F Mears M McTigue and G S DavidldquoMonoclonal antibody hapten radiopharmaceutical deliveryrdquoNuclear Medicine Communications vol 7 no 8 pp 569ndash5801986
[230] S E Halpern and R O Dillman ldquoProblems associated withradioimmunodetection and possibilities for future solutionsrdquo JBiol Response Mod vol 6 no 3 pp 235ndash262 1987
[231] H Hong J Sun and W Cai ldquoRadionuclide-based cancerimaging targeting the carcinoembryonic antigenrdquo BiomarkerInsights vol 3 pp 435ndash451 2008
[232] G J Forster E B Santos P M Smith-Jones P Zanzonico andS M Larson ldquoPretargeted radioimmunotherapy with a single-chain antibodystreptavidin construct and radiolabeledDOTA-biotin Strategies for reduction of the renal doserdquo Journal ofNuclear Medicine vol 47 no 1 pp 140ndash149 2006
[233] Z Yao M Zhang H Kobayashi et al ldquoImproved targeting ofradiolabeled streptavidin in tumors pretargeted with biotiny-lated monoclonal antibodies through an avidin chaserdquo Journalof Nuclear Medicine vol 36 no 5 pp 837ndash841 1995
[234] C-H Chang R M Sharkey E A Rossi et al ldquoMolecularAdvances in Pretargeting Radioimunotherapy with BispecificAntibodies 1 Supported in part by USPHS Grant R01-CA-84379from the NIH and Department of Energy Grant DE-FG01-00NE22941 (both to R M S)1rdquo Mol Cancer Ther vol 1 no 7pp 553ndash563 2002
[235] R M Sharkey E A Rossi W J McBride C-H Chang andD M Goldenberg ldquoRecombinant Bispecific Monoclonal Anti-bodies Prepared by theDock-and-Lock Strategy for PretargetedRadioimmunotherapyrdquo Seminars in Nuclear Medicine vol 40no 3 pp 190ndash203 2010
[236] R M Sharkey E A Rossi C-H Chang and D M Golden-berg ldquoImproved cancer therapy and molecular imaging withmultivalent multispecific antibodiesrdquo Cancer Biotherapy andRadiopharmaceuticals vol 25 no 1 pp 1ndash12 2010
[237] D M Goldenberg R M Sharkey G Paganelli J Barbet andJ Chatal ldquoAntibody pretargeting advances cancer radioim-munodetection and radioimmunotherapyrdquo Journal of ClinicalOncology vol 24 no 5 pp 823ndash834 2006
[238] O C Boerman F G van Schaijk W J G Oyen and FH M Corstens ldquoPretargeted radioimmunotherapy of cancerprogress step by steprdquo Journal of Nuclear Medicine vol 44 no3 pp 400ndash411 2003
[239] J Schuhmacher S Kaul G Klivenyi et al ldquoImmunoscintigra-phy with positron emission tomography Gallium-68 chelateimaging of breast cancer pretargeted with bispecific anti-MUC1anti-Ga chelate antibodiesrdquo Cancer Research vol 61 no9 pp 3712ndash3717 2001
[240] J Schuhmacher G Klivenyi S Kaul et al ldquoPretargeting ofhuman mammary carcinoma xenografts with bispecific anti-MUC1anti-Ga chelate antibodies and immunoscintigraphywith PETrdquo Nuclear Medicine and Biology vol 28 no 7 pp 821ndash828 2001
[241] C Somasundaram S Matzku J Schuhmacher and M ZollerldquoDevelopment of a bispecific monoclonal antibody against agallium-67 chelate and the human melanoma-associated anti-gen p97 for potential use in pretargeted immunoscintigraphyrdquoCancer Immunology Immunotherapy vol 36 no 5 pp 337ndash3451993
[242] E A Rossi D L Rossi R Stein D M Goldenberg and C-H Chang ldquoA bispecific antibody-IFN1205722b immunocytokine tar-geting CD20 and HLA-DR is highly toxic to human lymphomaandmultiplemyeloma cellsrdquoCancer Research vol 70 no 19 pp7600ndash7609 2010
[243] R M Sharkey H Karacay S Litwin et al ldquoImproved ther-apeutic results by pretargeted radioimmunotherapy of non-Hodgkinrsquos lymphoma with a new recombinant trivalent anti-CD20 bispecific antibodyrdquo Cancer Research vol 68 no 13 pp5282ndash5290 2008
[244] G L Griffiths C-H Chang W J McBride et al ldquoReagentsandmethods for PETusing bispecific antibody pretargeting and68Ga-radiolabeled bivalent hapten-peptide-chelate conjugatesrdquoJournal of Nuclear Medicine vol 45 no 1 pp 30ndash39 2004
[245] J Watine M Miedouge and B Friedberg ldquoCarcinoembryonicantigen as an independent prognostic factor of recurrence andsurvival in patients resected for colorectal liver metastases Asystematic reviewrdquo Diseases of the Colon amp Rectum vol 44 no12 pp 1791ndash1799 2001
[246] M J Goldstein and E P Mitchell ldquoCarcinoembryonic antigenin the staging and follow-up of patients with colorectal cancerrdquoCancer Investigation vol 23 no 4 pp 338ndash351 2005
[247] D V Gold D M Goldenberg H Karacay et al ldquoA novelbispecific trivalent antibody construct for targeting pancreaticcarcinomardquo Cancer Research vol 68 no 12 pp 4819ndash48262008
[248] J Schuhmacher G Klivenyi R Matys et al ldquoMultistep tumortargeting in nudemice using bispecific antibodies and a galliumchelate suitable for immunoscintigraphy with positron emis-sion tomographyrdquo Cancer Research vol 55 no 1 pp 115ndash1231995
[249] G Klivenyi J Schuhmacher E Patzelt et al ldquoGallium-68chelate imaging of human colon carcinoma xenografts pre-targeted with bispecific anti-CD44(V6)anti-gallium chelateantibodiesrdquo Journal ofNuclearMedicine vol 39 no 10 pp 1769ndash1776 1998
[250] M Zoller J Schuhmacher J Reed W Maier-Borst and SMatzku ldquoEstablishment and characterization of monoclonal
24 Contrast Media amp Molecular Imaging
antibodies against an octahedral gallium chelate suitable forimmunoscintigraphy with PETrdquo Journal of Nuclear Medicinevol 33 no 7 pp 1366ndash1372 1992
[251] R M Sharkey T M Cardillo E A Rossi et al ldquoSignal ampli-fication in molecular imaging by pretargeting a multivalentbispecific antibodyrdquo Nature Medicine vol 11 no 11 pp 1250ndash1255 2005
[252] D M Goldenberg and R M Sharkey ldquoNovel radiolabeledantibody conjugatesrdquo Oncogene vol 26 no 25 pp 3734ndash37442007
[253] D M Goldenberg E A Rossi R M Sharkey W J McBrideand C-H Chang ldquoMultifunctional antibodies by the dock-and-lock method for improved cancer imaging and therapy bypretargetingrdquo Journal of NuclearMedicine vol 49 no 1 pp 158ndash163 2008
[254] R Schoffelen R M Sharkey D M Goldenberg et al ldquoPre-targeted immuno-positron emission tomography imaging ofcarcinoembryonic antigen-expressing tumors with a bispecificantibody and a68Ga- And18F-labeled hapten peptide in micewith human tumor xenograftsrdquoMolecular Cancer Therapeuticsvol 9 no 4 pp 1019ndash1027 2010
[255] E S Bos W H Kuijpers M Meesters-Winters et al ldquoIn vitroevaluation of DNA-DNA hybridization as a two-step approachin radioimmunotherapy of cancerrdquoCancer Research vol 54 no13 pp 3479ndash3486 1994
[256] G Paganelli M Bartolomei M Ferrari et al ldquoPre-TargetedLocoregional Radioimmunotherapy withrdquo Cancer biotherapyand radiopharmaceuticals vol 16 no 3 pp 227ndash235 2001
[257] A Forero P L Weiden J M Vose et al ldquoPhase 1 trial of a novelanti-CD20 fusion protein in pretargeted radioimmunotherapyfor B-cell non-Hodgkin lymphomardquo Blood vol 104 no 1 pp227ndash236 2004
[258] DM Goldenberg C-H Chang E A RossiW J McBride andR M Sharkey ldquoPretargeted molecular imaging and radioim-munotherapyrdquoTheranostics vol 2 no 5 pp 523ndash540 2012
[259] H Karacay R M Sharkey W J McBride E A Rossi C-HChang and D M Goldenberg ldquoOptimization of hapten-peptide labeling for pretargeted immunoPET of bispecificantibody using generator-produced 68Gardquo Journal of NuclearMedicine vol 52 no 4 pp 555ndash559 2011
[260] J R Oh and B C Ahn ldquoFalse-positive uptake on radioiodinewhole-body scintigraphy physiologic and pathologic variantsunrelated to thyroid cancerrdquo American Journal of NuclearMedicine and Molecular Imaging vol 2 no 2 pp 141ndash150 2012
[261] E Frampas C Rousseau C Bodet-Milin J Barbet J-F Chataland F Kraeber-Bodere ldquoImprovement of radioimmunotherapyusing pretargetingrdquo Frontiers in Oncology vol 3 Article ID00159 2013
[262] C S McKay and M G Finn ldquoClick chemistry in complexmixtures Bioorthogonal bioconjugationrdquo Chemistry amp Biologyvol 21 no 9 pp 1075ndash1101 2014
[263] B L Oliveira Z Guo and G J Bernardes ldquoInverse electrondemand DielsndashAlder reactions in chemical biologyrdquo ChemicalSociety Reviews vol 46 no 16 pp 4895ndash4950 2017
[264] B Nichols Z Qin J Yang D R Vera and N K Devaraj ldquo68Gachelating bioorthogonal tetrazine polymers for the multisteplabeling of cancer biomarkersrdquo Chemical Communications vol50 no 40 pp 5215ndash5217 2014
[265] R Rossin P R Verkerk S M van den Bosch et al ldquoInvivo chemistry for pretargeted tumor imaging in live micerdquoAngewandte Chemie International Edition vol 49 no 19 pp3375ndash3378 2010
[266] B M Zeglis K K Sevak T Reiner et al ldquoA pretargetedPET imaging strategy based on bioorthogonal diels-alder clickchemistryrdquo Journal of Nuclear Medicine vol 54 no 8 pp 1389ndash1396 2013
[267] J L Houghton R Membreno D Abdel-Atti et al ldquoEstablish-ment of the invivo efficacy of pretargeted radioimmunotherapyutilizing inverse electron demand diels-alder click chemistryrdquoMolecular Cancer Therapeutics vol 16 no 1 pp 124ndash133 2017
[268] J Funkhouser ldquoReinventing pharma the theranostic revolu-tionrdquo Current Drug Discovery pp 17ndash19 2002
[269] J Sorensen I Velikyan A Wennborg et al ldquoMeasuring HER2-expression in metastatic breast cancer using 68Ga-ABY025PETCTrdquo European Journal of Nuclear Medicine and MolecularImaging vol 41 pp S226ndashS226 2014
[270] I Velikyan A Wennborg J Feldwisch et al ldquoGMP compliantpreparation of a 68Gallium-labeled Affibody analogue forbreast cancer patient examination first-in-manrdquoEur JNuclMedMol Imaging vol 41 pp S228ndashS229 2014
[271] K Oberg ldquoMolecular imaging radiotherapy Theranostics forpersonalized patient management of neuroendocrine tumors(NETs)rdquoTheranostics vol 2 no 5 pp 448ndash458 2012
[272] I Velikyan AWennborg J FeldwischH Lindman J Carlssonand J Sorensen ldquoGood manufacturing practice production of [(68) Ga]Ga-ABY-025 for HER2 specific breast cancer imagingrdquoAmerican Journal of Nuclear Medicine and Molecular Imagingvol 6 no 2 pp 135ndash153 2016
[273] M Sandstrom K Lindskog I Velikyan et al ldquoBiodistributionand radiation dosimetry of the anti-HER2 Affibody molecule68Ga-ABY-025 in breast cancer patientsrdquo Journal of NuclearMedicine vol 57 no 6 pp 867ndash871 2016
[274] D Sandberg V Tolmachev I Velikyan et al ldquoIntra-imagereferencing for simplified assessment of HER2-expression inbreast cancer metastases using the Affibody molecule ABY-025with PET and SPECTrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 44 no 8 pp 1337ndash1346 2017
[275] H ZhangM AMoroz I Serganova et al ldquoImaging expressionof the human somatostatin receptor subtype-2 reporter genewith 68Ga-DOTATOCrdquo Journal ofNuclearMedicine vol 52 no1 pp 123ndash131 2011
[276] M Naji and A Al-Nahhas ldquo68Ga-labelled peptides in themanagement of neuroectodermal tumoursrdquo European Journalof Nuclear Medicine and Molecular Imaging vol 39 no 1 ppS61ndashS67 2012
[277] I Velikyan ldquoThe diversity of 68Ga-Based imaging agentsrdquoRecent Results in Cancer Research vol 194 pp 101ndash131 2013
[278] K Ferreira H-Y Hu V Fetz et al ldquoMultivalent siderophore-dotam conjugates as theranostics for imaging and treatment ofbacterial infectionsrdquo Angewandte Chemie International Editionvol 56 no 28 pp 8272ndash8276 2017
Computational and Mathematical Methods in Medicine
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14 Contrast Media amp Molecular Imaging
H
ON
NN
O
OO
OO
NH
NS
NH
ONH
O
HO
ONH
O
Ga
HN
NH
NH
O
OO
HNN
HN
NH
NH
O
OO
HNN
（2
(a)
NH
O
O
NH
N
NNGa
O O
O O
O
O
O
N N
NN
OO
（2
(b)
N
N
O
O
N
N
O
O
O
NH
O
O
ONH
NHS
O
H
HO
NH
+
minus
(c)
Figure 8 Schematic presentation of pretargeting techniques (a) bispecific antibodies engineered to specifically bind with radiolabelledhapten molecules (b) bioorthogonal click chemistry for fast and specific covalent binding between for example a trans-cyclooctenefunctionalized antibody and a radiolabelled tetrazine (c) interaction between antibody-(strept)avidin conjugate and radiolabelled biotinutilizing extremely high affinity of (strept)avidin and biotin
Contrast Media amp Molecular Imaging 15
a considerable number of potential antibody biomarkersthat could be considered for the imaging of infection andinflammation
10 Theranostics Potential
Theranostics [268] embraces realization of personalizedmedicine by conducting diagnosis on individual basis andproviding possibility of predicting the efficacy of a specifictreatment and following up the response to the treatmentenabling adjustment of the latter very early in the processIn the context of nuclear medicine wherein the radiophar-maceuticals targeted at biomarkers specific to a disease cancarry either diagnostic radionuclides or therapeutic ones theconcept can be denoted as radiotheranostics [28] The tar-geted molecular imaging such as PET can offer noninvasivediagnosis specific to the disease for example tumour-typespecific and provide accurate localization of the lesions Thestrongest advantage of PET is the potential for quantificationof the target for example receptor expression investigationof the uptake kinetics and estimation of the dosimetryThesecharacteristics of PET allow for individualized treatmentselection and planning monitoring of treatment responseand detection of recurrent diseaseThe individualized patientmanagement provides such advantages as optimization ofthe treatment regimen for the improved response and exclu-sion of futile treatments minimization of risks and toxicitywith overall outcome of reduced cost and patient distressThe importance of individualized patient management wasdemonstrated by clinical studies wherein the influence ofdose of the administered radiopharmaceutical targeted atreceptors overexpressed in cancer lesions on the diagnosticoutcome was investigated in the same patient [85 269270] 68Ga-labelled SST analogues [26ndash28 271] and Affibodymolecules [5 272ndash274] used respectively in NENs andbreast cancer patients are the most prominent examplesof (radio)theranostics involving 68GaPET wherein 68Ga-labelled analogues were used not only for localization of thelesions but also for staging patient stratification prognosistherapy selection and monitoring of the response to thetreatment of NETs and other cancer types [2ndash4 6 85 176275ndash277]
The methodology can be translated to inflammationand infection allowing for accurate and specific selection oftreatment regimen and for follow-up and evaluation of theresponse to therapy resulting in improved treatment efficacyand decreased cost and side effects The accommodation ofboth imaging function and antibiotic function in the samemolecule is a novel example of a theranostic agent [278]A series of siderophores conjugated with DOTA moiety forthe radiolabelling and with antibiotics for the treatmentof bacterial infection were investigated preclinically Theaccumulation of the intravenously administered ampicillinconjugate in the site of subcutaneously injected P aeruginosain mice was clearly and focally visualized within 06 h withretention for at least 24 h These results obtained usinganalogues carrying dye for optical imaging can be translatedto 68Ga-labelled counterparts for PET
11 Conclusions
The medical need for specific agents for noninvasive quan-titative and whole-body imaging of inflammation and infec-tion has not been met yet despite decades of research How-ever the prerequisites in terms of identification of potentialtargets design and synthesis of the respective ligands andimaging technologies are evolving very fast The potentialof accurate and quantitative lesion localization as well asmonitoring of the treatment response promises personalizedpatient management
The use of 68Ga in oncology is established proving thestrong potential of 68Ga for the promotion of PET technol-ogy for effective and efficient diagnostics and personalizedmedicineThe experience of oncological 68Ga-based agents isgetting translated to inflammation and infection Pretargetedimaging technology opens wide possibilities based on anti-body biomarkers
Conflicts of Interest
The author declares that there are no conflicts of interestregarding the publication of this article
References
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[2] I Velikyan ldquo 68Ga-based radiopharmaceuticals Production andapplication relationshiprdquo Molecules vol 20 no 7 pp 12913ndash12943 2015
[3] M Fani P Peitl and I Velikyan ldquoCurrent status of radiophar-maceuticals for the theranostics of neuroendocrine neoplasmsrdquoPharmaceuticals vol 10 no 1 article no 30 2017
[4] I Velikyan ldquoPositron emitting [68Ga]Ga-based imaging agentsChemistry and diversityrdquoMedicinal Chemistry vol 7 no 5 pp345ndash379 2011
[5] J Sorensen I Velikyan D Sandberg et al ldquoMeasuringHER2-receptor expression in metastatic breast cancer using[68Ga]ABY-025 Affibody PETCTrdquo Theranostics vol 6 no 2pp 262ndash271 2016
[6] I Velikyan ldquoProspective of 68Ga-Radiopharmaceutical devel-opmentrdquoTheranostics vol 4 no 1 pp 47ndash80 2014
[7] P Lankinen T J Makinen T A Poyhonen et al ldquo68Ga-DOTAVAP-P1 PET imaging capable of demonstrating the phaseof inflammation in healing bones and the progress of infectionin osteomyelitic bonesrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 35 no 2 pp 352ndash364 2008
[8] T UjulaMHuttunen P Luoto et al ldquoMatrixmetalloproteinase9 targeting peptides Syntheses 68Ga-labeling and preliminaryevaluation in a rat melanoma xenograft modelrdquo BioconjugateChemistry vol 21 no 9 pp 1612ndash1621 2010
[9] A Autio T Ujula P Luoto S Salomaki S Jalkanen and ARoivainen ldquoPET imaging of inflammation and adenocarcinomaxenografts using vascular adhesion protein 1 targeting peptide68Ga-DOTAVAP-P1 Comparison with 18F-FDGrdquo EuropeanJournal of Nuclear Medicine and Molecular Imaging vol 37 no10 pp 1918ndash1925 2010
16 Contrast Media amp Molecular Imaging
[10] J Silvola A Autio P Luoto S Jalkanen andA Roivainen ldquoPre-liminary evaluation of novel 68Ga-DOTAVAP-PEG-P2 peptidetargeting vascular adhesion protein-1rdquo Clinical Physiology andFunctional Imaging vol 30 no 1 pp 75ndash78 2010
[11] T Ujula S Salomaki P Virsu et al ldquoSynthesis 68Ga labelingand preliminary evaluation of DOTA peptide binding vascularadhesion protein-1 a potential PET imaging agent for diagnos-ing osteomyelitisrdquo Nuclear Medicine and Biology vol 36 no 6pp 631ndash641 2009
[12] A Autio T Henttinen H J Sipila S Jalkanen and ARoivainen ldquoMini-PEG spacering of VAP-1-targeting 68Ga-DOTAVAP-P1 peptide improves PET imaging of inflamma-tionrdquo EJNMMI Research vol 1 no 1 pp 1ndash7 2011
[13] K Aalto A Autio E A Kiss et al ldquoSiglec-9 is a novel leukocyteligand for vascular adhesion protein-1 and can be used in PETimaging of inflammation and cancerrdquo Blood vol 118 no 13 pp3725ndash3733 2011
[14] V Kumar D K Boddeti S G Evans F Roesch and RHowman-Giles ldquoPotential use of 68Ga-apo-transferrin as a PETimaging agent for detecting Staphylococcus aureus infectionrdquoNuclear Medicine and Biology vol 38 no 3 pp 393ndash398 2011
[15] M Petrik H Haas G Dobrozemsky et al ldquo68Ga-siderophoresfor PET imaging of invasive pulmonary aspergillosis Proof ofprinciplerdquo Journal of Nuclear Medicine vol 51 no 4 pp 639ndash645 2010
[16] M Petrik H Haas M Schrettl A Helbok M Blatzer and CDecristoforo ldquoIn vitro and in vivo evaluation of selected 68Ga-siderophores for infection imagingrdquo Nuclear Medicine andBiology vol 39 no 3 pp 361ndash369 2012
[17] M Petrik GM Franssen H Haas et al ldquoPreclinical evaluationof two 68Ga-siderophores as potential radiopharmaceuticals forAspergillus fumigatus infection imagingrdquo European Journal ofNuclearMedicine andMolecular Imaging vol 39 no 7 pp 1175ndash1183 2012
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Contrast Media amp Molecular Imaging 17
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[50] M Kiugel I Dijkgraaf V Kyto et al ldquoDimeric [68Ga]DOTA-RGD Peptide Targeting 120572 ltinfgtvltinfgt 120573 ltinfgt3ltinfgt Inte-grin Reveals Extracellular Matrix Alterations after MyocardialInfarctionrdquo Molecular Imaging and Biology vol 16 no 6 pp793ndash801 2014
[51] M Gronman M Tarkia T Kiviniemi et al ldquoImaging of 120572v1205733integrin expression in experimental myocardial ischemia with[68Ga]NODAGA-RGD positron emission tomographyrdquo Jour-nal of Translational Medicine vol 15 no 1 p 144 2017
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18 Contrast Media amp Molecular Imaging
[72] T Ebenhan J R Zeevaart and J D Venter ldquoPreclinicalevaluation of 68Ga-labeled 1 4 7-triazacyclononane-1 4 7-triacetic acid-ubiquicidin as a radioligand for PET infectionimagingrdquo Journal of Nuclear Medicine vol 55 no 2 pp 308ndash314 2014
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[75] S Chopra B Singh A Koul A Mishra and H Wester ldquoSyn-thesis of DOTA conjugated GF-17 and RAWVAWR-NH2 andradiolabeling with 68Ga as a potential PET tracer for infectionimagingrdquo J Nucl Med vol 57 Supplement 2 p 1115 2016
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[88] B P Burke G S Clemente and S J Archibald ldquoRecentadvances in chelator design and labelling methodology for68Ga radiopharmaceuticalsrdquo Journal of Labelled Compoundsand Radiopharmaceuticals vol 57 no 4 pp 239ndash243 2014
[89] I Velikyan U Rosenstrom S Estrada et al ldquoSynthesis andpreclinical evaluation of 68Ga-labeled collagelin analogs forimaging and quantification of fibrosisrdquo Nuclear Medicine andBiology vol 41 no 9 pp 728ndash736 2014
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[91] J Notni J Simecek and H-J Wester ldquoPhosphinic acid func-tionalized polyazacycloalkane chelators for radiodiagnosticsand radiotherapeutics Unique characteristics and applicationsrdquoChemMedChem vol 9 no 6 pp 1107ndash1115 2014
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[94] B P Waldron D Parker C Burchardt D S Yufit M ZimnyandF Roesch ldquoStructure and stability of hexadentate complexesof ligands based on AAZTA for efficient PET labelling withgallium-68rdquo Chemical Communications vol 49 no 6 pp 579ndash581 2013
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[96] I Velikyan H Maecke and B Langstrom ldquoConvenient prepa-ration of 68Ga-based PET-radiopharmaceuticals at room tem-peraturerdquo Bioconjugate Chemistry vol 19 no 2 pp 569ndash5732008
[97] J Erchegyi R Cescato B Waser J E Rivier and J C ReubildquoN-Imidazolebenzyl-histidine substitution in somatostatin andin its octapeptide analogue modulates receptor selectivity andfunctionrdquo Journal of Medicinal Chemistry vol 54 no 17 pp5981ndash5987 2011
[98] R Saha N Saha R S Donofrio and L L Bestervelt ldquoMicrobialsiderophores Amini reviewrdquo Journal of Basic Microbiology vol53 no 4 pp 303ndash317 2013
[99] V Nikolova S Angelova N Markova and T Dudev ldquoGalliumas a Therapeutic Agent A Thermodynamic Evaluation of theCompetition between Ga3+ and Fe3+ Ions in MetalloproteinsrdquoThe Journal of Physical Chemistry B vol 120 no 9 pp 2241ndash2248 2016
[100] C R Chitambar ldquoGallium and its competing roles with ironin biological systemsrdquo Biochimica et Biophysica Acta (BBA) -Molecular Cell Research vol 1863 no 8 pp 2044ndash2053 2016
[101] J A Lessa M A Soares and R G dos Santos ldquoGallium(III)complexes with 2-acetylpyridine-derived thiosemicarbazonesantimicrobial and cytotoxic effects and investigation on theinteractions with tubulinrdquo BioMetals vol 26 pp 151ndash165 2013
Contrast Media amp Molecular Imaging 19
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[104] M Kircher and C Lapa ldquoNovel Noninvasive Nuclear MedicineImaging Techniques for Cardiac Inflammationrdquo Current Car-diovascular Imaging Reports vol 10 no 2 article no 6 2017
[105] D AHammoud ldquoMolecular imaging of inflammation Currentstatusrdquo Journal of Nuclear Medicine vol 57 no 8 pp 1161ndash11652016
[106] D R Brenner D Scherer K Muir et al ldquoA review of the appli-cation of inflammatory biomarkers in epidemiologic cancerresearchrdquo Cancer Epidemiology Biomarkers amp Prevention vol23 no 9 pp 1729ndash1751 2014
[107] M D Turner B Nedjai T Hurst and D J PenningtonldquoCytokines and chemokines at the crossroads of cell signallingand inflammatory diseaserdquo Biochimica et Biophysica Acta (BBA)- Molecular Cell Research vol 1843 no 11 pp 2563ndash2582 2014
[108] L Werner H Guzner-Gur and I Dotan ldquoInvolvement ofCXCR4CXCR7CXCL12 interactions in inflammatory boweldiseaserdquoTheranostics vol 3 no 1 pp 40ndash46 2013
[109] S Jalkanen and M Salmi ldquoVAP-1 and CD73 endothelial cellsurface enzymes in leukocyte extravasationrdquo ArteriosclerosisThrombosis and Vascular Biology vol 28 no 1 pp 18ndash26 2008
[110] G Malviya F Galli I Sonni and A Signore ldquoImaging T-lymphocytes in inflammatory diseases A nuclear medicineapproachrdquo The Quarterly Journal of Nuclear Medicine andMolecular Imaging vol 58 no 3 pp 237ndash257 2014
[111] S Gratz H J RennenO C BoermanW J Oyen and P Burmaldquo(99m)Tc-interleukin-8 for imaging acute osteomyelitisrdquo Jour-nal of Nuclear Medicine vol 42 no 8 pp 1257ndash1264 2001
[112] S Gratz H J Rennen O C Boerman W J Oyen andF H Corstens ldquoRapid imaging of experimental colitis with(99m)Tc-interleukin-8 in rabbitsrdquo Journal of Nuclear Medicnevol 42 no 6 pp 917ndash923 2001
[113] C Alkim H Alkim A R Koksal S Boga and I SenldquoAngiogenesis in inflammatory bowel diseaserdquo InternationalJournal of Inflammation vol 2015 Article ID 970890 2015
[114] I S Alam T H Witney G Tomasi et al ldquoRadiolabeled RGDtracer kinetics annotates differential 120572v1205733 integrin expressionlinked to cell intrinsic and vessel expressionrdquoMolecular Imagingand Biology vol 16 no 4 pp 558ndash566 2014
[115] J Notni K Pohle and H-J Wester ldquoBe spoilt for choice withradiolabelled RGD peptides Preclinical evaluation of 68Ga-TRAP(RGD)3rdquoNuclear Medicine and Biology vol 40 no 1 pp33ndash41 2013
[116] J Oxboel M Brandt-Larsen C Schjoeth-Eskesen et al ldquoCom-parison of two new angiogenesis PET tracers 68Ga-NODAGA-E[c(RGDyK)]2 and 64Cu-NODAGA-E[c(RGDyK)]2 in vivoimaging studies in human xenograft tumorsrdquo Nuclear Medicineand Biology vol 41 no 3 pp 259ndash267 2014
[117] J Simecek J Notni T G Kapp H Kessler and H-J WesterldquoBenefits of NOPO as chelator in gallium-68 peptides exempli-fied by preclinical characterization of 68Ga-NOPO-c(RGDfK)rdquoMolecular Pharmaceutics vol 11 no 5 pp 1687ndash1695 2014
[118] M Trajkovic-Arsic P Mohajerani A Sarantopoulos et alldquoMultimodal molecular imaging of integrin avb3 for in vivodetection of pancreatic cancerrdquo Journal of NuclearMedicine vol55 no 3 pp 446ndash451 2014
[119] H Cai and P S Conti ldquoRGD-based PET tracers for imagingreceptor integrin 120572 v1205733 expressionrdquo Journal of Labelled Com-pounds and Radiopharmaceuticals vol 56 no 5 pp 264ndash2792013
[120] I Dijkgraaf S Y A Terry W J Mcbride et al ldquoImagingintegrin alpha-v-beta-3 expression in tumors with an 18F-labeled dimeric RGD peptiderdquo Contrast Media amp MolecularImaging vol 8 no 3 pp 238ndash245 2013
[121] P A Knetsch M Petrik C Rangger et al ldquo[68Ga]NS3-RGD and [68Ga] Oxo-DO3A-RGD for imaging 120572v1205733 integrinexpression Synthesis evaluation and comparisonrdquo NuclearMedicine and Biology vol 40 no 1 pp 65ndash72 2013
[122] Z Liu and F Wang ldquoDevelopment of RGD-based radiotracersfor tumor imaging and therapy Translating from bench tobedsiderdquo Current Molecular Medicine vol 13 no 10 pp 1487ndash1505 2013
[123] H Choi J H Phi J C Paeng et al ldquoImaging of integrin 120572v1205733expression using 68Ga-RGD positron emission tomography inpediatric cerebral infarctrdquoMolecular Imaging vol 12 no 4 pp213ndash217 2013
[124] H-J Yoon K W Kang I K Chun et al ldquoCorrelation of breastcancer subtypes based on estrogen receptor progesteronereceptor and HER2 with functional imaging parameters from68Ga-RGD PETCT and 18F-FDG PETCTrdquo European Journalof Nuclear Medicine and Molecular Imaging vol 41 no 8 pp1534ndash1543 2014
[125] R P Baum H R Kulkarni D Muller et al ldquoFirst-in-human study demonstrating tumor-angiogenesis by PETCTimaging with 68Ga-NODAGA-THERANOST a high-affinitypeptidomimetic for 120572v1205733 integrin receptor targetingrdquo CancerBiotherapy andRadiopharmaceuticals vol 30 no 4 pp 152ndash1592015
[126] R Haubner A Finkenstedt A Stegmayr et alldquo[68Ga]NODAGA-RGD ndash Metabolic stability biodistributionand dosimetry data from patients with hepatocellularcarcinoma and liver cirrhosisrdquo European Journal of NuclearMedicine and Molecular Imaging vol 43 no 11 pp 2005ndash20132016
[127] V Lopez-Rodrıguez C Galindo-Sarco F O Garcıa-Perez GFerro-Flores O Arrieta and M A Avila-Rodrıguez ldquoPET-based human dosimetry of the dimeric 120572v1205733 integrin ligand68Ga-DOTA-E-[c(RGDfK)]2 a potential tracer for imagingtumor angiogenesisrdquo Journal of Nuclear Medicine vol 57 no 3pp 404ndash409 2016
[128] M V Backer Z Levashova V Patel et al ldquoMolecular imagingof VEGF receptors in angiogenic vasculature with single-chainVEGF-based probesrdquo Nature Medicine vol 13 no 4 pp 504ndash509 2007
[129] MV Backer Z Levashova R Levenson F G Blankenberg andJ M Backer ldquoCysteine-containing fusion tag for site-specificconjugation of therapeutic and imaging agents to targetingproteinsrdquoMethods in Molecular Biology (Clifton NJ) vol 494pp 275ndash294 2008
[130] M Eder A V Krivoshein M Backer J M Backer UHaberkorn and M Eisenhut ldquoScVEGF-PEG-HBED-CC andscVEGF-PEG-NOTA conjugates comparison of easy-to-labelrecombinant proteins for [68Ga]PET imaging of VEGF recep-tors in angiogenic vasculaturerdquo Nuclear Medicine and Biologyvol 37 no 4 pp 405ndash412 2010
[131] E Blom I Velikyan A Monazzam P Razifar et al ldquoSynthe-sis and characterization of scVEGF-PEG-[ 68Ga]NOTA andscVEGF-PEG-[ 68Ga]DOTA PET tracersrdquo Journal of Labelled
20 Contrast Media amp Molecular Imaging
Compounds and Radiopharmaceuticals vol 54 no 11 pp 685ndash692 2011
[132] S Gratz M Behe and O C Boerman ldquo 99119898Tc-E-selectinbinding peptide for imaging acute osteomyelitis in a novel ratmodelrdquo Nuclear Medicine Communications vol 22 no 9 pp1003ndash1013 2001
[133] S B Jensen M Kakela L Joslashdal et al ldquoExploring the radiosyn-thesis and in vitro characteristics of [68Ga]Ga-DOTA-Siglec-9rdquoJournal of Labelled Compounds and Radiopharmaceuticals vol60 no 9 pp 439ndash449 2017
[134] B A Teicher and S P Fricker ldquoCXCL12 (SDF-1)CXCR4pathway in cancerrdquo Clinical Cancer Research vol 16 no 11 pp2927ndash2931 2010
[135] O Jacobson I D Weiss D O Kiesewetter J M Farber andX Chen ldquoPET of tumor CXCR4 expression with 4-18F-T140rdquoJournal of Nuclear Medicine vol 51 no 11 pp 1796ndash1804 2010
[136] A Aghanejad A R Jalilian Y Fazaeli et al ldquoSynthesis andevaluation of [67Ga]-AMD3100 A novel imaging agent fortargeting the chemokine receptorCXCR4rdquo Scientia Pharmaceu-tica vol 82 no 1 pp 29ndash42 2014
[137] O Jacobson I D Weiss L P Szajek et al ldquoPET imaging ofCXCR4 using copper-64 labeled peptide antagonistrdquoTheranos-tics vol 1 pp 251ndash262 2011
[138] O Jacobson I D Weiss L P Szajek et al ldquoImprovement ofCXCR4 tracer specificity for PET imagingrdquo Journal of Con-trolled Release vol 157 no 2 pp 216ndash223 2012
[139] H J Wester U Keller M Schottelius et al ldquoDisclosing theCXCR4 expression in lymphoproliferative diseases by targetedmolecular imagingrdquo Theranostics vol 5 no 6 pp 618ndash6302015
[140] E Gourni O Demmer M Schottelius et al ldquoPET of CXCR4expression by a 68Ga-labeled highly specific targeted contrastagentrdquo Journal of NuclearMedicine vol 52 no 11 pp 1803ndash18102011
[141] O Demmer I Dijkgraaf U Schumacher et al ldquoDesignsynthesis and functionalization of dimeric peptides targetingchemokine receptor CXCR4rdquo Journal of Medicinal Chemistryvol 54 no 21 pp 7648ndash7662 2011
[142] O Demmer E Gourni U Schumacher H Kessler and H-JWester ldquoPET Imaging of CXCR4 Receptors in Cancer by a NewOptimized Ligandrdquo ChemMedChem vol 6 no 10 pp 1789ndash1791 2011
[143] U Hennrich L Seyler M Schafer et al ldquoSynthesis and invitro evaluation of 68Ga-DOTA-4-FBn-TN14003 a novel tracerfor the imaging of CXCR4 expressionrdquo Bioorganic amp MedicinalChemistry vol 20 no 4 pp 1502ndash1510 2012
[144] G P C George E Stevens O Aberg et al ldquoPreclinical evalua-tion of a CXCR4-specific 68Ga-labelled TN14003 derivative forcancer PET imagingrdquo Bioorganic amp Medicinal Chemistry vol22 no 2 pp 796ndash803 2014
[145] S Poty E Gourni P Desogere et al ldquoAMD3100 A VersatilePlatform for CXCR4 Targeting 68Ga-Based Radiopharmaceu-ticalsrdquo Bioconjugate Chemistry vol 27 no 3 pp 752ndash761 2016
[146] K Philipp-Abbrederis K Herrmann S Knop et al ldquoIn vivomolecular imaging of chemokine receptor CXCR4 expressionin patients with advancedmultiple myelomardquo EMBOMolecularMedicine vol 7 no 4 pp 477ndash487 2015
[147] Z Wang M Zhang L Wang et al ldquoProspective study of 68Ga-NOTA-NFB Radiation dosimetry in healthy volunteers andfirst application in glioma patientsrdquo Theranostics vol 5 no 8pp 882ndash889 2015
[148] I M Jackson P J Scott and S Thompson ldquoClinical Applica-tions of Radiolabeled Peptides for PETrdquo Seminars in NuclearMedicine vol 47 no 5 pp 493ndash523 2017
[149] C Lapa T Reiter R A Werner et al ldquo[68Ga]Pentixafor-PETCT for Imaging of Chemokine Receptor 4 Expression afterMyocardial Infarctionrdquo JACC Cardiovascular Imaging vol 8no 12 pp 1466ndash1468 2015
[150] C Rischpler S G Nekolla H Kossmann et al ldquoUpregu-lated myocardial CXCR4-expression after myocardial infarc-tion assessed by simultaneous GA-68 pentixafor PETMRIrdquoJournal of Nuclear Cardiology vol 23 no 1 pp 131ndash133 2016
[151] F Hyafil J Pelisek I Laitinen et al ldquoImaging the CytokineReceptorCXCR4 in atherosclerotic plaqueswith the radiotracer68Ga-Pentixafor for PETrdquo Journal of Nuclear Medicine vol 58no 3 pp 499ndash506 2017
[152] Y Yi ldquoFolate receptor-targeted diagnostics and therapeutics forinflammatory diseasesrdquo ImmuneNetwork vol 16 no 6 pp 337ndash343 2016
[153] C M Paulos M J Turk G J Breur and P S Low ldquoFolatereceptor-mediated targeting of therapeutic and imaging agentsto activated macrophages in rheumatoid arthritisrdquo AdvancedDrug Delivery Reviews vol 56 no 8 pp 1205ndash1217 2004
[154] W Han R Zaynagetdinov F E Yull et al ldquoMolecular imagingof folate receptor 120573-positive macrophages during acute lunginflammationrdquo American Journal of Respiratory Cell and Molec-ular Biology vol 53 no 1 pp 50ndash59 2015
[155] B Kuhle C Muller and T L Ross ldquoA Novel 68Ga-Labeledpteroic acid-based PET tracer for tumor imaging via the folatereceptorrdquo Recent Results in Cancer Research vol 194 pp 257ndash267 2013
[156] C Brand V A Longo M Groaning W A Weber and TReiner ldquoDevelopment of a New Folate-Derived Ga-68-BasedPET Imaging AgentrdquoMolecular Imaging and Biology vol 19 no5 pp 754ndash761 2017
[157] M Fani XWang G Nicolas et al ldquoDevelopment of new folate-based PET radiotracers Preclinical evaluation of 68Ga-DOTA-folate conjugatesrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 38 no 1 pp 108ndash119 2011
[158] C J Mathias M R Lewis D E Reichert et al ldquoPreparationof 66Ga- and 68Ga-labeled Ga(III)-deferoxamine-folate aspotential folate-receptor-targeted PET radiopharmaceuticalsrdquoNuclear Medicine and Biology vol 30 no 7 pp 725ndash731 2003
[159] S-M Kim N Choi S Hwang et al ldquoFolate receptor-specific positron emission tomography imaging with folic acid-conjugated tissue inhibitor of metalloproteinase-2rdquo Bulletin ofthe Korean Chemical Society vol 34 no 11 pp 3243ndash3248 2013
[160] M Fani M-L Tamma G P Nicolas et al ldquoIn vivo imagingof folate receptor positive tumor xenografts using novel 68Ga-NODAGA-folate conjugatesrdquo Molecular Pharmaceutics vol 9no 5 pp 1136ndash1145 2012
[161] C Muller and R Schibli ldquoProspects in folate receptor-targetedradionuclide therapyrdquo Frontiers in Oncology vol 3 Article IDArticle 249 2013
[162] A Jain A Mathur U Pandey et al ldquoSynthesis and evaluationof a 68Ga labeled folic acid derivative for targeting folatereceptorsrdquo Applied Radiation and Isotopes vol 116 pp 77ndash842016
[163] W Xia A R Hilgenbrink E L Matteson M B Lockwood J-X Cheng and P S Low ldquoA functional folate receptor is inducedduring macrophage activation and can be used to target drugsto activated macrophagesrdquo Blood vol 113 no 2 pp 438ndash4462009
Contrast Media amp Molecular Imaging 21
[164] E P Krenning W A P Breeman P P M Kooij et alldquoLocalisation of endocrine-related tumours with radioiodi-nated analogue of somatostatinrdquoThe Lancet vol 1 no 8632 pp242ndash244 1989
[165] E P Krenning D J KwekkeboomWH Bakker et al ldquoSomato-statin receptor scintigraphy with [111In-DTPA-d-Phe1]- and[123I-Tyr3]-octreotide the Rotterdam experience with morethan 1000 patientsrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 20 no 8 pp 716ndash731 1993
[166] A Stahl G Meisetschlager M Schottelius et al ldquo[123I]Mtr-TOCA a radioiodinated and carbohydrated analogue ofoctreotide Scintigraphic comparison with [111In]octreotiderdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 33 no 1 pp 45ndash52 2006
[167] R Lebtahi J le Cloirec C Houzard et al ldquoDetection of neu-roendocrine tumors 99mTc-P829 scintigraphy compared with111In-pentetreotide scintigraphyrdquo Journal of Nuclear Medicinevol 43 no 7 pp 889ndash895 2002
[168] C Decristoforo T Maina B Nock M Gabriel P Cordopatisand R Moncayo ldquo99mTc-demotate 1 First data in tumourpatients - Results of a pilotphase I studyrdquo European Journal ofNuclearMedicine andMolecular Imaging vol 30 no 9 pp 1211ndash1219 2003
[169] C Decristoforo S J Mather W Cholewinski E DonnemillerG Riccabona and R Moncayo ldquo(99m)Tc-EDDAHYNIC-TOC A new (99m)Tc-labelled radiopharmaceutical forimaging somatostatin receptor-positive tumours First clinicalresults and intra-patient comparison with 111In-labelledoctreotide derivativesrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 27 no 9 pp 1318ndash1325 2000
[170] A Hubalewska-Dydejczyk K Fross-Baron R Mikołajczak etal ldquo99mTc-EDDAHYNIC-octreotate scintigraphy an efficientmethod for the detection and staging of carcinoid tumoursResults of 3 yearsrsquo experiencerdquo European Journal of NuclearMedicine and Molecular Imaging vol 33 no 10 pp 1123ndash11332006
[171] M Bangard M Behe S Guhlke et al ldquoDetection of somato-statin receptor-positive tumours using the new 99mC-tricine-HYNIC-D-Phe1-Tyr3-octreotide First results in patients andcomparison with 111In-DTPA-D-Phe1-octreotiderdquo EuropeanJournal of Nuclear Medicine and Molecular Imaging vol 27 no6 pp 628ndash637 2000
[172] A Helisch G J Forster H Reber et al ldquoPre-therapeuticdosimetry and biodistribution of 86Y-DOTA- Phe1-Tyr3-octreotide versus 111In-pentetreotide in patients with advancedneuroendocrine tumoursrdquo European Journal of NuclearMedicine and Molecular Imaging vol 31 no 10 pp 1386ndash13922004
[173] M Henze J Schuhmacher P Hipp et al ldquoPET imaging ofsomatostatin receptors using [68GA]DOTA-D-Phe1-Tyr3-Octreotide First results in patients with meningiomasrdquo Journalof Nuclear Medicine vol 42 no 7 pp 1053ndash1056 2001
[174] I Kayani J B Bomanji A Groves et al ldquoFunctional imaging ofneuroendocrine tumors with combined PETCT using 68Ga-DOTATATE (Dota-DPhe1 Tyr3-octreotate) and 18F-FDGrdquoCancer vol 112 no 11 pp 2447ndash2455 2008
[175] A Al-Nahhas ldquoNuclear medicine imaging of neuroendocrinetumoursrdquo Clinical Medicine vol 12 no 4 pp 377ndash380 2012
[176] V Ambrosini S Nicolini P Caroli et al ldquoPETCT imaging indifferent types of lung cancer an overviewrdquo European Journal ofRadiology vol 81 no 5 pp 988ndash1001 2012
[177] V Ambrosini D Campana P Tomassetti and S Fanti ldquo68Ga-labelled peptides for diagnosis of gastroenteropancreatic NETrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 39 no 1 pp S52ndashS60 2012
[178] K E Oberg J-C Reubi D J Kwekkeboom and E P KrenningldquoRole of somatostatins in gastroenteropancreatic neuroen-docrine tumor development and therapyrdquoGastroenterology vol139 no 3 pp 753-753 2010
[179] K Oberg ldquoGallium-68 somatostatin receptor PETCT Is ittime to replace 111Indium DTPA octreotide for patients withneuroendocrine tumorsrdquo Endocrine Journal vol 42 no 1 pp3-4 2012
[180] R Srirajaskanthan I Kayani A M Quigley J Soh M ECaplin and J Bomanji ldquoThe role of 68Ga-DOTATATE PET inpatients with neuroendocrine tumors and negative or equivocalfindings on 111In-DTPA-octreotide scintigraphyrdquo Journal ofNuclear Medicine vol 51 no 6 pp 875ndash882 2010
[181] A Kroiss D Putzer and C Uprimny ldquoFunctional imag-ing in phaeochromocytoma and neuroblastoma with 68Ga-DOTA-Tyr3-octreotide positron emission tomography and123I-metaiodobenzylguanidinerdquo European Journal of NuclearMedicine and Molecular Imaging vol 38 no 5 pp 865ndash8732011
[182] M Naji C Zhao S J Welsh et al ldquo68Ga-DOTA-TATE PETvs 123I-MIBG in identifying malignant neural crest tumoursrdquoMolecular Imaging and Biology vol 13 no 4 pp 769ndash775 2011
[183] V Ambrosini P Tomassetti P Castellucci et al ldquoComparisonbetween 68Ga-DOTA-NOC and 18F-DOPA PET for the detec-tion of gastro-entero-pancreatic and lung neuro-endocrinetumoursrdquo European Journal of Nuclear Medicine and MolecularImaging vol 35 no 8 pp 1431ndash1438 2008
[184] D Putzer M Gabriel B Henninger et al ldquoBone metastasesin patients with neuroendocrine tumor 68Ga- DOTA-Tyr3-octreotide PET in comparison to CT and bone scintigraphyrdquoJournal of Nuclear Medicine vol 50 no 8 pp 1214ndash1221 2009
[185] L K Anzola-Fuentes M Chianelli F Galli et al ldquoSomatostatinreceptor scintigraphy in patients with rheumatoid arthritis andsecondary Sjogrenrsquos syndrome treated with Infliximab a pilotstudyrdquo EJNMMI Research vol 6 no 1 article no 49 2016
[186] T Nobashi Y Nakamoto T Kubo et al ldquoThe utility of PETCTwith 68Ga-DOTATOC in sarcoidosis comparison with 67Ga-scintigraphyrdquoAnnals ofNuclearMedicine vol 30 no 8 pp 544ndash552 2016
[187] C Boy T A Heusner T D Poeppel et al ldquo68Ga-DOTATOCPETCT and somatostatin receptor (sst1-sst5) expression innormal human tissue Correlation of sst2mRNAand SUVmaxrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 38 no 7 pp 1224ndash1236 2011
[188] P Rinne S Hellberg M Kiugel et al ldquoComparison of Somato-statin Receptor 2-Targeting PET Tracers in the Detection ofMouse Atherosclerotic Plaquesrdquo Molecular Imaging and Biol-ogy vol 18 no 1 pp 99ndash108 2016
[189] M Asti E Ferrari S Croci et al ldquoSynthesis and characteri-zation of 68Ga-labeled curcumin and curcuminoid complexesas potential radiotracers for imaging of cancer and alzheimersdiseaserdquo Inorganic Chemistry vol 53 no 10 pp 4922ndash49332014
[190] A Signore I Santino and A W J M Glaudemans ldquoIn vivoimaging of microorganismsrdquo Clinical and Translational Imag-ing vol 4 no 3 pp 161-162 2016
[191] S Auletta F Galli C Lauri D Martinelli I Santino andA Signore ldquoImaging bacteria with radiolabelled quinolones
22 Contrast Media amp Molecular Imaging
cephalosporins and siderophores for imaging infection a sys-tematic reviewrdquo Clinical and Translational Imaging vol 4 no 4pp 229ndash252 2016
[192] X Ning S Lee Z Wang et al ldquoMaltodextrin-based imagingprobes detect bacteria in vivo with high sensitivity and speci-ficityrdquo Nature Materials vol 10 no 8 pp 602ndash607 2011
[193] J Ady andY Fong ldquoImaging for infection Fromvisualization ofinflammation to visualization of microbesrdquo Surgical Infectionsvol 15 no 6 pp 700ndash707 2014
[194] J M Sierra D Rodriguez-Puig A Soriano J Mensa C Pieraand J Vila ldquoAccumulation of 99mTc-ciprofloxacin in Staphy-lococcus aureus and Pseudomonas aeruginosardquo AntimicrobialAgents and Chemotherapy vol 52 no 7 pp 2691-2692 2008
[195] D I Andersson and D Hughes ldquoMicrobiological effects ofsublethal levels of antibioticsrdquoNature ReviewsMicrobiology vol12 no 7 pp 465ndash478 2014
[196] N Dumarey D Blocklet T Appelboom L Tant and ASchoutens ldquoInfecton is not specific for bacterial osteo-articularinfective pathologyrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 29 no 4 pp 530ndash535 2002
[197] K E Britton D W Wareham S S Das et al ldquoImaging bacte-rial infection with 99mTc-ciprofloxacin (Infecton)rdquo Journal ofClinical Pathology vol 55 no 11 pp 817ndash823 2002
[198] G Ferro-Flores M A Avila-Rodrıguez and F O Garcıa-PerezldquoImaging of bacteria with radiolabeled ubiquicidin by SPECTand PET techniquesrdquo Clinical and Translational Imaging vol 4no 3 pp 175ndash182 2016
[199] P S Hiemstra M T van den Barselaar M Roest P H Nibber-ing and R van Furth ldquoUbiquicidin a novel murine microbi-cidal protein present in the cytosolic fraction of macrophagesrdquoJournal of Leukocyte Biology vol 66 no 3 pp 423ndash428 1999
[200] M S Akhtar A Qaisar J Irfanullah et al ldquoAntimicrobialpeptide 99mTc-ubiquicidin 29ndash41 as human infection-imagingagent clinical trialrdquo Journal of Nuclear Medicne vol 46 no 4pp 567ndash573 2005
[201] M Assadi K Vahdat I Nabipour et al ldquoDiagnostic value of99mTc-ubiquicidin scintigraphy for osteomyelitis and compar-isons with 99mTc-methylene diphosphonate scintigraphy andmagnetic resonance imagingrdquo Nuclear Medicine Communica-tions vol 32 no 8 pp 716ndash723 2011
[202] T Emery ldquoExchange of Iron by Gallium in SiderophoresrdquoBiochemistry vol 25 no 16 pp 4629ndash4633 1986
[203] M Petrik C Zhai H Haas and C Decristoforo ldquoSiderophoresfor molecular imaging applicationsrdquo Clinical and TranslationalImaging vol 5 no 1 pp 15ndash27 2017
[204] H J Flint E A BayerM T Rincon R Lamed and B AWhiteldquoPolysaccharide utilization by gut bacteria potential for newinsights from genomic analysisrdquo Nature Reviews Microbiologyvol 6 no 2 pp 121ndash131 2008
[205] GGowrishankarMNamavari E B Jouannot et al ldquoInvestiga-tion of 6-[18F]-fluoromaltose as a novel PET tracer for imagingbacterial infectionrdquo PLoS ONE vol 9 no 9 Article ID e1079512014
[206] N Gholipour M Akhlaghi A M Kheirabadi et al ldquoChelator-free radiolabeling of dextran with 68Ga for PET studiesrdquoJournal of Radioanalytical and Nuclear Chemistry vol 311 no3 pp 1811ndash1817 2017
[207] C Bettegowda C A Foss I Cheong et al ldquoImaging bac-terial infections with radiolabeled 1-(21015840-deoxy-21015840- fluoro-120573-D-arabinofuranosyl)-5-iodouracilrdquo Proceedings of the NationalAcadamy of Sciences of the United States of America vol 102 no4 pp 1145ndash1150 2005
[208] S A Soghomonyan M Doubrovin J Pike et al ldquoPositronemission tomography (PET) imaging of tumor-localizedSalmonella expressing HSV1-TKrdquo Cancer GeneTherapy vol 12no 1 pp 101ndash108 2005
[209] C Palestro K Nichols S Sheikh-Fayyaz S Dewey P Singhaland K Bhargava ldquoCan Gallium-68 PET differentiate acuteinterstitial nephritis from acute tubular necrosisrdquo Journal ofNuclear Medicne vol 57 Supplement 2 p 551 2016
[210] A J Morguet D L Munz V Ivancevic et al ldquoImmunoscintig-raphy using technetium-99m-labeled anti-NCA-95 antigranu-locyte antibodies as an adjunct to echocardiography in subacuteinfective endocarditisrdquo Journal of the American College ofCardiology vol 23 no 5 pp 1171ndash1178 1994
[211] C van der Laken O Boerman W Oyen et al ldquoIn Vivo Expres-sion of Interleukin-1 Receptors during Various ExperimentallyInduced Inflammatory Conditionsrdquo The Journal of InfectiousDiseases vol 177 no 5 pp 1398ndash1401 1998
[212] C J Van Der Laken O C Boerman W J G Oyen M T PVan De Ven J W M Van Der Meer and F H M CorstensldquoScintigraphic detection of infection and inflammation Newdevelopments with special emphasis on receptor interactionrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 25 no 5 pp 535ndash546 1998
[213] C J van der LakenOC BoermanW J GOyenM T P van deVen J W M van der Meer and F H M Corstens ldquoImaging ofinfection in rabbits with radioiodinated interleukin-1 (120572 and 120573)its receptor antagonist and a chemotactic peptide a comparativestudyrdquo European Journal of Nuclear Medicine and MolecularImaging vol 25 no 4 pp 347ndash352 1998
[214] C J Van Der Laken O C BoermanW J G Oyen M T P VanDe Ven F H M Corstens and J W M Ven Der Meer ldquoThekinetics of radiolabelled interleukin-8 in infection and sterileinflammationrdquo Nuclear Medicine Communications vol 19 no3 pp 271ndash282 1998
[215] E Lazzeri P Erba M Perri et al ldquoScintigraphic imaging ofvertebral osteomyelitis with 111in-biotinrdquoThe Spine Journal vol33 no 7 pp E198ndashE204 2008
[216] E Blom B Langstrom and I Velikyan ldquo68Ga-labeling of biotinanalogues and their characterizationrdquo Bioconjugate Chemistryvol 20 no 6 pp 1146ndash1151 2009
[217] O Eriksson F Carlsson E Blom et al ldquoPreclinical evaluationof a 68Ga-labeled biotin analogue for applications in islettransplantationrdquo Nuclear Medicine and Biology vol 39 no 3pp 415ndash421 2012
[218] E A Weinstein A A Ordonez V P DeMarco et alldquoImaging Enterobacteriaceae infection in vivo with 18F-fluoro-deoxysorbitol positron emission tomographyrdquo Science Transla-tional Medicine vol 6 no 259 p 259ra146 2014
[219] K M Nielsen M H Kyneb A K O Alstrup et alldquo68Ga-labeled phage-display selected peptides as tracers forpositron emission tomography imaging of Staphylococcusaureus biofilm-associated infections Selection radiolabellingand preliminary biological evaluationrdquo Nuclear Medicine andBiology vol 43 no 10 pp 593ndash605 2016
[220] T J Makinen P Lankinen T Poyhonen J Jalava H T Aroand A Roivainen ldquoComparison of 18F-FDG and 68Ga PETimaging in the assessment of experimental osteomyelitis due toStaphylococcus aureusrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 32 no 11 pp 1259ndash1268 2005
[221] JMU Silvola I LaitinenH J Sipila et al ldquoUptake of 68galliumin atherosclerotic plaques in LDLRminusminusApoB100100micerdquo EJN-MMI Research vol 1 no 1 pp 1ndash8 2011
Contrast Media amp Molecular Imaging 23
[222] T A Wynn ldquoCellular and molecular mechanisms of fibrosisrdquoThe Journal of Pathology vol 214 no 2 pp 199ndash210 2008
[223] T Derlin D Jonigk J Bauersachs and FM Bengel ldquoMolecularImaging of Chemokine Receptor CXCR4 in NonndashSmall CellLung Cancer Using 68Ga-Pentixafor PETCT ComparisonWith 18F-FDGrdquo Clinical Nuclear Medicine 2016
[224] I Velikyan U Rosenstrom T N Bulenga O Eriksson andG Antoni ldquoFeasibility of multiple examinations using68ga-labelled collagelin analogues Organ distribution in rat forextrapolation to human organ and whole-body radiationdosimetryrdquo Pharmaceuticals vol 9 no 2 article no 31 2016
[225] S Jadhav M Kakela J Makila et al ldquoSynthesis and in VivoPET Imaging of Hyaluronan Conjugates of OligonucleotidesrdquoBioconjugate Chemistry vol 27 no 2 pp 391ndash403 2016
[226] A Autio A Saraste N Kudomi et al ldquoAssessment of bloodflow with (68) Ga-DOTA PET in experimental inflammation avalidation study using (15) O-waterrdquo American Journal ofNuclear Medicine and Molecular Imaging vol 4 no 6 pp 571ndash579 2014
[227] G Davies A Rolle A Maurer et al ldquoTowards translationalimmunoPETMR imaging of invasive pulmonary aspergillosisthe Humanised Monoclonal Antibody JF5 detects in vivordquoTheranostics vol 7 no 14 pp 3398ndash3414 2017
[228] DGoodwin CMeares GDavid et al ldquoMonoclonal antibodiesas reversible equilibrium carriers of radiopharmaceuticalsrdquoInternational Journal of Radiation Applications and Instrumen-tation Part B Nuclear Medicine and Biology vol 13 no 4 pp383ndash391 1986
[229] D A Goodwin C F Mears M McTigue and G S DavidldquoMonoclonal antibody hapten radiopharmaceutical deliveryrdquoNuclear Medicine Communications vol 7 no 8 pp 569ndash5801986
[230] S E Halpern and R O Dillman ldquoProblems associated withradioimmunodetection and possibilities for future solutionsrdquo JBiol Response Mod vol 6 no 3 pp 235ndash262 1987
[231] H Hong J Sun and W Cai ldquoRadionuclide-based cancerimaging targeting the carcinoembryonic antigenrdquo BiomarkerInsights vol 3 pp 435ndash451 2008
[232] G J Forster E B Santos P M Smith-Jones P Zanzonico andS M Larson ldquoPretargeted radioimmunotherapy with a single-chain antibodystreptavidin construct and radiolabeledDOTA-biotin Strategies for reduction of the renal doserdquo Journal ofNuclear Medicine vol 47 no 1 pp 140ndash149 2006
[233] Z Yao M Zhang H Kobayashi et al ldquoImproved targeting ofradiolabeled streptavidin in tumors pretargeted with biotiny-lated monoclonal antibodies through an avidin chaserdquo Journalof Nuclear Medicine vol 36 no 5 pp 837ndash841 1995
[234] C-H Chang R M Sharkey E A Rossi et al ldquoMolecularAdvances in Pretargeting Radioimunotherapy with BispecificAntibodies 1 Supported in part by USPHS Grant R01-CA-84379from the NIH and Department of Energy Grant DE-FG01-00NE22941 (both to R M S)1rdquo Mol Cancer Ther vol 1 no 7pp 553ndash563 2002
[235] R M Sharkey E A Rossi W J McBride C-H Chang andD M Goldenberg ldquoRecombinant Bispecific Monoclonal Anti-bodies Prepared by theDock-and-Lock Strategy for PretargetedRadioimmunotherapyrdquo Seminars in Nuclear Medicine vol 40no 3 pp 190ndash203 2010
[236] R M Sharkey E A Rossi C-H Chang and D M Golden-berg ldquoImproved cancer therapy and molecular imaging withmultivalent multispecific antibodiesrdquo Cancer Biotherapy andRadiopharmaceuticals vol 25 no 1 pp 1ndash12 2010
[237] D M Goldenberg R M Sharkey G Paganelli J Barbet andJ Chatal ldquoAntibody pretargeting advances cancer radioim-munodetection and radioimmunotherapyrdquo Journal of ClinicalOncology vol 24 no 5 pp 823ndash834 2006
[238] O C Boerman F G van Schaijk W J G Oyen and FH M Corstens ldquoPretargeted radioimmunotherapy of cancerprogress step by steprdquo Journal of Nuclear Medicine vol 44 no3 pp 400ndash411 2003
[239] J Schuhmacher S Kaul G Klivenyi et al ldquoImmunoscintigra-phy with positron emission tomography Gallium-68 chelateimaging of breast cancer pretargeted with bispecific anti-MUC1anti-Ga chelate antibodiesrdquo Cancer Research vol 61 no9 pp 3712ndash3717 2001
[240] J Schuhmacher G Klivenyi S Kaul et al ldquoPretargeting ofhuman mammary carcinoma xenografts with bispecific anti-MUC1anti-Ga chelate antibodies and immunoscintigraphywith PETrdquo Nuclear Medicine and Biology vol 28 no 7 pp 821ndash828 2001
[241] C Somasundaram S Matzku J Schuhmacher and M ZollerldquoDevelopment of a bispecific monoclonal antibody against agallium-67 chelate and the human melanoma-associated anti-gen p97 for potential use in pretargeted immunoscintigraphyrdquoCancer Immunology Immunotherapy vol 36 no 5 pp 337ndash3451993
[242] E A Rossi D L Rossi R Stein D M Goldenberg and C-H Chang ldquoA bispecific antibody-IFN1205722b immunocytokine tar-geting CD20 and HLA-DR is highly toxic to human lymphomaandmultiplemyeloma cellsrdquoCancer Research vol 70 no 19 pp7600ndash7609 2010
[243] R M Sharkey H Karacay S Litwin et al ldquoImproved ther-apeutic results by pretargeted radioimmunotherapy of non-Hodgkinrsquos lymphoma with a new recombinant trivalent anti-CD20 bispecific antibodyrdquo Cancer Research vol 68 no 13 pp5282ndash5290 2008
[244] G L Griffiths C-H Chang W J McBride et al ldquoReagentsandmethods for PETusing bispecific antibody pretargeting and68Ga-radiolabeled bivalent hapten-peptide-chelate conjugatesrdquoJournal of Nuclear Medicine vol 45 no 1 pp 30ndash39 2004
[245] J Watine M Miedouge and B Friedberg ldquoCarcinoembryonicantigen as an independent prognostic factor of recurrence andsurvival in patients resected for colorectal liver metastases Asystematic reviewrdquo Diseases of the Colon amp Rectum vol 44 no12 pp 1791ndash1799 2001
[246] M J Goldstein and E P Mitchell ldquoCarcinoembryonic antigenin the staging and follow-up of patients with colorectal cancerrdquoCancer Investigation vol 23 no 4 pp 338ndash351 2005
[247] D V Gold D M Goldenberg H Karacay et al ldquoA novelbispecific trivalent antibody construct for targeting pancreaticcarcinomardquo Cancer Research vol 68 no 12 pp 4819ndash48262008
[248] J Schuhmacher G Klivenyi R Matys et al ldquoMultistep tumortargeting in nudemice using bispecific antibodies and a galliumchelate suitable for immunoscintigraphy with positron emis-sion tomographyrdquo Cancer Research vol 55 no 1 pp 115ndash1231995
[249] G Klivenyi J Schuhmacher E Patzelt et al ldquoGallium-68chelate imaging of human colon carcinoma xenografts pre-targeted with bispecific anti-CD44(V6)anti-gallium chelateantibodiesrdquo Journal ofNuclearMedicine vol 39 no 10 pp 1769ndash1776 1998
[250] M Zoller J Schuhmacher J Reed W Maier-Borst and SMatzku ldquoEstablishment and characterization of monoclonal
24 Contrast Media amp Molecular Imaging
antibodies against an octahedral gallium chelate suitable forimmunoscintigraphy with PETrdquo Journal of Nuclear Medicinevol 33 no 7 pp 1366ndash1372 1992
[251] R M Sharkey T M Cardillo E A Rossi et al ldquoSignal ampli-fication in molecular imaging by pretargeting a multivalentbispecific antibodyrdquo Nature Medicine vol 11 no 11 pp 1250ndash1255 2005
[252] D M Goldenberg and R M Sharkey ldquoNovel radiolabeledantibody conjugatesrdquo Oncogene vol 26 no 25 pp 3734ndash37442007
[253] D M Goldenberg E A Rossi R M Sharkey W J McBrideand C-H Chang ldquoMultifunctional antibodies by the dock-and-lock method for improved cancer imaging and therapy bypretargetingrdquo Journal of NuclearMedicine vol 49 no 1 pp 158ndash163 2008
[254] R Schoffelen R M Sharkey D M Goldenberg et al ldquoPre-targeted immuno-positron emission tomography imaging ofcarcinoembryonic antigen-expressing tumors with a bispecificantibody and a68Ga- And18F-labeled hapten peptide in micewith human tumor xenograftsrdquoMolecular Cancer Therapeuticsvol 9 no 4 pp 1019ndash1027 2010
[255] E S Bos W H Kuijpers M Meesters-Winters et al ldquoIn vitroevaluation of DNA-DNA hybridization as a two-step approachin radioimmunotherapy of cancerrdquoCancer Research vol 54 no13 pp 3479ndash3486 1994
[256] G Paganelli M Bartolomei M Ferrari et al ldquoPre-TargetedLocoregional Radioimmunotherapy withrdquo Cancer biotherapyand radiopharmaceuticals vol 16 no 3 pp 227ndash235 2001
[257] A Forero P L Weiden J M Vose et al ldquoPhase 1 trial of a novelanti-CD20 fusion protein in pretargeted radioimmunotherapyfor B-cell non-Hodgkin lymphomardquo Blood vol 104 no 1 pp227ndash236 2004
[258] DM Goldenberg C-H Chang E A RossiW J McBride andR M Sharkey ldquoPretargeted molecular imaging and radioim-munotherapyrdquoTheranostics vol 2 no 5 pp 523ndash540 2012
[259] H Karacay R M Sharkey W J McBride E A Rossi C-HChang and D M Goldenberg ldquoOptimization of hapten-peptide labeling for pretargeted immunoPET of bispecificantibody using generator-produced 68Gardquo Journal of NuclearMedicine vol 52 no 4 pp 555ndash559 2011
[260] J R Oh and B C Ahn ldquoFalse-positive uptake on radioiodinewhole-body scintigraphy physiologic and pathologic variantsunrelated to thyroid cancerrdquo American Journal of NuclearMedicine and Molecular Imaging vol 2 no 2 pp 141ndash150 2012
[261] E Frampas C Rousseau C Bodet-Milin J Barbet J-F Chataland F Kraeber-Bodere ldquoImprovement of radioimmunotherapyusing pretargetingrdquo Frontiers in Oncology vol 3 Article ID00159 2013
[262] C S McKay and M G Finn ldquoClick chemistry in complexmixtures Bioorthogonal bioconjugationrdquo Chemistry amp Biologyvol 21 no 9 pp 1075ndash1101 2014
[263] B L Oliveira Z Guo and G J Bernardes ldquoInverse electrondemand DielsndashAlder reactions in chemical biologyrdquo ChemicalSociety Reviews vol 46 no 16 pp 4895ndash4950 2017
[264] B Nichols Z Qin J Yang D R Vera and N K Devaraj ldquo68Gachelating bioorthogonal tetrazine polymers for the multisteplabeling of cancer biomarkersrdquo Chemical Communications vol50 no 40 pp 5215ndash5217 2014
[265] R Rossin P R Verkerk S M van den Bosch et al ldquoInvivo chemistry for pretargeted tumor imaging in live micerdquoAngewandte Chemie International Edition vol 49 no 19 pp3375ndash3378 2010
[266] B M Zeglis K K Sevak T Reiner et al ldquoA pretargetedPET imaging strategy based on bioorthogonal diels-alder clickchemistryrdquo Journal of Nuclear Medicine vol 54 no 8 pp 1389ndash1396 2013
[267] J L Houghton R Membreno D Abdel-Atti et al ldquoEstablish-ment of the invivo efficacy of pretargeted radioimmunotherapyutilizing inverse electron demand diels-alder click chemistryrdquoMolecular Cancer Therapeutics vol 16 no 1 pp 124ndash133 2017
[268] J Funkhouser ldquoReinventing pharma the theranostic revolu-tionrdquo Current Drug Discovery pp 17ndash19 2002
[269] J Sorensen I Velikyan A Wennborg et al ldquoMeasuring HER2-expression in metastatic breast cancer using 68Ga-ABY025PETCTrdquo European Journal of Nuclear Medicine and MolecularImaging vol 41 pp S226ndashS226 2014
[270] I Velikyan A Wennborg J Feldwisch et al ldquoGMP compliantpreparation of a 68Gallium-labeled Affibody analogue forbreast cancer patient examination first-in-manrdquoEur JNuclMedMol Imaging vol 41 pp S228ndashS229 2014
[271] K Oberg ldquoMolecular imaging radiotherapy Theranostics forpersonalized patient management of neuroendocrine tumors(NETs)rdquoTheranostics vol 2 no 5 pp 448ndash458 2012
[272] I Velikyan AWennborg J FeldwischH Lindman J Carlssonand J Sorensen ldquoGood manufacturing practice production of [(68) Ga]Ga-ABY-025 for HER2 specific breast cancer imagingrdquoAmerican Journal of Nuclear Medicine and Molecular Imagingvol 6 no 2 pp 135ndash153 2016
[273] M Sandstrom K Lindskog I Velikyan et al ldquoBiodistributionand radiation dosimetry of the anti-HER2 Affibody molecule68Ga-ABY-025 in breast cancer patientsrdquo Journal of NuclearMedicine vol 57 no 6 pp 867ndash871 2016
[274] D Sandberg V Tolmachev I Velikyan et al ldquoIntra-imagereferencing for simplified assessment of HER2-expression inbreast cancer metastases using the Affibody molecule ABY-025with PET and SPECTrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 44 no 8 pp 1337ndash1346 2017
[275] H ZhangM AMoroz I Serganova et al ldquoImaging expressionof the human somatostatin receptor subtype-2 reporter genewith 68Ga-DOTATOCrdquo Journal ofNuclearMedicine vol 52 no1 pp 123ndash131 2011
[276] M Naji and A Al-Nahhas ldquo68Ga-labelled peptides in themanagement of neuroectodermal tumoursrdquo European Journalof Nuclear Medicine and Molecular Imaging vol 39 no 1 ppS61ndashS67 2012
[277] I Velikyan ldquoThe diversity of 68Ga-Based imaging agentsrdquoRecent Results in Cancer Research vol 194 pp 101ndash131 2013
[278] K Ferreira H-Y Hu V Fetz et al ldquoMultivalent siderophore-dotam conjugates as theranostics for imaging and treatment ofbacterial infectionsrdquo Angewandte Chemie International Editionvol 56 no 28 pp 8272ndash8276 2017
Computational and Mathematical Methods in Medicine
Hindawiwwwhindawicom Volume 2018
Behavioural Neurology
OphthalmologyJournal of
Hindawiwwwhindawicom Volume 2018
Diabetes ResearchJournal of
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Hindawiwwwhindawicom Volume 2018
Research and TreatmentAIDS
Hindawiwwwhindawicom Volume 2018
Gastroenterology Research and Practice
Hindawiwwwhindawicom Volume 2018
Parkinsonrsquos Disease
Evidence-Based Complementary andAlternative Medicine
Volume 2018Hindawiwwwhindawicom
Submit your manuscripts atwwwhindawicom
Contrast Media amp Molecular Imaging 15
a considerable number of potential antibody biomarkersthat could be considered for the imaging of infection andinflammation
10 Theranostics Potential
Theranostics [268] embraces realization of personalizedmedicine by conducting diagnosis on individual basis andproviding possibility of predicting the efficacy of a specifictreatment and following up the response to the treatmentenabling adjustment of the latter very early in the processIn the context of nuclear medicine wherein the radiophar-maceuticals targeted at biomarkers specific to a disease cancarry either diagnostic radionuclides or therapeutic ones theconcept can be denoted as radiotheranostics [28] The tar-geted molecular imaging such as PET can offer noninvasivediagnosis specific to the disease for example tumour-typespecific and provide accurate localization of the lesions Thestrongest advantage of PET is the potential for quantificationof the target for example receptor expression investigationof the uptake kinetics and estimation of the dosimetryThesecharacteristics of PET allow for individualized treatmentselection and planning monitoring of treatment responseand detection of recurrent diseaseThe individualized patientmanagement provides such advantages as optimization ofthe treatment regimen for the improved response and exclu-sion of futile treatments minimization of risks and toxicitywith overall outcome of reduced cost and patient distressThe importance of individualized patient management wasdemonstrated by clinical studies wherein the influence ofdose of the administered radiopharmaceutical targeted atreceptors overexpressed in cancer lesions on the diagnosticoutcome was investigated in the same patient [85 269270] 68Ga-labelled SST analogues [26ndash28 271] and Affibodymolecules [5 272ndash274] used respectively in NENs andbreast cancer patients are the most prominent examplesof (radio)theranostics involving 68GaPET wherein 68Ga-labelled analogues were used not only for localization of thelesions but also for staging patient stratification prognosistherapy selection and monitoring of the response to thetreatment of NETs and other cancer types [2ndash4 6 85 176275ndash277]
The methodology can be translated to inflammationand infection allowing for accurate and specific selection oftreatment regimen and for follow-up and evaluation of theresponse to therapy resulting in improved treatment efficacyand decreased cost and side effects The accommodation ofboth imaging function and antibiotic function in the samemolecule is a novel example of a theranostic agent [278]A series of siderophores conjugated with DOTA moiety forthe radiolabelling and with antibiotics for the treatmentof bacterial infection were investigated preclinically Theaccumulation of the intravenously administered ampicillinconjugate in the site of subcutaneously injected P aeruginosain mice was clearly and focally visualized within 06 h withretention for at least 24 h These results obtained usinganalogues carrying dye for optical imaging can be translatedto 68Ga-labelled counterparts for PET
11 Conclusions
The medical need for specific agents for noninvasive quan-titative and whole-body imaging of inflammation and infec-tion has not been met yet despite decades of research How-ever the prerequisites in terms of identification of potentialtargets design and synthesis of the respective ligands andimaging technologies are evolving very fast The potentialof accurate and quantitative lesion localization as well asmonitoring of the treatment response promises personalizedpatient management
The use of 68Ga in oncology is established proving thestrong potential of 68Ga for the promotion of PET technol-ogy for effective and efficient diagnostics and personalizedmedicineThe experience of oncological 68Ga-based agents isgetting translated to inflammation and infection Pretargetedimaging technology opens wide possibilities based on anti-body biomarkers
Conflicts of Interest
The author declares that there are no conflicts of interestregarding the publication of this article
References
[1] I Velikyan ldquoContinued rapid growth inGa applications update2013 to June 2014rdquo Journal of Labelled CompoundsampRadiophar-maceuticals pp 99ndash121 2015
[2] I Velikyan ldquo 68Ga-based radiopharmaceuticals Production andapplication relationshiprdquo Molecules vol 20 no 7 pp 12913ndash12943 2015
[3] M Fani P Peitl and I Velikyan ldquoCurrent status of radiophar-maceuticals for the theranostics of neuroendocrine neoplasmsrdquoPharmaceuticals vol 10 no 1 article no 30 2017
[4] I Velikyan ldquoPositron emitting [68Ga]Ga-based imaging agentsChemistry and diversityrdquoMedicinal Chemistry vol 7 no 5 pp345ndash379 2011
[5] J Sorensen I Velikyan D Sandberg et al ldquoMeasuringHER2-receptor expression in metastatic breast cancer using[68Ga]ABY-025 Affibody PETCTrdquo Theranostics vol 6 no 2pp 262ndash271 2016
[6] I Velikyan ldquoProspective of 68Ga-Radiopharmaceutical devel-opmentrdquoTheranostics vol 4 no 1 pp 47ndash80 2014
[7] P Lankinen T J Makinen T A Poyhonen et al ldquo68Ga-DOTAVAP-P1 PET imaging capable of demonstrating the phaseof inflammation in healing bones and the progress of infectionin osteomyelitic bonesrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 35 no 2 pp 352ndash364 2008
[8] T UjulaMHuttunen P Luoto et al ldquoMatrixmetalloproteinase9 targeting peptides Syntheses 68Ga-labeling and preliminaryevaluation in a rat melanoma xenograft modelrdquo BioconjugateChemistry vol 21 no 9 pp 1612ndash1621 2010
[9] A Autio T Ujula P Luoto S Salomaki S Jalkanen and ARoivainen ldquoPET imaging of inflammation and adenocarcinomaxenografts using vascular adhesion protein 1 targeting peptide68Ga-DOTAVAP-P1 Comparison with 18F-FDGrdquo EuropeanJournal of Nuclear Medicine and Molecular Imaging vol 37 no10 pp 1918ndash1925 2010
16 Contrast Media amp Molecular Imaging
[10] J Silvola A Autio P Luoto S Jalkanen andA Roivainen ldquoPre-liminary evaluation of novel 68Ga-DOTAVAP-PEG-P2 peptidetargeting vascular adhesion protein-1rdquo Clinical Physiology andFunctional Imaging vol 30 no 1 pp 75ndash78 2010
[11] T Ujula S Salomaki P Virsu et al ldquoSynthesis 68Ga labelingand preliminary evaluation of DOTA peptide binding vascularadhesion protein-1 a potential PET imaging agent for diagnos-ing osteomyelitisrdquo Nuclear Medicine and Biology vol 36 no 6pp 631ndash641 2009
[12] A Autio T Henttinen H J Sipila S Jalkanen and ARoivainen ldquoMini-PEG spacering of VAP-1-targeting 68Ga-DOTAVAP-P1 peptide improves PET imaging of inflamma-tionrdquo EJNMMI Research vol 1 no 1 pp 1ndash7 2011
[13] K Aalto A Autio E A Kiss et al ldquoSiglec-9 is a novel leukocyteligand for vascular adhesion protein-1 and can be used in PETimaging of inflammation and cancerrdquo Blood vol 118 no 13 pp3725ndash3733 2011
[14] V Kumar D K Boddeti S G Evans F Roesch and RHowman-Giles ldquoPotential use of 68Ga-apo-transferrin as a PETimaging agent for detecting Staphylococcus aureus infectionrdquoNuclear Medicine and Biology vol 38 no 3 pp 393ndash398 2011
[15] M Petrik H Haas G Dobrozemsky et al ldquo68Ga-siderophoresfor PET imaging of invasive pulmonary aspergillosis Proof ofprinciplerdquo Journal of Nuclear Medicine vol 51 no 4 pp 639ndash645 2010
[16] M Petrik H Haas M Schrettl A Helbok M Blatzer and CDecristoforo ldquoIn vitro and in vivo evaluation of selected 68Ga-siderophores for infection imagingrdquo Nuclear Medicine andBiology vol 39 no 3 pp 361ndash369 2012
[17] M Petrik GM Franssen H Haas et al ldquoPreclinical evaluationof two 68Ga-siderophores as potential radiopharmaceuticals forAspergillus fumigatus infection imagingrdquo European Journal ofNuclearMedicine andMolecular Imaging vol 39 no 7 pp 1175ndash1183 2012
[18] A Rizzello D Di Pierro F Lodi et al ldquoSynthesis and qualitycontrol of 68Ga citrate for routine clinical PETrdquo NuclearMedicine Communications vol 30 no 7 pp 542ndash545 2009
[19] C Nanni C Errani and L Boriani ldquo 68Ga-citrate PETCT forevaluating patients with infections of the bone preliminaryresultsrdquo Journal of Nuclear Medicine vol 51 no 12 pp 1932ndash1936 2010
[20] S S Das A V Hall D W Wareham and K E Britton ldquoInfec-tion imaging with radiopharmaceuticals in the 21st centuryrdquoBrazilian Archives of Biology and Technology vol 45 no spepp 25ndash37 2002
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[22] T Yusa K Tateda A Ohara and S Miyazaki ldquoNew possiblebiomarkers for diagnosis of infections and diagnostic distinc-tion between bacterial and viral infections in childrenrdquo Journalof Infection and Chemotherapy vol 23 no 2 pp 96ndash100 2017
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[25] F Rosch and R P Baum ldquoGenerator-based PET radiophar-maceuticals for molecular imaging of tumours On the way
to THERANOSTICSrdquo Dalton Transactions vol 40 no 23 pp6104ndash6111 2011
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[28] I Velikyan ldquoRadionuclides for Imaging andTherapy in Oncol-ogyrdquo Cancer Theranostics pp 285ndash325 2014
[29] J Czernin andWAWeber ldquoIssues and controversies in nuclearmedicine Introductionrdquo Journal of Nuclear Medicine vol 52no Supplement 2 pp 1Sndash2S 2011
[30] S J Goldsmith and S Vallabhajosula ldquoClinically proven radio-pharmaceuticals for infection imaging mechanisms and appli-cationsrdquo Seminars in Nuclear Medicine vol 39 no 1 pp 2ndash102009
[31] M F Tsan ldquoMechanism of gallium-67 accumulation in inflam-matory lesionsrdquo Journal of Nuclear Medicine vol 26 no 1 pp88ndash92 1985
[32] S L Kipper ldquoRadiolabelled leukocyte imaging of the abdomenrdquoin Nuclear Medicine Annual J Freeman Ed pp 81ndash126 RavenPress New York NY USA 1995
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[34] C J Palestro ldquoThe current role of gallium imaging in infectionrdquoSeminars in Nuclear Medicine vol 24 no 2 pp 128ndash141 1994
[35] M S Akhtar M B Imran M A Nadeem and A ShahidldquoAntimicrobial peptides as infection imaging agents better thanradiolabeled antibioticsrdquo International Journal of Peptides vol2012 Article ID 965238 19 pages 2012
[36] D Delbeke and G M Segall ldquoStatus of and trends in nuclearmedicine in the United Statesrdquo Journal of Nuclear Medicine vol52 no 2 2011
[37] S S Gambhir J Czernin J Schwimmer D H Silverman R EColeman and M E Phelps ldquoA tabulated summary of the FDGPET literaturerdquo Journal of Nuclear Medicine vol 42 pp 1Sndash93S2001
[38] M J Lindsay B A Siegel S R Tunis et al ldquoThe NationalOncologic PET Registry ExpandedMedicare coverage for PETunder coverage with evidence developmentrdquo American Journalof Roentgenology vol 188 no 4 pp 1109ndash1113 2007
[39] F Gemmel H Van Den Wyngaert C Love M M Welling PGemmel and C J Palestro ldquoProsthetic joint infectionsradionuclide state-of-the-art imagingrdquo European Journal ofNuclearMedicine andMolecular Imaging vol 39 no 5 pp 892ndash909 2012
[40] J Sorensen ldquoHow does the patient benefit from clinical PETrdquoTheranostics vol 2 no 5 pp 427ndash436 2012
[41] S L Rice C A Roney P Daumar and J S Lewis ldquoThe nextgeneration of positron emission tomography radiopharmaceu-ticals in oncologyrdquo Seminars in Nuclear Medicine vol 41 no 4pp 265ndash282 2011
[42] R LWahl JMHerman and E Ford ldquoThePromise and Pitfallsof Positron Emission Tomography and Single-Photon EmissionComputed Tomography Molecular Imaging-Guided RadiationTherapyrdquo Seminars in Radiation Oncology vol 21 no 2 pp 88ndash100 2011
Contrast Media amp Molecular Imaging 17
[43] A W J M Glaudemans R H J A Slart J M Van Dijl MVan Oosten and G M Van Dam ldquoMolecular imaging of infec-tious and inflammatory diseases A terra incognitardquo Journal ofNuclear Medicine vol 56 no 5 pp 659ndash661 2015
[44] X Li W Bauer I Israel et al ldquoTargeting p-selectin by gallium-68-labeled fucoidan positron emission tomography for nonin-vasive characterization of vulnerable plaques Correlation within vivo 176t mrirdquo Arteriosclerosis Thrombosis and VascularBiology vol 34 no 8 pp 1661ndash1667 2014
[45] S Eichendorff P Svendsen D Bender et al ldquoBiodistributionand PET Imaging of a Novel [68Ga]-Anti-CD163-AntibodyConjugate in Rats with Collagen-Induced Arthritis and inControlsrdquoMolecular Imaging and Biology vol 17 no 1 pp 87ndash93 2014
[46] Z Zhu Y Yin K Zheng et al ldquoEvaluation of synovial angiogen-esis in patients with rheumatoid arthritis using 68Ga-PRGD2PETCT A prospective proof-of-concept cohort studyrdquo Annalsof the Rheumatic Diseases vol 73 no 6 pp 1269ndash1272 2014
[47] J S Eo J C Paeng S Lee et al ldquoAngiogenesis imaging inmyocardial infarction using 68Ga-NOTA- RGD PET Charac-terization and application to therapeutic efficacy monitoring inratsrdquo Coronary Artery Disease vol 24 no 4 pp 303ndash311 2013
[48] J H Kim Y-H Kim Y J Kim et al ldquoQuantitative positronemission tomography imaging of angiogenesis in rats with fore-limb ischemia using 68Ga-NOTA-c(RGDyK)rdquo Angiogenesisvol 16 no 4 pp 837ndash846 2013
[49] I Laitinen J Notni K Pohle et al ldquoComparison of cyclicRGD peptides for 120572v1205733 integrin detection in a rat model ofmyocardial infarctionrdquo EJNMMI Research vol 3 no 1 pp 1ndash9 2013
[50] M Kiugel I Dijkgraaf V Kyto et al ldquoDimeric [68Ga]DOTA-RGD Peptide Targeting 120572 ltinfgtvltinfgt 120573 ltinfgt3ltinfgt Inte-grin Reveals Extracellular Matrix Alterations after MyocardialInfarctionrdquo Molecular Imaging and Biology vol 16 no 6 pp793ndash801 2014
[51] M Gronman M Tarkia T Kiviniemi et al ldquoImaging of 120572v1205733integrin expression in experimental myocardial ischemia with[68Ga]NODAGA-RGD positron emission tomographyrdquo Jour-nal of Translational Medicine vol 15 no 1 p 144 2017
[52] J Haukkala I Laitinen P Luoto et al ldquo68Ga-DOTA-RGDpep-tide Biodistribution and binding into atherosclerotic plaquesin micerdquo European Journal of Nuclear Medicine and MolecularImaging vol 36 no 12 pp 2058ndash2067 2009
[53] H Virtanen A Autio R Siitonen et al ldquo68Ga-DOTA-Siglec-9- a new imaging tool to detect synovitisrdquo Arthritis Research ampTherapy vol 17 no 1 article no 308 2015
[54] J Retamal J Sorensen M Lubberink et al ldquoFeasibility of(68) Ga-labeled Siglec-9 peptide for the imaging of acutelung inflammation a pilot study in a porcine model of acuterespiratory distress syndromerdquoAm JNuclMedMol Imaging vol6 no 1 pp 18ndash31 2016
[55] J M U Silvola H Virtanen R Siitonen et al ldquoLeukocytetrafficking-associated vascular adhesion protein 1 is expressedand functionally active in atherosclerotic plaquesrdquo ScientificReports vol 6 Article ID 35089 2016
[56] H Ahtinen J Kulkova L Lindholm et al ldquo68Ga-DOTA-Siglec-9 PETCT imaging of peri-implant tissue responses andstaphylococcal infectionsrdquo EJNMMI Research vol 4 no 1article no 45 pp 1ndash11 2014
[57] A Autio S Jalkanen and A Roivainen ldquoNuclear imaging ofinflammation Homing-associated molecules as targetsrdquo EJN-MMI Research vol 3 no 1 pp 1ndash7 2013
[58] J TThackeray T Derlin AHaghikia et al ldquoMolecular Imagingof the Chemokine Receptor CXCR4 after Acute MyocardialInfarctionrdquo JACC Cardiovascular Imaging vol 8 no 12 pp1417ndash1426 2015
[59] J S Schmid A Schirbel A K Buck S Kropf H-J Westerand C Lapa ldquoPentixafor-Positron Emission TomographyComputed Tomography Detects Chemokine Receptor CXCR4Expression after Ischemic Strokerdquo Circulation CardiovascularImaging vol 9 no 9 Article ID e005217 2016
[60] J Zhou G Hao H Weng et al ldquoIn vivo evaluation ofmedical device-associated inflammation using a macrophage-specific positron emission tomography (PET) imaging proberdquoBioorganic amp Medicinal Chemistry Letters vol 23 no 7 pp2044ndash2047 2013
[61] S A Kularatne M-J Belanger X Meng et al ldquoComparativeanalysis of folate derived PET imaging agents with [ 18F]-2-fluoro-2-deoxy-d-glucose using a rodent inflammatory pawmodelrdquo Molecular Pharmaceutics vol 10 no 8 pp 3103ndash31112013
[62] V Ambrosini M Zompatori F De Luca et al ldquo68Ga-DOTANOCPETCTAllows Somatostatin Receptor Imaging inIdiopathic Pulmonary Fibrosis Preliminary Resultsrdquo Journal ofNuclear Medicine vol 51 no 12 pp 1950ndash1955 2010
[63] T Lincke J Singer R Kluge O Sabri and R Paschke ldquoRela-tive quantification of indium-111 pentetreotide and gallium-68DOTATOC uptake in the thyroid gland and association withthyroid pathologiesrdquoThyroid vol 19 no 4 pp 381ndash389 2009
[64] A Rominger T Saam E Vogl et al ldquoIn vivo imaging ofmacrophage activity in the coronary arteries using 68Ga-DOTATATE PETCT correlation with coronary calcium bur-den and risk factorsrdquo Journal of Nuclear Medicine vol 51 no 2pp 193ndash197 2010
[65] J M Tarkin F R Joshi N R Evans et al ldquoDetection ofAtherosclerotic Inflammation by 68Ga-DOTATATE PET Com-pared to [18F]FDG PET Imagingrdquo Journal of the AmericanCollege of Cardiology vol 69 no 14 pp 1774ndash1791 2017
[66] S-P Lee H-J Im S Kang et al ldquoNoninvasive imaging ofmyocardial inflammation in myocarditis using 68Ga-taggedmannosylated human serum albumin positron emissiontomographyrdquoTheranostics vol 7 no 2 pp 413ndash424 2017
[67] Z Zha J Song S R Choi et al ldquo68Ga-Bivalent PolypegylatedStyrylpyridine Conjugates for Imaging A120573 Plaques in CerebralAmyloid Angiopathyrdquo Bioconjugate Chemistry vol 27 no 5 pp1314ndash1323 2016
[68] H Watanabe M Ono S Iikuni et al ldquoA 68Ga complex basedon benzofuran scaffold for the detection of 120573-amyloid plaquesrdquoBioorganic amp Medicinal Chemistry Letters vol 24 no 20 pp4834ndash4837 2014
[69] D Cressier M Dhilly T T Cao Pham et al ldquoGallium-68 Com-plexes Conjugated to Pittsburgh Compound B Radiolabelingand Biological EvaluationrdquoMolecular Imaging and Biology vol18 no 3 pp 334ndash343 2016
[70] D Satpati CArjun R KrishnamohanG Samuel and S Baner-jee ldquo68Ga-labeledCiprofloxacinConjugates as Radiotracers forTargeting Bacterial InfectionrdquoChemical Biology ampDrug Designvol 87 no 5 pp 680ndash686 2016
[71] T Ebenhan N Chadwick and M M Sathekge ldquoPeptidesynthesis characterization and 68Ga-radiolabeling of NOTA-conjugated ubiquicidin fragments for prospective infectionimaging with PETCTrdquo Nuclear Medicine and Biology vol 41no 5 pp 390ndash400 2014
18 Contrast Media amp Molecular Imaging
[72] T Ebenhan J R Zeevaart and J D Venter ldquoPreclinicalevaluation of 68Ga-labeled 1 4 7-triazacyclononane-1 4 7-triacetic acid-ubiquicidin as a radioligand for PET infectionimagingrdquo Journal of Nuclear Medicine vol 55 no 2 pp 308ndash314 2014
[73] B B Mokaleng T Ebenhan S Ramesh et al ldquoSynthesis 68Ga-radiolabeling and preliminary in vivo assessment of adepsipeptide-derived compound as a potential PETCTinfection imaging agentrdquo BioMed Research International vol2015 Article ID 284354 2015
[74] T Ebenhan B Mokaleng J Venter H Kruger J Zeevaart andM Sathekge ldquoPreclinical Assessment of a 68Ga-DOTA-Functionalized Depsipeptide as a Radiodiagnostic InfectionImaging AgentrdquoMolecules vol 22 no 9 p 1403 2017
[75] S Chopra B Singh A Koul A Mishra and H Wester ldquoSyn-thesis of DOTA conjugated GF-17 and RAWVAWR-NH2 andradiolabeling with 68Ga as a potential PET tracer for infectionimagingrdquo J Nucl Med vol 57 Supplement 2 p 1115 2016
[76] M Petrik HHaas P Laverman et al ldquo 68Ga-triacetylfusarinineC and 68Ga-ferrioxamine e for aspergillus infection imaginguptake specificity in various microorganismsrdquoMolecular Imag-ing and Biology vol 16 no 1 pp 102ndash108 2014
[77] V Kumar and D K Boddeti ldquo 68Ga-radiopharmaceuticals forPET imaging of infection and inflammationrdquo Recent Results inCancer Research vol 194 pp 189ndash219 2013
[78] M Vorster A Maes A Jacobs et al ldquoEvaluating the possiblerole of 68Ga-citrate PETCT in the characterization of indeter-minate lung lesionsrdquo Annals of Nuclear Medicine vol 28 no 6pp 523ndash530 2014
[79] M Vorster B Mokaleng M M Sathekge and T Ebenhan ldquoAmodified technique for efficient radiolabeling of 68Ga-citratefrom a SnO2-based 68Ge68Ga generator for better infectionimagingrdquoHellenic Journal of Nuclear Medicine vol 16 no 3 pp193ndash198 2013
[80] S Salomaeki J Kemppainen U Hohenthal et al ldquoHead-to-head comparison of 68Ga-Citrate and 18F-FDG PETCT fordetection of infectious foci in patients with staphylococcusaureus bacteraemiardquo Contrast Media amp Molecular Imaging vol2017 p 8 2017
[81] L Fass ldquoImaging and cancer a reviewrdquoMolecular Oncology vol2 no 2 pp 115ndash152 2008
[82] A Chopra L Shan W C Eckelman et al ldquoMolecular imagingand contrast agent database (MICAD) Evolution and progressrdquoMolecular Imaging and Biology vol 14 no 1 pp 4ndash13 2012
[83] A Sanchez-Crespo P Andreo and S A Larsson ldquoPositronflight in human tissues and its influence on PET image spatialresolutionrdquo European Journal of Nuclear Medicine and Molecu-lar Imaging vol 31 no 1 pp 44ndash51 2004
[84] H W A M De Jong L Perk G W M Visser R Boellaard GAM S Van Dongen and A A Lammertsma ldquoHigh resolutionPET imaging characteristics of68Ga 124i and89Zr comparedto18Frdquo in Proceedings of the Nuclear Science Symposium Con-ference Record 2005 IEEE pp 1624ndash1627 Puerto Rico October2005
[85] I Velikyan A Sundin B Eriksson et al ldquoIn vivo bindingof [68Ga]-DOTATOC to somatostatin receptors in neuroen-docrine tumours - impact of peptide massrdquo Nuclear Medicineand Biology vol 37 no 3 pp 265ndash275 2010
[86] U Eberlein and M Lassmann ldquoDosimetry of [68Ga]-labeledcompoundsrdquo Applied Radiation and Isotopes vol 76 pp 70ndash742013
[87] C PettinatoA SarnelliMDiDonna et al ldquo68Ga-DOTANOCBiodistribution and dosimetry in patients affected by neuroen-docrine tumorsrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 35 no 1 pp 72ndash79 2008
[88] B P Burke G S Clemente and S J Archibald ldquoRecentadvances in chelator design and labelling methodology for68Ga radiopharmaceuticalsrdquo Journal of Labelled Compoundsand Radiopharmaceuticals vol 57 no 4 pp 239ndash243 2014
[89] I Velikyan U Rosenstrom S Estrada et al ldquoSynthesis andpreclinical evaluation of 68Ga-labeled collagelin analogs forimaging and quantification of fibrosisrdquo Nuclear Medicine andBiology vol 41 no 9 pp 728ndash736 2014
[90] M F Ferreira G Pereira J P Andre and etal C ldquoGa[NO2A-N-(120572-amino)propionate] chelates Synthesis and evaluation aspotential tracers for 68Ga PETrdquoDalton Transactions vol 43 no21 pp 8037ndash8047 2014
[91] J Notni J Simecek and H-J Wester ldquoPhosphinic acid func-tionalized polyazacycloalkane chelators for radiodiagnosticsand radiotherapeutics Unique characteristics and applicationsrdquoChemMedChem vol 9 no 6 pp 1107ndash1115 2014
[92] J Simecek O Zemek P Hermann J Notni and H J WesterldquoTailored gallium( III) chelator NOPO synthesis characteriza-tion bioconjugation and application in preclinical Ga-68-PETimagingrdquoMolecular Pharmaceutics 2013
[93] D Parker B P Waldron and D S Yufit ldquoCrystallographicand solution NMR structural analyses of four hexacoordinatedgallium(iii) complexes based on ligands derived from 6-amino-perhydro-14-diazepinerdquo Dalton Transactions vol 42 no 22pp 8001ndash8008 2013
[94] B P Waldron D Parker C Burchardt D S Yufit M ZimnyandF Roesch ldquoStructure and stability of hexadentate complexesof ligands based on AAZTA for efficient PET labelling withgallium-68rdquo Chemical Communications vol 49 no 6 pp 579ndash581 2013
[95] D Parker and B PWaldron ldquoConformational analysis and syn-thetic approaches to polydentate perhydro-diazepine ligandsfor the complexation of gallium(iii)rdquo Organic amp BiomolecularChemistry vol 11 no 17 pp 2827ndash2838 2013
[96] I Velikyan H Maecke and B Langstrom ldquoConvenient prepa-ration of 68Ga-based PET-radiopharmaceuticals at room tem-peraturerdquo Bioconjugate Chemistry vol 19 no 2 pp 569ndash5732008
[97] J Erchegyi R Cescato B Waser J E Rivier and J C ReubildquoN-Imidazolebenzyl-histidine substitution in somatostatin andin its octapeptide analogue modulates receptor selectivity andfunctionrdquo Journal of Medicinal Chemistry vol 54 no 17 pp5981ndash5987 2011
[98] R Saha N Saha R S Donofrio and L L Bestervelt ldquoMicrobialsiderophores Amini reviewrdquo Journal of Basic Microbiology vol53 no 4 pp 303ndash317 2013
[99] V Nikolova S Angelova N Markova and T Dudev ldquoGalliumas a Therapeutic Agent A Thermodynamic Evaluation of theCompetition between Ga3+ and Fe3+ Ions in MetalloproteinsrdquoThe Journal of Physical Chemistry B vol 120 no 9 pp 2241ndash2248 2016
[100] C R Chitambar ldquoGallium and its competing roles with ironin biological systemsrdquo Biochimica et Biophysica Acta (BBA) -Molecular Cell Research vol 1863 no 8 pp 2044ndash2053 2016
[101] J A Lessa M A Soares and R G dos Santos ldquoGallium(III)complexes with 2-acetylpyridine-derived thiosemicarbazonesantimicrobial and cytotoxic effects and investigation on theinteractions with tubulinrdquo BioMetals vol 26 pp 151ndash165 2013
Contrast Media amp Molecular Imaging 19
[102] M van Oosten M Hahn L M A Crane et al ldquoTargetedimaging of bacterial infections Advances hurdles and hopesrdquoFEMS Microbiology Reviews vol 39 no 6 pp 892ndash916 2015
[103] M Vorster AMaes C V DWiele andM Sathekge ldquoGallium-68 PET A Powerful Generator-based Alternative to Infectionand Inflammation Imagingrdquo Seminars in Nuclear Medicine vol46 no 5 pp 436ndash447 2016
[104] M Kircher and C Lapa ldquoNovel Noninvasive Nuclear MedicineImaging Techniques for Cardiac Inflammationrdquo Current Car-diovascular Imaging Reports vol 10 no 2 article no 6 2017
[105] D AHammoud ldquoMolecular imaging of inflammation Currentstatusrdquo Journal of Nuclear Medicine vol 57 no 8 pp 1161ndash11652016
[106] D R Brenner D Scherer K Muir et al ldquoA review of the appli-cation of inflammatory biomarkers in epidemiologic cancerresearchrdquo Cancer Epidemiology Biomarkers amp Prevention vol23 no 9 pp 1729ndash1751 2014
[107] M D Turner B Nedjai T Hurst and D J PenningtonldquoCytokines and chemokines at the crossroads of cell signallingand inflammatory diseaserdquo Biochimica et Biophysica Acta (BBA)- Molecular Cell Research vol 1843 no 11 pp 2563ndash2582 2014
[108] L Werner H Guzner-Gur and I Dotan ldquoInvolvement ofCXCR4CXCR7CXCL12 interactions in inflammatory boweldiseaserdquoTheranostics vol 3 no 1 pp 40ndash46 2013
[109] S Jalkanen and M Salmi ldquoVAP-1 and CD73 endothelial cellsurface enzymes in leukocyte extravasationrdquo ArteriosclerosisThrombosis and Vascular Biology vol 28 no 1 pp 18ndash26 2008
[110] G Malviya F Galli I Sonni and A Signore ldquoImaging T-lymphocytes in inflammatory diseases A nuclear medicineapproachrdquo The Quarterly Journal of Nuclear Medicine andMolecular Imaging vol 58 no 3 pp 237ndash257 2014
[111] S Gratz H J RennenO C BoermanW J Oyen and P Burmaldquo(99m)Tc-interleukin-8 for imaging acute osteomyelitisrdquo Jour-nal of Nuclear Medicine vol 42 no 8 pp 1257ndash1264 2001
[112] S Gratz H J Rennen O C Boerman W J Oyen andF H Corstens ldquoRapid imaging of experimental colitis with(99m)Tc-interleukin-8 in rabbitsrdquo Journal of Nuclear Medicnevol 42 no 6 pp 917ndash923 2001
[113] C Alkim H Alkim A R Koksal S Boga and I SenldquoAngiogenesis in inflammatory bowel diseaserdquo InternationalJournal of Inflammation vol 2015 Article ID 970890 2015
[114] I S Alam T H Witney G Tomasi et al ldquoRadiolabeled RGDtracer kinetics annotates differential 120572v1205733 integrin expressionlinked to cell intrinsic and vessel expressionrdquoMolecular Imagingand Biology vol 16 no 4 pp 558ndash566 2014
[115] J Notni K Pohle and H-J Wester ldquoBe spoilt for choice withradiolabelled RGD peptides Preclinical evaluation of 68Ga-TRAP(RGD)3rdquoNuclear Medicine and Biology vol 40 no 1 pp33ndash41 2013
[116] J Oxboel M Brandt-Larsen C Schjoeth-Eskesen et al ldquoCom-parison of two new angiogenesis PET tracers 68Ga-NODAGA-E[c(RGDyK)]2 and 64Cu-NODAGA-E[c(RGDyK)]2 in vivoimaging studies in human xenograft tumorsrdquo Nuclear Medicineand Biology vol 41 no 3 pp 259ndash267 2014
[117] J Simecek J Notni T G Kapp H Kessler and H-J WesterldquoBenefits of NOPO as chelator in gallium-68 peptides exempli-fied by preclinical characterization of 68Ga-NOPO-c(RGDfK)rdquoMolecular Pharmaceutics vol 11 no 5 pp 1687ndash1695 2014
[118] M Trajkovic-Arsic P Mohajerani A Sarantopoulos et alldquoMultimodal molecular imaging of integrin avb3 for in vivodetection of pancreatic cancerrdquo Journal of NuclearMedicine vol55 no 3 pp 446ndash451 2014
[119] H Cai and P S Conti ldquoRGD-based PET tracers for imagingreceptor integrin 120572 v1205733 expressionrdquo Journal of Labelled Com-pounds and Radiopharmaceuticals vol 56 no 5 pp 264ndash2792013
[120] I Dijkgraaf S Y A Terry W J Mcbride et al ldquoImagingintegrin alpha-v-beta-3 expression in tumors with an 18F-labeled dimeric RGD peptiderdquo Contrast Media amp MolecularImaging vol 8 no 3 pp 238ndash245 2013
[121] P A Knetsch M Petrik C Rangger et al ldquo[68Ga]NS3-RGD and [68Ga] Oxo-DO3A-RGD for imaging 120572v1205733 integrinexpression Synthesis evaluation and comparisonrdquo NuclearMedicine and Biology vol 40 no 1 pp 65ndash72 2013
[122] Z Liu and F Wang ldquoDevelopment of RGD-based radiotracersfor tumor imaging and therapy Translating from bench tobedsiderdquo Current Molecular Medicine vol 13 no 10 pp 1487ndash1505 2013
[123] H Choi J H Phi J C Paeng et al ldquoImaging of integrin 120572v1205733expression using 68Ga-RGD positron emission tomography inpediatric cerebral infarctrdquoMolecular Imaging vol 12 no 4 pp213ndash217 2013
[124] H-J Yoon K W Kang I K Chun et al ldquoCorrelation of breastcancer subtypes based on estrogen receptor progesteronereceptor and HER2 with functional imaging parameters from68Ga-RGD PETCT and 18F-FDG PETCTrdquo European Journalof Nuclear Medicine and Molecular Imaging vol 41 no 8 pp1534ndash1543 2014
[125] R P Baum H R Kulkarni D Muller et al ldquoFirst-in-human study demonstrating tumor-angiogenesis by PETCTimaging with 68Ga-NODAGA-THERANOST a high-affinitypeptidomimetic for 120572v1205733 integrin receptor targetingrdquo CancerBiotherapy andRadiopharmaceuticals vol 30 no 4 pp 152ndash1592015
[126] R Haubner A Finkenstedt A Stegmayr et alldquo[68Ga]NODAGA-RGD ndash Metabolic stability biodistributionand dosimetry data from patients with hepatocellularcarcinoma and liver cirrhosisrdquo European Journal of NuclearMedicine and Molecular Imaging vol 43 no 11 pp 2005ndash20132016
[127] V Lopez-Rodrıguez C Galindo-Sarco F O Garcıa-Perez GFerro-Flores O Arrieta and M A Avila-Rodrıguez ldquoPET-based human dosimetry of the dimeric 120572v1205733 integrin ligand68Ga-DOTA-E-[c(RGDfK)]2 a potential tracer for imagingtumor angiogenesisrdquo Journal of Nuclear Medicine vol 57 no 3pp 404ndash409 2016
[128] M V Backer Z Levashova V Patel et al ldquoMolecular imagingof VEGF receptors in angiogenic vasculature with single-chainVEGF-based probesrdquo Nature Medicine vol 13 no 4 pp 504ndash509 2007
[129] MV Backer Z Levashova R Levenson F G Blankenberg andJ M Backer ldquoCysteine-containing fusion tag for site-specificconjugation of therapeutic and imaging agents to targetingproteinsrdquoMethods in Molecular Biology (Clifton NJ) vol 494pp 275ndash294 2008
[130] M Eder A V Krivoshein M Backer J M Backer UHaberkorn and M Eisenhut ldquoScVEGF-PEG-HBED-CC andscVEGF-PEG-NOTA conjugates comparison of easy-to-labelrecombinant proteins for [68Ga]PET imaging of VEGF recep-tors in angiogenic vasculaturerdquo Nuclear Medicine and Biologyvol 37 no 4 pp 405ndash412 2010
[131] E Blom I Velikyan A Monazzam P Razifar et al ldquoSynthe-sis and characterization of scVEGF-PEG-[ 68Ga]NOTA andscVEGF-PEG-[ 68Ga]DOTA PET tracersrdquo Journal of Labelled
20 Contrast Media amp Molecular Imaging
Compounds and Radiopharmaceuticals vol 54 no 11 pp 685ndash692 2011
[132] S Gratz M Behe and O C Boerman ldquo 99119898Tc-E-selectinbinding peptide for imaging acute osteomyelitis in a novel ratmodelrdquo Nuclear Medicine Communications vol 22 no 9 pp1003ndash1013 2001
[133] S B Jensen M Kakela L Joslashdal et al ldquoExploring the radiosyn-thesis and in vitro characteristics of [68Ga]Ga-DOTA-Siglec-9rdquoJournal of Labelled Compounds and Radiopharmaceuticals vol60 no 9 pp 439ndash449 2017
[134] B A Teicher and S P Fricker ldquoCXCL12 (SDF-1)CXCR4pathway in cancerrdquo Clinical Cancer Research vol 16 no 11 pp2927ndash2931 2010
[135] O Jacobson I D Weiss D O Kiesewetter J M Farber andX Chen ldquoPET of tumor CXCR4 expression with 4-18F-T140rdquoJournal of Nuclear Medicine vol 51 no 11 pp 1796ndash1804 2010
[136] A Aghanejad A R Jalilian Y Fazaeli et al ldquoSynthesis andevaluation of [67Ga]-AMD3100 A novel imaging agent fortargeting the chemokine receptorCXCR4rdquo Scientia Pharmaceu-tica vol 82 no 1 pp 29ndash42 2014
[137] O Jacobson I D Weiss L P Szajek et al ldquoPET imaging ofCXCR4 using copper-64 labeled peptide antagonistrdquoTheranos-tics vol 1 pp 251ndash262 2011
[138] O Jacobson I D Weiss L P Szajek et al ldquoImprovement ofCXCR4 tracer specificity for PET imagingrdquo Journal of Con-trolled Release vol 157 no 2 pp 216ndash223 2012
[139] H J Wester U Keller M Schottelius et al ldquoDisclosing theCXCR4 expression in lymphoproliferative diseases by targetedmolecular imagingrdquo Theranostics vol 5 no 6 pp 618ndash6302015
[140] E Gourni O Demmer M Schottelius et al ldquoPET of CXCR4expression by a 68Ga-labeled highly specific targeted contrastagentrdquo Journal of NuclearMedicine vol 52 no 11 pp 1803ndash18102011
[141] O Demmer I Dijkgraaf U Schumacher et al ldquoDesignsynthesis and functionalization of dimeric peptides targetingchemokine receptor CXCR4rdquo Journal of Medicinal Chemistryvol 54 no 21 pp 7648ndash7662 2011
[142] O Demmer E Gourni U Schumacher H Kessler and H-JWester ldquoPET Imaging of CXCR4 Receptors in Cancer by a NewOptimized Ligandrdquo ChemMedChem vol 6 no 10 pp 1789ndash1791 2011
[143] U Hennrich L Seyler M Schafer et al ldquoSynthesis and invitro evaluation of 68Ga-DOTA-4-FBn-TN14003 a novel tracerfor the imaging of CXCR4 expressionrdquo Bioorganic amp MedicinalChemistry vol 20 no 4 pp 1502ndash1510 2012
[144] G P C George E Stevens O Aberg et al ldquoPreclinical evalua-tion of a CXCR4-specific 68Ga-labelled TN14003 derivative forcancer PET imagingrdquo Bioorganic amp Medicinal Chemistry vol22 no 2 pp 796ndash803 2014
[145] S Poty E Gourni P Desogere et al ldquoAMD3100 A VersatilePlatform for CXCR4 Targeting 68Ga-Based Radiopharmaceu-ticalsrdquo Bioconjugate Chemistry vol 27 no 3 pp 752ndash761 2016
[146] K Philipp-Abbrederis K Herrmann S Knop et al ldquoIn vivomolecular imaging of chemokine receptor CXCR4 expressionin patients with advancedmultiple myelomardquo EMBOMolecularMedicine vol 7 no 4 pp 477ndash487 2015
[147] Z Wang M Zhang L Wang et al ldquoProspective study of 68Ga-NOTA-NFB Radiation dosimetry in healthy volunteers andfirst application in glioma patientsrdquo Theranostics vol 5 no 8pp 882ndash889 2015
[148] I M Jackson P J Scott and S Thompson ldquoClinical Applica-tions of Radiolabeled Peptides for PETrdquo Seminars in NuclearMedicine vol 47 no 5 pp 493ndash523 2017
[149] C Lapa T Reiter R A Werner et al ldquo[68Ga]Pentixafor-PETCT for Imaging of Chemokine Receptor 4 Expression afterMyocardial Infarctionrdquo JACC Cardiovascular Imaging vol 8no 12 pp 1466ndash1468 2015
[150] C Rischpler S G Nekolla H Kossmann et al ldquoUpregu-lated myocardial CXCR4-expression after myocardial infarc-tion assessed by simultaneous GA-68 pentixafor PETMRIrdquoJournal of Nuclear Cardiology vol 23 no 1 pp 131ndash133 2016
[151] F Hyafil J Pelisek I Laitinen et al ldquoImaging the CytokineReceptorCXCR4 in atherosclerotic plaqueswith the radiotracer68Ga-Pentixafor for PETrdquo Journal of Nuclear Medicine vol 58no 3 pp 499ndash506 2017
[152] Y Yi ldquoFolate receptor-targeted diagnostics and therapeutics forinflammatory diseasesrdquo ImmuneNetwork vol 16 no 6 pp 337ndash343 2016
[153] C M Paulos M J Turk G J Breur and P S Low ldquoFolatereceptor-mediated targeting of therapeutic and imaging agentsto activated macrophages in rheumatoid arthritisrdquo AdvancedDrug Delivery Reviews vol 56 no 8 pp 1205ndash1217 2004
[154] W Han R Zaynagetdinov F E Yull et al ldquoMolecular imagingof folate receptor 120573-positive macrophages during acute lunginflammationrdquo American Journal of Respiratory Cell and Molec-ular Biology vol 53 no 1 pp 50ndash59 2015
[155] B Kuhle C Muller and T L Ross ldquoA Novel 68Ga-Labeledpteroic acid-based PET tracer for tumor imaging via the folatereceptorrdquo Recent Results in Cancer Research vol 194 pp 257ndash267 2013
[156] C Brand V A Longo M Groaning W A Weber and TReiner ldquoDevelopment of a New Folate-Derived Ga-68-BasedPET Imaging AgentrdquoMolecular Imaging and Biology vol 19 no5 pp 754ndash761 2017
[157] M Fani XWang G Nicolas et al ldquoDevelopment of new folate-based PET radiotracers Preclinical evaluation of 68Ga-DOTA-folate conjugatesrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 38 no 1 pp 108ndash119 2011
[158] C J Mathias M R Lewis D E Reichert et al ldquoPreparationof 66Ga- and 68Ga-labeled Ga(III)-deferoxamine-folate aspotential folate-receptor-targeted PET radiopharmaceuticalsrdquoNuclear Medicine and Biology vol 30 no 7 pp 725ndash731 2003
[159] S-M Kim N Choi S Hwang et al ldquoFolate receptor-specific positron emission tomography imaging with folic acid-conjugated tissue inhibitor of metalloproteinase-2rdquo Bulletin ofthe Korean Chemical Society vol 34 no 11 pp 3243ndash3248 2013
[160] M Fani M-L Tamma G P Nicolas et al ldquoIn vivo imagingof folate receptor positive tumor xenografts using novel 68Ga-NODAGA-folate conjugatesrdquo Molecular Pharmaceutics vol 9no 5 pp 1136ndash1145 2012
[161] C Muller and R Schibli ldquoProspects in folate receptor-targetedradionuclide therapyrdquo Frontiers in Oncology vol 3 Article IDArticle 249 2013
[162] A Jain A Mathur U Pandey et al ldquoSynthesis and evaluationof a 68Ga labeled folic acid derivative for targeting folatereceptorsrdquo Applied Radiation and Isotopes vol 116 pp 77ndash842016
[163] W Xia A R Hilgenbrink E L Matteson M B Lockwood J-X Cheng and P S Low ldquoA functional folate receptor is inducedduring macrophage activation and can be used to target drugsto activated macrophagesrdquo Blood vol 113 no 2 pp 438ndash4462009
Contrast Media amp Molecular Imaging 21
[164] E P Krenning W A P Breeman P P M Kooij et alldquoLocalisation of endocrine-related tumours with radioiodi-nated analogue of somatostatinrdquoThe Lancet vol 1 no 8632 pp242ndash244 1989
[165] E P Krenning D J KwekkeboomWH Bakker et al ldquoSomato-statin receptor scintigraphy with [111In-DTPA-d-Phe1]- and[123I-Tyr3]-octreotide the Rotterdam experience with morethan 1000 patientsrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 20 no 8 pp 716ndash731 1993
[166] A Stahl G Meisetschlager M Schottelius et al ldquo[123I]Mtr-TOCA a radioiodinated and carbohydrated analogue ofoctreotide Scintigraphic comparison with [111In]octreotiderdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 33 no 1 pp 45ndash52 2006
[167] R Lebtahi J le Cloirec C Houzard et al ldquoDetection of neu-roendocrine tumors 99mTc-P829 scintigraphy compared with111In-pentetreotide scintigraphyrdquo Journal of Nuclear Medicinevol 43 no 7 pp 889ndash895 2002
[168] C Decristoforo T Maina B Nock M Gabriel P Cordopatisand R Moncayo ldquo99mTc-demotate 1 First data in tumourpatients - Results of a pilotphase I studyrdquo European Journal ofNuclearMedicine andMolecular Imaging vol 30 no 9 pp 1211ndash1219 2003
[169] C Decristoforo S J Mather W Cholewinski E DonnemillerG Riccabona and R Moncayo ldquo(99m)Tc-EDDAHYNIC-TOC A new (99m)Tc-labelled radiopharmaceutical forimaging somatostatin receptor-positive tumours First clinicalresults and intra-patient comparison with 111In-labelledoctreotide derivativesrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 27 no 9 pp 1318ndash1325 2000
[170] A Hubalewska-Dydejczyk K Fross-Baron R Mikołajczak etal ldquo99mTc-EDDAHYNIC-octreotate scintigraphy an efficientmethod for the detection and staging of carcinoid tumoursResults of 3 yearsrsquo experiencerdquo European Journal of NuclearMedicine and Molecular Imaging vol 33 no 10 pp 1123ndash11332006
[171] M Bangard M Behe S Guhlke et al ldquoDetection of somato-statin receptor-positive tumours using the new 99mC-tricine-HYNIC-D-Phe1-Tyr3-octreotide First results in patients andcomparison with 111In-DTPA-D-Phe1-octreotiderdquo EuropeanJournal of Nuclear Medicine and Molecular Imaging vol 27 no6 pp 628ndash637 2000
[172] A Helisch G J Forster H Reber et al ldquoPre-therapeuticdosimetry and biodistribution of 86Y-DOTA- Phe1-Tyr3-octreotide versus 111In-pentetreotide in patients with advancedneuroendocrine tumoursrdquo European Journal of NuclearMedicine and Molecular Imaging vol 31 no 10 pp 1386ndash13922004
[173] M Henze J Schuhmacher P Hipp et al ldquoPET imaging ofsomatostatin receptors using [68GA]DOTA-D-Phe1-Tyr3-Octreotide First results in patients with meningiomasrdquo Journalof Nuclear Medicine vol 42 no 7 pp 1053ndash1056 2001
[174] I Kayani J B Bomanji A Groves et al ldquoFunctional imaging ofneuroendocrine tumors with combined PETCT using 68Ga-DOTATATE (Dota-DPhe1 Tyr3-octreotate) and 18F-FDGrdquoCancer vol 112 no 11 pp 2447ndash2455 2008
[175] A Al-Nahhas ldquoNuclear medicine imaging of neuroendocrinetumoursrdquo Clinical Medicine vol 12 no 4 pp 377ndash380 2012
[176] V Ambrosini S Nicolini P Caroli et al ldquoPETCT imaging indifferent types of lung cancer an overviewrdquo European Journal ofRadiology vol 81 no 5 pp 988ndash1001 2012
[177] V Ambrosini D Campana P Tomassetti and S Fanti ldquo68Ga-labelled peptides for diagnosis of gastroenteropancreatic NETrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 39 no 1 pp S52ndashS60 2012
[178] K E Oberg J-C Reubi D J Kwekkeboom and E P KrenningldquoRole of somatostatins in gastroenteropancreatic neuroen-docrine tumor development and therapyrdquoGastroenterology vol139 no 3 pp 753-753 2010
[179] K Oberg ldquoGallium-68 somatostatin receptor PETCT Is ittime to replace 111Indium DTPA octreotide for patients withneuroendocrine tumorsrdquo Endocrine Journal vol 42 no 1 pp3-4 2012
[180] R Srirajaskanthan I Kayani A M Quigley J Soh M ECaplin and J Bomanji ldquoThe role of 68Ga-DOTATATE PET inpatients with neuroendocrine tumors and negative or equivocalfindings on 111In-DTPA-octreotide scintigraphyrdquo Journal ofNuclear Medicine vol 51 no 6 pp 875ndash882 2010
[181] A Kroiss D Putzer and C Uprimny ldquoFunctional imag-ing in phaeochromocytoma and neuroblastoma with 68Ga-DOTA-Tyr3-octreotide positron emission tomography and123I-metaiodobenzylguanidinerdquo European Journal of NuclearMedicine and Molecular Imaging vol 38 no 5 pp 865ndash8732011
[182] M Naji C Zhao S J Welsh et al ldquo68Ga-DOTA-TATE PETvs 123I-MIBG in identifying malignant neural crest tumoursrdquoMolecular Imaging and Biology vol 13 no 4 pp 769ndash775 2011
[183] V Ambrosini P Tomassetti P Castellucci et al ldquoComparisonbetween 68Ga-DOTA-NOC and 18F-DOPA PET for the detec-tion of gastro-entero-pancreatic and lung neuro-endocrinetumoursrdquo European Journal of Nuclear Medicine and MolecularImaging vol 35 no 8 pp 1431ndash1438 2008
[184] D Putzer M Gabriel B Henninger et al ldquoBone metastasesin patients with neuroendocrine tumor 68Ga- DOTA-Tyr3-octreotide PET in comparison to CT and bone scintigraphyrdquoJournal of Nuclear Medicine vol 50 no 8 pp 1214ndash1221 2009
[185] L K Anzola-Fuentes M Chianelli F Galli et al ldquoSomatostatinreceptor scintigraphy in patients with rheumatoid arthritis andsecondary Sjogrenrsquos syndrome treated with Infliximab a pilotstudyrdquo EJNMMI Research vol 6 no 1 article no 49 2016
[186] T Nobashi Y Nakamoto T Kubo et al ldquoThe utility of PETCTwith 68Ga-DOTATOC in sarcoidosis comparison with 67Ga-scintigraphyrdquoAnnals ofNuclearMedicine vol 30 no 8 pp 544ndash552 2016
[187] C Boy T A Heusner T D Poeppel et al ldquo68Ga-DOTATOCPETCT and somatostatin receptor (sst1-sst5) expression innormal human tissue Correlation of sst2mRNAand SUVmaxrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 38 no 7 pp 1224ndash1236 2011
[188] P Rinne S Hellberg M Kiugel et al ldquoComparison of Somato-statin Receptor 2-Targeting PET Tracers in the Detection ofMouse Atherosclerotic Plaquesrdquo Molecular Imaging and Biol-ogy vol 18 no 1 pp 99ndash108 2016
[189] M Asti E Ferrari S Croci et al ldquoSynthesis and characteri-zation of 68Ga-labeled curcumin and curcuminoid complexesas potential radiotracers for imaging of cancer and alzheimersdiseaserdquo Inorganic Chemistry vol 53 no 10 pp 4922ndash49332014
[190] A Signore I Santino and A W J M Glaudemans ldquoIn vivoimaging of microorganismsrdquo Clinical and Translational Imag-ing vol 4 no 3 pp 161-162 2016
[191] S Auletta F Galli C Lauri D Martinelli I Santino andA Signore ldquoImaging bacteria with radiolabelled quinolones
22 Contrast Media amp Molecular Imaging
cephalosporins and siderophores for imaging infection a sys-tematic reviewrdquo Clinical and Translational Imaging vol 4 no 4pp 229ndash252 2016
[192] X Ning S Lee Z Wang et al ldquoMaltodextrin-based imagingprobes detect bacteria in vivo with high sensitivity and speci-ficityrdquo Nature Materials vol 10 no 8 pp 602ndash607 2011
[193] J Ady andY Fong ldquoImaging for infection Fromvisualization ofinflammation to visualization of microbesrdquo Surgical Infectionsvol 15 no 6 pp 700ndash707 2014
[194] J M Sierra D Rodriguez-Puig A Soriano J Mensa C Pieraand J Vila ldquoAccumulation of 99mTc-ciprofloxacin in Staphy-lococcus aureus and Pseudomonas aeruginosardquo AntimicrobialAgents and Chemotherapy vol 52 no 7 pp 2691-2692 2008
[195] D I Andersson and D Hughes ldquoMicrobiological effects ofsublethal levels of antibioticsrdquoNature ReviewsMicrobiology vol12 no 7 pp 465ndash478 2014
[196] N Dumarey D Blocklet T Appelboom L Tant and ASchoutens ldquoInfecton is not specific for bacterial osteo-articularinfective pathologyrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 29 no 4 pp 530ndash535 2002
[197] K E Britton D W Wareham S S Das et al ldquoImaging bacte-rial infection with 99mTc-ciprofloxacin (Infecton)rdquo Journal ofClinical Pathology vol 55 no 11 pp 817ndash823 2002
[198] G Ferro-Flores M A Avila-Rodrıguez and F O Garcıa-PerezldquoImaging of bacteria with radiolabeled ubiquicidin by SPECTand PET techniquesrdquo Clinical and Translational Imaging vol 4no 3 pp 175ndash182 2016
[199] P S Hiemstra M T van den Barselaar M Roest P H Nibber-ing and R van Furth ldquoUbiquicidin a novel murine microbi-cidal protein present in the cytosolic fraction of macrophagesrdquoJournal of Leukocyte Biology vol 66 no 3 pp 423ndash428 1999
[200] M S Akhtar A Qaisar J Irfanullah et al ldquoAntimicrobialpeptide 99mTc-ubiquicidin 29ndash41 as human infection-imagingagent clinical trialrdquo Journal of Nuclear Medicne vol 46 no 4pp 567ndash573 2005
[201] M Assadi K Vahdat I Nabipour et al ldquoDiagnostic value of99mTc-ubiquicidin scintigraphy for osteomyelitis and compar-isons with 99mTc-methylene diphosphonate scintigraphy andmagnetic resonance imagingrdquo Nuclear Medicine Communica-tions vol 32 no 8 pp 716ndash723 2011
[202] T Emery ldquoExchange of Iron by Gallium in SiderophoresrdquoBiochemistry vol 25 no 16 pp 4629ndash4633 1986
[203] M Petrik C Zhai H Haas and C Decristoforo ldquoSiderophoresfor molecular imaging applicationsrdquo Clinical and TranslationalImaging vol 5 no 1 pp 15ndash27 2017
[204] H J Flint E A BayerM T Rincon R Lamed and B AWhiteldquoPolysaccharide utilization by gut bacteria potential for newinsights from genomic analysisrdquo Nature Reviews Microbiologyvol 6 no 2 pp 121ndash131 2008
[205] GGowrishankarMNamavari E B Jouannot et al ldquoInvestiga-tion of 6-[18F]-fluoromaltose as a novel PET tracer for imagingbacterial infectionrdquo PLoS ONE vol 9 no 9 Article ID e1079512014
[206] N Gholipour M Akhlaghi A M Kheirabadi et al ldquoChelator-free radiolabeling of dextran with 68Ga for PET studiesrdquoJournal of Radioanalytical and Nuclear Chemistry vol 311 no3 pp 1811ndash1817 2017
[207] C Bettegowda C A Foss I Cheong et al ldquoImaging bac-terial infections with radiolabeled 1-(21015840-deoxy-21015840- fluoro-120573-D-arabinofuranosyl)-5-iodouracilrdquo Proceedings of the NationalAcadamy of Sciences of the United States of America vol 102 no4 pp 1145ndash1150 2005
[208] S A Soghomonyan M Doubrovin J Pike et al ldquoPositronemission tomography (PET) imaging of tumor-localizedSalmonella expressing HSV1-TKrdquo Cancer GeneTherapy vol 12no 1 pp 101ndash108 2005
[209] C Palestro K Nichols S Sheikh-Fayyaz S Dewey P Singhaland K Bhargava ldquoCan Gallium-68 PET differentiate acuteinterstitial nephritis from acute tubular necrosisrdquo Journal ofNuclear Medicne vol 57 Supplement 2 p 551 2016
[210] A J Morguet D L Munz V Ivancevic et al ldquoImmunoscintig-raphy using technetium-99m-labeled anti-NCA-95 antigranu-locyte antibodies as an adjunct to echocardiography in subacuteinfective endocarditisrdquo Journal of the American College ofCardiology vol 23 no 5 pp 1171ndash1178 1994
[211] C van der Laken O Boerman W Oyen et al ldquoIn Vivo Expres-sion of Interleukin-1 Receptors during Various ExperimentallyInduced Inflammatory Conditionsrdquo The Journal of InfectiousDiseases vol 177 no 5 pp 1398ndash1401 1998
[212] C J Van Der Laken O C Boerman W J G Oyen M T PVan De Ven J W M Van Der Meer and F H M CorstensldquoScintigraphic detection of infection and inflammation Newdevelopments with special emphasis on receptor interactionrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 25 no 5 pp 535ndash546 1998
[213] C J van der LakenOC BoermanW J GOyenM T P van deVen J W M van der Meer and F H M Corstens ldquoImaging ofinfection in rabbits with radioiodinated interleukin-1 (120572 and 120573)its receptor antagonist and a chemotactic peptide a comparativestudyrdquo European Journal of Nuclear Medicine and MolecularImaging vol 25 no 4 pp 347ndash352 1998
[214] C J Van Der Laken O C BoermanW J G Oyen M T P VanDe Ven F H M Corstens and J W M Ven Der Meer ldquoThekinetics of radiolabelled interleukin-8 in infection and sterileinflammationrdquo Nuclear Medicine Communications vol 19 no3 pp 271ndash282 1998
[215] E Lazzeri P Erba M Perri et al ldquoScintigraphic imaging ofvertebral osteomyelitis with 111in-biotinrdquoThe Spine Journal vol33 no 7 pp E198ndashE204 2008
[216] E Blom B Langstrom and I Velikyan ldquo68Ga-labeling of biotinanalogues and their characterizationrdquo Bioconjugate Chemistryvol 20 no 6 pp 1146ndash1151 2009
[217] O Eriksson F Carlsson E Blom et al ldquoPreclinical evaluationof a 68Ga-labeled biotin analogue for applications in islettransplantationrdquo Nuclear Medicine and Biology vol 39 no 3pp 415ndash421 2012
[218] E A Weinstein A A Ordonez V P DeMarco et alldquoImaging Enterobacteriaceae infection in vivo with 18F-fluoro-deoxysorbitol positron emission tomographyrdquo Science Transla-tional Medicine vol 6 no 259 p 259ra146 2014
[219] K M Nielsen M H Kyneb A K O Alstrup et alldquo68Ga-labeled phage-display selected peptides as tracers forpositron emission tomography imaging of Staphylococcusaureus biofilm-associated infections Selection radiolabellingand preliminary biological evaluationrdquo Nuclear Medicine andBiology vol 43 no 10 pp 593ndash605 2016
[220] T J Makinen P Lankinen T Poyhonen J Jalava H T Aroand A Roivainen ldquoComparison of 18F-FDG and 68Ga PETimaging in the assessment of experimental osteomyelitis due toStaphylococcus aureusrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 32 no 11 pp 1259ndash1268 2005
[221] JMU Silvola I LaitinenH J Sipila et al ldquoUptake of 68galliumin atherosclerotic plaques in LDLRminusminusApoB100100micerdquo EJN-MMI Research vol 1 no 1 pp 1ndash8 2011
Contrast Media amp Molecular Imaging 23
[222] T A Wynn ldquoCellular and molecular mechanisms of fibrosisrdquoThe Journal of Pathology vol 214 no 2 pp 199ndash210 2008
[223] T Derlin D Jonigk J Bauersachs and FM Bengel ldquoMolecularImaging of Chemokine Receptor CXCR4 in NonndashSmall CellLung Cancer Using 68Ga-Pentixafor PETCT ComparisonWith 18F-FDGrdquo Clinical Nuclear Medicine 2016
[224] I Velikyan U Rosenstrom T N Bulenga O Eriksson andG Antoni ldquoFeasibility of multiple examinations using68ga-labelled collagelin analogues Organ distribution in rat forextrapolation to human organ and whole-body radiationdosimetryrdquo Pharmaceuticals vol 9 no 2 article no 31 2016
[225] S Jadhav M Kakela J Makila et al ldquoSynthesis and in VivoPET Imaging of Hyaluronan Conjugates of OligonucleotidesrdquoBioconjugate Chemistry vol 27 no 2 pp 391ndash403 2016
[226] A Autio A Saraste N Kudomi et al ldquoAssessment of bloodflow with (68) Ga-DOTA PET in experimental inflammation avalidation study using (15) O-waterrdquo American Journal ofNuclear Medicine and Molecular Imaging vol 4 no 6 pp 571ndash579 2014
[227] G Davies A Rolle A Maurer et al ldquoTowards translationalimmunoPETMR imaging of invasive pulmonary aspergillosisthe Humanised Monoclonal Antibody JF5 detects in vivordquoTheranostics vol 7 no 14 pp 3398ndash3414 2017
[228] DGoodwin CMeares GDavid et al ldquoMonoclonal antibodiesas reversible equilibrium carriers of radiopharmaceuticalsrdquoInternational Journal of Radiation Applications and Instrumen-tation Part B Nuclear Medicine and Biology vol 13 no 4 pp383ndash391 1986
[229] D A Goodwin C F Mears M McTigue and G S DavidldquoMonoclonal antibody hapten radiopharmaceutical deliveryrdquoNuclear Medicine Communications vol 7 no 8 pp 569ndash5801986
[230] S E Halpern and R O Dillman ldquoProblems associated withradioimmunodetection and possibilities for future solutionsrdquo JBiol Response Mod vol 6 no 3 pp 235ndash262 1987
[231] H Hong J Sun and W Cai ldquoRadionuclide-based cancerimaging targeting the carcinoembryonic antigenrdquo BiomarkerInsights vol 3 pp 435ndash451 2008
[232] G J Forster E B Santos P M Smith-Jones P Zanzonico andS M Larson ldquoPretargeted radioimmunotherapy with a single-chain antibodystreptavidin construct and radiolabeledDOTA-biotin Strategies for reduction of the renal doserdquo Journal ofNuclear Medicine vol 47 no 1 pp 140ndash149 2006
[233] Z Yao M Zhang H Kobayashi et al ldquoImproved targeting ofradiolabeled streptavidin in tumors pretargeted with biotiny-lated monoclonal antibodies through an avidin chaserdquo Journalof Nuclear Medicine vol 36 no 5 pp 837ndash841 1995
[234] C-H Chang R M Sharkey E A Rossi et al ldquoMolecularAdvances in Pretargeting Radioimunotherapy with BispecificAntibodies 1 Supported in part by USPHS Grant R01-CA-84379from the NIH and Department of Energy Grant DE-FG01-00NE22941 (both to R M S)1rdquo Mol Cancer Ther vol 1 no 7pp 553ndash563 2002
[235] R M Sharkey E A Rossi W J McBride C-H Chang andD M Goldenberg ldquoRecombinant Bispecific Monoclonal Anti-bodies Prepared by theDock-and-Lock Strategy for PretargetedRadioimmunotherapyrdquo Seminars in Nuclear Medicine vol 40no 3 pp 190ndash203 2010
[236] R M Sharkey E A Rossi C-H Chang and D M Golden-berg ldquoImproved cancer therapy and molecular imaging withmultivalent multispecific antibodiesrdquo Cancer Biotherapy andRadiopharmaceuticals vol 25 no 1 pp 1ndash12 2010
[237] D M Goldenberg R M Sharkey G Paganelli J Barbet andJ Chatal ldquoAntibody pretargeting advances cancer radioim-munodetection and radioimmunotherapyrdquo Journal of ClinicalOncology vol 24 no 5 pp 823ndash834 2006
[238] O C Boerman F G van Schaijk W J G Oyen and FH M Corstens ldquoPretargeted radioimmunotherapy of cancerprogress step by steprdquo Journal of Nuclear Medicine vol 44 no3 pp 400ndash411 2003
[239] J Schuhmacher S Kaul G Klivenyi et al ldquoImmunoscintigra-phy with positron emission tomography Gallium-68 chelateimaging of breast cancer pretargeted with bispecific anti-MUC1anti-Ga chelate antibodiesrdquo Cancer Research vol 61 no9 pp 3712ndash3717 2001
[240] J Schuhmacher G Klivenyi S Kaul et al ldquoPretargeting ofhuman mammary carcinoma xenografts with bispecific anti-MUC1anti-Ga chelate antibodies and immunoscintigraphywith PETrdquo Nuclear Medicine and Biology vol 28 no 7 pp 821ndash828 2001
[241] C Somasundaram S Matzku J Schuhmacher and M ZollerldquoDevelopment of a bispecific monoclonal antibody against agallium-67 chelate and the human melanoma-associated anti-gen p97 for potential use in pretargeted immunoscintigraphyrdquoCancer Immunology Immunotherapy vol 36 no 5 pp 337ndash3451993
[242] E A Rossi D L Rossi R Stein D M Goldenberg and C-H Chang ldquoA bispecific antibody-IFN1205722b immunocytokine tar-geting CD20 and HLA-DR is highly toxic to human lymphomaandmultiplemyeloma cellsrdquoCancer Research vol 70 no 19 pp7600ndash7609 2010
[243] R M Sharkey H Karacay S Litwin et al ldquoImproved ther-apeutic results by pretargeted radioimmunotherapy of non-Hodgkinrsquos lymphoma with a new recombinant trivalent anti-CD20 bispecific antibodyrdquo Cancer Research vol 68 no 13 pp5282ndash5290 2008
[244] G L Griffiths C-H Chang W J McBride et al ldquoReagentsandmethods for PETusing bispecific antibody pretargeting and68Ga-radiolabeled bivalent hapten-peptide-chelate conjugatesrdquoJournal of Nuclear Medicine vol 45 no 1 pp 30ndash39 2004
[245] J Watine M Miedouge and B Friedberg ldquoCarcinoembryonicantigen as an independent prognostic factor of recurrence andsurvival in patients resected for colorectal liver metastases Asystematic reviewrdquo Diseases of the Colon amp Rectum vol 44 no12 pp 1791ndash1799 2001
[246] M J Goldstein and E P Mitchell ldquoCarcinoembryonic antigenin the staging and follow-up of patients with colorectal cancerrdquoCancer Investigation vol 23 no 4 pp 338ndash351 2005
[247] D V Gold D M Goldenberg H Karacay et al ldquoA novelbispecific trivalent antibody construct for targeting pancreaticcarcinomardquo Cancer Research vol 68 no 12 pp 4819ndash48262008
[248] J Schuhmacher G Klivenyi R Matys et al ldquoMultistep tumortargeting in nudemice using bispecific antibodies and a galliumchelate suitable for immunoscintigraphy with positron emis-sion tomographyrdquo Cancer Research vol 55 no 1 pp 115ndash1231995
[249] G Klivenyi J Schuhmacher E Patzelt et al ldquoGallium-68chelate imaging of human colon carcinoma xenografts pre-targeted with bispecific anti-CD44(V6)anti-gallium chelateantibodiesrdquo Journal ofNuclearMedicine vol 39 no 10 pp 1769ndash1776 1998
[250] M Zoller J Schuhmacher J Reed W Maier-Borst and SMatzku ldquoEstablishment and characterization of monoclonal
24 Contrast Media amp Molecular Imaging
antibodies against an octahedral gallium chelate suitable forimmunoscintigraphy with PETrdquo Journal of Nuclear Medicinevol 33 no 7 pp 1366ndash1372 1992
[251] R M Sharkey T M Cardillo E A Rossi et al ldquoSignal ampli-fication in molecular imaging by pretargeting a multivalentbispecific antibodyrdquo Nature Medicine vol 11 no 11 pp 1250ndash1255 2005
[252] D M Goldenberg and R M Sharkey ldquoNovel radiolabeledantibody conjugatesrdquo Oncogene vol 26 no 25 pp 3734ndash37442007
[253] D M Goldenberg E A Rossi R M Sharkey W J McBrideand C-H Chang ldquoMultifunctional antibodies by the dock-and-lock method for improved cancer imaging and therapy bypretargetingrdquo Journal of NuclearMedicine vol 49 no 1 pp 158ndash163 2008
[254] R Schoffelen R M Sharkey D M Goldenberg et al ldquoPre-targeted immuno-positron emission tomography imaging ofcarcinoembryonic antigen-expressing tumors with a bispecificantibody and a68Ga- And18F-labeled hapten peptide in micewith human tumor xenograftsrdquoMolecular Cancer Therapeuticsvol 9 no 4 pp 1019ndash1027 2010
[255] E S Bos W H Kuijpers M Meesters-Winters et al ldquoIn vitroevaluation of DNA-DNA hybridization as a two-step approachin radioimmunotherapy of cancerrdquoCancer Research vol 54 no13 pp 3479ndash3486 1994
[256] G Paganelli M Bartolomei M Ferrari et al ldquoPre-TargetedLocoregional Radioimmunotherapy withrdquo Cancer biotherapyand radiopharmaceuticals vol 16 no 3 pp 227ndash235 2001
[257] A Forero P L Weiden J M Vose et al ldquoPhase 1 trial of a novelanti-CD20 fusion protein in pretargeted radioimmunotherapyfor B-cell non-Hodgkin lymphomardquo Blood vol 104 no 1 pp227ndash236 2004
[258] DM Goldenberg C-H Chang E A RossiW J McBride andR M Sharkey ldquoPretargeted molecular imaging and radioim-munotherapyrdquoTheranostics vol 2 no 5 pp 523ndash540 2012
[259] H Karacay R M Sharkey W J McBride E A Rossi C-HChang and D M Goldenberg ldquoOptimization of hapten-peptide labeling for pretargeted immunoPET of bispecificantibody using generator-produced 68Gardquo Journal of NuclearMedicine vol 52 no 4 pp 555ndash559 2011
[260] J R Oh and B C Ahn ldquoFalse-positive uptake on radioiodinewhole-body scintigraphy physiologic and pathologic variantsunrelated to thyroid cancerrdquo American Journal of NuclearMedicine and Molecular Imaging vol 2 no 2 pp 141ndash150 2012
[261] E Frampas C Rousseau C Bodet-Milin J Barbet J-F Chataland F Kraeber-Bodere ldquoImprovement of radioimmunotherapyusing pretargetingrdquo Frontiers in Oncology vol 3 Article ID00159 2013
[262] C S McKay and M G Finn ldquoClick chemistry in complexmixtures Bioorthogonal bioconjugationrdquo Chemistry amp Biologyvol 21 no 9 pp 1075ndash1101 2014
[263] B L Oliveira Z Guo and G J Bernardes ldquoInverse electrondemand DielsndashAlder reactions in chemical biologyrdquo ChemicalSociety Reviews vol 46 no 16 pp 4895ndash4950 2017
[264] B Nichols Z Qin J Yang D R Vera and N K Devaraj ldquo68Gachelating bioorthogonal tetrazine polymers for the multisteplabeling of cancer biomarkersrdquo Chemical Communications vol50 no 40 pp 5215ndash5217 2014
[265] R Rossin P R Verkerk S M van den Bosch et al ldquoInvivo chemistry for pretargeted tumor imaging in live micerdquoAngewandte Chemie International Edition vol 49 no 19 pp3375ndash3378 2010
[266] B M Zeglis K K Sevak T Reiner et al ldquoA pretargetedPET imaging strategy based on bioorthogonal diels-alder clickchemistryrdquo Journal of Nuclear Medicine vol 54 no 8 pp 1389ndash1396 2013
[267] J L Houghton R Membreno D Abdel-Atti et al ldquoEstablish-ment of the invivo efficacy of pretargeted radioimmunotherapyutilizing inverse electron demand diels-alder click chemistryrdquoMolecular Cancer Therapeutics vol 16 no 1 pp 124ndash133 2017
[268] J Funkhouser ldquoReinventing pharma the theranostic revolu-tionrdquo Current Drug Discovery pp 17ndash19 2002
[269] J Sorensen I Velikyan A Wennborg et al ldquoMeasuring HER2-expression in metastatic breast cancer using 68Ga-ABY025PETCTrdquo European Journal of Nuclear Medicine and MolecularImaging vol 41 pp S226ndashS226 2014
[270] I Velikyan A Wennborg J Feldwisch et al ldquoGMP compliantpreparation of a 68Gallium-labeled Affibody analogue forbreast cancer patient examination first-in-manrdquoEur JNuclMedMol Imaging vol 41 pp S228ndashS229 2014
[271] K Oberg ldquoMolecular imaging radiotherapy Theranostics forpersonalized patient management of neuroendocrine tumors(NETs)rdquoTheranostics vol 2 no 5 pp 448ndash458 2012
[272] I Velikyan AWennborg J FeldwischH Lindman J Carlssonand J Sorensen ldquoGood manufacturing practice production of [(68) Ga]Ga-ABY-025 for HER2 specific breast cancer imagingrdquoAmerican Journal of Nuclear Medicine and Molecular Imagingvol 6 no 2 pp 135ndash153 2016
[273] M Sandstrom K Lindskog I Velikyan et al ldquoBiodistributionand radiation dosimetry of the anti-HER2 Affibody molecule68Ga-ABY-025 in breast cancer patientsrdquo Journal of NuclearMedicine vol 57 no 6 pp 867ndash871 2016
[274] D Sandberg V Tolmachev I Velikyan et al ldquoIntra-imagereferencing for simplified assessment of HER2-expression inbreast cancer metastases using the Affibody molecule ABY-025with PET and SPECTrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 44 no 8 pp 1337ndash1346 2017
[275] H ZhangM AMoroz I Serganova et al ldquoImaging expressionof the human somatostatin receptor subtype-2 reporter genewith 68Ga-DOTATOCrdquo Journal ofNuclearMedicine vol 52 no1 pp 123ndash131 2011
[276] M Naji and A Al-Nahhas ldquo68Ga-labelled peptides in themanagement of neuroectodermal tumoursrdquo European Journalof Nuclear Medicine and Molecular Imaging vol 39 no 1 ppS61ndashS67 2012
[277] I Velikyan ldquoThe diversity of 68Ga-Based imaging agentsrdquoRecent Results in Cancer Research vol 194 pp 101ndash131 2013
[278] K Ferreira H-Y Hu V Fetz et al ldquoMultivalent siderophore-dotam conjugates as theranostics for imaging and treatment ofbacterial infectionsrdquo Angewandte Chemie International Editionvol 56 no 28 pp 8272ndash8276 2017
Computational and Mathematical Methods in Medicine
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Research and TreatmentAIDS
Hindawiwwwhindawicom Volume 2018
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Evidence-Based Complementary andAlternative Medicine
Volume 2018Hindawiwwwhindawicom
Submit your manuscripts atwwwhindawicom
16 Contrast Media amp Molecular Imaging
[10] J Silvola A Autio P Luoto S Jalkanen andA Roivainen ldquoPre-liminary evaluation of novel 68Ga-DOTAVAP-PEG-P2 peptidetargeting vascular adhesion protein-1rdquo Clinical Physiology andFunctional Imaging vol 30 no 1 pp 75ndash78 2010
[11] T Ujula S Salomaki P Virsu et al ldquoSynthesis 68Ga labelingand preliminary evaluation of DOTA peptide binding vascularadhesion protein-1 a potential PET imaging agent for diagnos-ing osteomyelitisrdquo Nuclear Medicine and Biology vol 36 no 6pp 631ndash641 2009
[12] A Autio T Henttinen H J Sipila S Jalkanen and ARoivainen ldquoMini-PEG spacering of VAP-1-targeting 68Ga-DOTAVAP-P1 peptide improves PET imaging of inflamma-tionrdquo EJNMMI Research vol 1 no 1 pp 1ndash7 2011
[13] K Aalto A Autio E A Kiss et al ldquoSiglec-9 is a novel leukocyteligand for vascular adhesion protein-1 and can be used in PETimaging of inflammation and cancerrdquo Blood vol 118 no 13 pp3725ndash3733 2011
[14] V Kumar D K Boddeti S G Evans F Roesch and RHowman-Giles ldquoPotential use of 68Ga-apo-transferrin as a PETimaging agent for detecting Staphylococcus aureus infectionrdquoNuclear Medicine and Biology vol 38 no 3 pp 393ndash398 2011
[15] M Petrik H Haas G Dobrozemsky et al ldquo68Ga-siderophoresfor PET imaging of invasive pulmonary aspergillosis Proof ofprinciplerdquo Journal of Nuclear Medicine vol 51 no 4 pp 639ndash645 2010
[16] M Petrik H Haas M Schrettl A Helbok M Blatzer and CDecristoforo ldquoIn vitro and in vivo evaluation of selected 68Ga-siderophores for infection imagingrdquo Nuclear Medicine andBiology vol 39 no 3 pp 361ndash369 2012
[17] M Petrik GM Franssen H Haas et al ldquoPreclinical evaluationof two 68Ga-siderophores as potential radiopharmaceuticals forAspergillus fumigatus infection imagingrdquo European Journal ofNuclearMedicine andMolecular Imaging vol 39 no 7 pp 1175ndash1183 2012
[18] A Rizzello D Di Pierro F Lodi et al ldquoSynthesis and qualitycontrol of 68Ga citrate for routine clinical PETrdquo NuclearMedicine Communications vol 30 no 7 pp 542ndash545 2009
[19] C Nanni C Errani and L Boriani ldquo 68Ga-citrate PETCT forevaluating patients with infections of the bone preliminaryresultsrdquo Journal of Nuclear Medicine vol 51 no 12 pp 1932ndash1936 2010
[20] S S Das A V Hall D W Wareham and K E Britton ldquoInfec-tion imaging with radiopharmaceuticals in the 21st centuryrdquoBrazilian Archives of Biology and Technology vol 45 no spepp 25ndash37 2002
[21] A Signore and A W J M Glaudemans ldquoThe molecularimaging approach to image infections and inflammation bynuclear medicine techniquesrdquo Annals of Nuclear Medicine vol25 no 10 pp 681ndash700 2011
[22] T Yusa K Tateda A Ohara and S Miyazaki ldquoNew possiblebiomarkers for diagnosis of infections and diagnostic distinc-tion between bacterial and viral infections in childrenrdquo Journalof Infection and Chemotherapy vol 23 no 2 pp 96ndash100 2017
[23] A Signore A W J M Glaudemans O Gheysens C Lauriand O A Catalano ldquoNuclear Medicine Imaging in PediatricInfection or Chronic Inflammatory Diseasesrdquo Seminars inNuclear Medicine vol 47 no 3 pp 286ndash303 2017
[24] I Velikyan ldquoMolecular imaging and radiotherapyTheranosticsfor personalized patient managementrdquo Theranostics vol 2 no5 pp 424ndash426 2012
[25] F Rosch and R P Baum ldquoGenerator-based PET radiophar-maceuticals for molecular imaging of tumours On the way
to THERANOSTICSrdquo Dalton Transactions vol 40 no 23 pp6104ndash6111 2011
[26] R P Baum H R Kulkarni and C Carreras ldquoPeptides andreceptors in image-guided therapy Theranostics for neuroen-docrine neoplasmsrdquo Seminars in Nuclear Medicine vol 42 no3 pp 190ndash207 2012
[27] R P Baum and H R Kulkarni ldquoTheranostics From molecularimaging using Ga-68 labeled tracers and PETCT to per-sonalized radionuclide therapy - the bad berka experiencerdquoTheranostics vol 2 no 5 pp 437ndash447 2012
[28] I Velikyan ldquoRadionuclides for Imaging andTherapy in Oncol-ogyrdquo Cancer Theranostics pp 285ndash325 2014
[29] J Czernin andWAWeber ldquoIssues and controversies in nuclearmedicine Introductionrdquo Journal of Nuclear Medicine vol 52no Supplement 2 pp 1Sndash2S 2011
[30] S J Goldsmith and S Vallabhajosula ldquoClinically proven radio-pharmaceuticals for infection imaging mechanisms and appli-cationsrdquo Seminars in Nuclear Medicine vol 39 no 1 pp 2ndash102009
[31] M F Tsan ldquoMechanism of gallium-67 accumulation in inflam-matory lesionsrdquo Journal of Nuclear Medicine vol 26 no 1 pp88ndash92 1985
[32] S L Kipper ldquoRadiolabelled leukocyte imaging of the abdomenrdquoin Nuclear Medicine Annual J Freeman Ed pp 81ndash126 RavenPress New York NY USA 1995
[33] F Jamar J Buscombe A Chiti et al ldquoEANMSNMMI guidelinefor 18F-FDG use in inflammation and infectionrdquo Journal ofNuclear Medicine vol 54 no 4 pp 647ndash658 2013
[34] C J Palestro ldquoThe current role of gallium imaging in infectionrdquoSeminars in Nuclear Medicine vol 24 no 2 pp 128ndash141 1994
[35] M S Akhtar M B Imran M A Nadeem and A ShahidldquoAntimicrobial peptides as infection imaging agents better thanradiolabeled antibioticsrdquo International Journal of Peptides vol2012 Article ID 965238 19 pages 2012
[36] D Delbeke and G M Segall ldquoStatus of and trends in nuclearmedicine in the United Statesrdquo Journal of Nuclear Medicine vol52 no 2 2011
[37] S S Gambhir J Czernin J Schwimmer D H Silverman R EColeman and M E Phelps ldquoA tabulated summary of the FDGPET literaturerdquo Journal of Nuclear Medicine vol 42 pp 1Sndash93S2001
[38] M J Lindsay B A Siegel S R Tunis et al ldquoThe NationalOncologic PET Registry ExpandedMedicare coverage for PETunder coverage with evidence developmentrdquo American Journalof Roentgenology vol 188 no 4 pp 1109ndash1113 2007
[39] F Gemmel H Van Den Wyngaert C Love M M Welling PGemmel and C J Palestro ldquoProsthetic joint infectionsradionuclide state-of-the-art imagingrdquo European Journal ofNuclearMedicine andMolecular Imaging vol 39 no 5 pp 892ndash909 2012
[40] J Sorensen ldquoHow does the patient benefit from clinical PETrdquoTheranostics vol 2 no 5 pp 427ndash436 2012
[41] S L Rice C A Roney P Daumar and J S Lewis ldquoThe nextgeneration of positron emission tomography radiopharmaceu-ticals in oncologyrdquo Seminars in Nuclear Medicine vol 41 no 4pp 265ndash282 2011
[42] R LWahl JMHerman and E Ford ldquoThePromise and Pitfallsof Positron Emission Tomography and Single-Photon EmissionComputed Tomography Molecular Imaging-Guided RadiationTherapyrdquo Seminars in Radiation Oncology vol 21 no 2 pp 88ndash100 2011
Contrast Media amp Molecular Imaging 17
[43] A W J M Glaudemans R H J A Slart J M Van Dijl MVan Oosten and G M Van Dam ldquoMolecular imaging of infec-tious and inflammatory diseases A terra incognitardquo Journal ofNuclear Medicine vol 56 no 5 pp 659ndash661 2015
[44] X Li W Bauer I Israel et al ldquoTargeting p-selectin by gallium-68-labeled fucoidan positron emission tomography for nonin-vasive characterization of vulnerable plaques Correlation within vivo 176t mrirdquo Arteriosclerosis Thrombosis and VascularBiology vol 34 no 8 pp 1661ndash1667 2014
[45] S Eichendorff P Svendsen D Bender et al ldquoBiodistributionand PET Imaging of a Novel [68Ga]-Anti-CD163-AntibodyConjugate in Rats with Collagen-Induced Arthritis and inControlsrdquoMolecular Imaging and Biology vol 17 no 1 pp 87ndash93 2014
[46] Z Zhu Y Yin K Zheng et al ldquoEvaluation of synovial angiogen-esis in patients with rheumatoid arthritis using 68Ga-PRGD2PETCT A prospective proof-of-concept cohort studyrdquo Annalsof the Rheumatic Diseases vol 73 no 6 pp 1269ndash1272 2014
[47] J S Eo J C Paeng S Lee et al ldquoAngiogenesis imaging inmyocardial infarction using 68Ga-NOTA- RGD PET Charac-terization and application to therapeutic efficacy monitoring inratsrdquo Coronary Artery Disease vol 24 no 4 pp 303ndash311 2013
[48] J H Kim Y-H Kim Y J Kim et al ldquoQuantitative positronemission tomography imaging of angiogenesis in rats with fore-limb ischemia using 68Ga-NOTA-c(RGDyK)rdquo Angiogenesisvol 16 no 4 pp 837ndash846 2013
[49] I Laitinen J Notni K Pohle et al ldquoComparison of cyclicRGD peptides for 120572v1205733 integrin detection in a rat model ofmyocardial infarctionrdquo EJNMMI Research vol 3 no 1 pp 1ndash9 2013
[50] M Kiugel I Dijkgraaf V Kyto et al ldquoDimeric [68Ga]DOTA-RGD Peptide Targeting 120572 ltinfgtvltinfgt 120573 ltinfgt3ltinfgt Inte-grin Reveals Extracellular Matrix Alterations after MyocardialInfarctionrdquo Molecular Imaging and Biology vol 16 no 6 pp793ndash801 2014
[51] M Gronman M Tarkia T Kiviniemi et al ldquoImaging of 120572v1205733integrin expression in experimental myocardial ischemia with[68Ga]NODAGA-RGD positron emission tomographyrdquo Jour-nal of Translational Medicine vol 15 no 1 p 144 2017
[52] J Haukkala I Laitinen P Luoto et al ldquo68Ga-DOTA-RGDpep-tide Biodistribution and binding into atherosclerotic plaquesin micerdquo European Journal of Nuclear Medicine and MolecularImaging vol 36 no 12 pp 2058ndash2067 2009
[53] H Virtanen A Autio R Siitonen et al ldquo68Ga-DOTA-Siglec-9- a new imaging tool to detect synovitisrdquo Arthritis Research ampTherapy vol 17 no 1 article no 308 2015
[54] J Retamal J Sorensen M Lubberink et al ldquoFeasibility of(68) Ga-labeled Siglec-9 peptide for the imaging of acutelung inflammation a pilot study in a porcine model of acuterespiratory distress syndromerdquoAm JNuclMedMol Imaging vol6 no 1 pp 18ndash31 2016
[55] J M U Silvola H Virtanen R Siitonen et al ldquoLeukocytetrafficking-associated vascular adhesion protein 1 is expressedand functionally active in atherosclerotic plaquesrdquo ScientificReports vol 6 Article ID 35089 2016
[56] H Ahtinen J Kulkova L Lindholm et al ldquo68Ga-DOTA-Siglec-9 PETCT imaging of peri-implant tissue responses andstaphylococcal infectionsrdquo EJNMMI Research vol 4 no 1article no 45 pp 1ndash11 2014
[57] A Autio S Jalkanen and A Roivainen ldquoNuclear imaging ofinflammation Homing-associated molecules as targetsrdquo EJN-MMI Research vol 3 no 1 pp 1ndash7 2013
[58] J TThackeray T Derlin AHaghikia et al ldquoMolecular Imagingof the Chemokine Receptor CXCR4 after Acute MyocardialInfarctionrdquo JACC Cardiovascular Imaging vol 8 no 12 pp1417ndash1426 2015
[59] J S Schmid A Schirbel A K Buck S Kropf H-J Westerand C Lapa ldquoPentixafor-Positron Emission TomographyComputed Tomography Detects Chemokine Receptor CXCR4Expression after Ischemic Strokerdquo Circulation CardiovascularImaging vol 9 no 9 Article ID e005217 2016
[60] J Zhou G Hao H Weng et al ldquoIn vivo evaluation ofmedical device-associated inflammation using a macrophage-specific positron emission tomography (PET) imaging proberdquoBioorganic amp Medicinal Chemistry Letters vol 23 no 7 pp2044ndash2047 2013
[61] S A Kularatne M-J Belanger X Meng et al ldquoComparativeanalysis of folate derived PET imaging agents with [ 18F]-2-fluoro-2-deoxy-d-glucose using a rodent inflammatory pawmodelrdquo Molecular Pharmaceutics vol 10 no 8 pp 3103ndash31112013
[62] V Ambrosini M Zompatori F De Luca et al ldquo68Ga-DOTANOCPETCTAllows Somatostatin Receptor Imaging inIdiopathic Pulmonary Fibrosis Preliminary Resultsrdquo Journal ofNuclear Medicine vol 51 no 12 pp 1950ndash1955 2010
[63] T Lincke J Singer R Kluge O Sabri and R Paschke ldquoRela-tive quantification of indium-111 pentetreotide and gallium-68DOTATOC uptake in the thyroid gland and association withthyroid pathologiesrdquoThyroid vol 19 no 4 pp 381ndash389 2009
[64] A Rominger T Saam E Vogl et al ldquoIn vivo imaging ofmacrophage activity in the coronary arteries using 68Ga-DOTATATE PETCT correlation with coronary calcium bur-den and risk factorsrdquo Journal of Nuclear Medicine vol 51 no 2pp 193ndash197 2010
[65] J M Tarkin F R Joshi N R Evans et al ldquoDetection ofAtherosclerotic Inflammation by 68Ga-DOTATATE PET Com-pared to [18F]FDG PET Imagingrdquo Journal of the AmericanCollege of Cardiology vol 69 no 14 pp 1774ndash1791 2017
[66] S-P Lee H-J Im S Kang et al ldquoNoninvasive imaging ofmyocardial inflammation in myocarditis using 68Ga-taggedmannosylated human serum albumin positron emissiontomographyrdquoTheranostics vol 7 no 2 pp 413ndash424 2017
[67] Z Zha J Song S R Choi et al ldquo68Ga-Bivalent PolypegylatedStyrylpyridine Conjugates for Imaging A120573 Plaques in CerebralAmyloid Angiopathyrdquo Bioconjugate Chemistry vol 27 no 5 pp1314ndash1323 2016
[68] H Watanabe M Ono S Iikuni et al ldquoA 68Ga complex basedon benzofuran scaffold for the detection of 120573-amyloid plaquesrdquoBioorganic amp Medicinal Chemistry Letters vol 24 no 20 pp4834ndash4837 2014
[69] D Cressier M Dhilly T T Cao Pham et al ldquoGallium-68 Com-plexes Conjugated to Pittsburgh Compound B Radiolabelingand Biological EvaluationrdquoMolecular Imaging and Biology vol18 no 3 pp 334ndash343 2016
[70] D Satpati CArjun R KrishnamohanG Samuel and S Baner-jee ldquo68Ga-labeledCiprofloxacinConjugates as Radiotracers forTargeting Bacterial InfectionrdquoChemical Biology ampDrug Designvol 87 no 5 pp 680ndash686 2016
[71] T Ebenhan N Chadwick and M M Sathekge ldquoPeptidesynthesis characterization and 68Ga-radiolabeling of NOTA-conjugated ubiquicidin fragments for prospective infectionimaging with PETCTrdquo Nuclear Medicine and Biology vol 41no 5 pp 390ndash400 2014
18 Contrast Media amp Molecular Imaging
[72] T Ebenhan J R Zeevaart and J D Venter ldquoPreclinicalevaluation of 68Ga-labeled 1 4 7-triazacyclononane-1 4 7-triacetic acid-ubiquicidin as a radioligand for PET infectionimagingrdquo Journal of Nuclear Medicine vol 55 no 2 pp 308ndash314 2014
[73] B B Mokaleng T Ebenhan S Ramesh et al ldquoSynthesis 68Ga-radiolabeling and preliminary in vivo assessment of adepsipeptide-derived compound as a potential PETCTinfection imaging agentrdquo BioMed Research International vol2015 Article ID 284354 2015
[74] T Ebenhan B Mokaleng J Venter H Kruger J Zeevaart andM Sathekge ldquoPreclinical Assessment of a 68Ga-DOTA-Functionalized Depsipeptide as a Radiodiagnostic InfectionImaging AgentrdquoMolecules vol 22 no 9 p 1403 2017
[75] S Chopra B Singh A Koul A Mishra and H Wester ldquoSyn-thesis of DOTA conjugated GF-17 and RAWVAWR-NH2 andradiolabeling with 68Ga as a potential PET tracer for infectionimagingrdquo J Nucl Med vol 57 Supplement 2 p 1115 2016
[76] M Petrik HHaas P Laverman et al ldquo 68Ga-triacetylfusarinineC and 68Ga-ferrioxamine e for aspergillus infection imaginguptake specificity in various microorganismsrdquoMolecular Imag-ing and Biology vol 16 no 1 pp 102ndash108 2014
[77] V Kumar and D K Boddeti ldquo 68Ga-radiopharmaceuticals forPET imaging of infection and inflammationrdquo Recent Results inCancer Research vol 194 pp 189ndash219 2013
[78] M Vorster A Maes A Jacobs et al ldquoEvaluating the possiblerole of 68Ga-citrate PETCT in the characterization of indeter-minate lung lesionsrdquo Annals of Nuclear Medicine vol 28 no 6pp 523ndash530 2014
[79] M Vorster B Mokaleng M M Sathekge and T Ebenhan ldquoAmodified technique for efficient radiolabeling of 68Ga-citratefrom a SnO2-based 68Ge68Ga generator for better infectionimagingrdquoHellenic Journal of Nuclear Medicine vol 16 no 3 pp193ndash198 2013
[80] S Salomaeki J Kemppainen U Hohenthal et al ldquoHead-to-head comparison of 68Ga-Citrate and 18F-FDG PETCT fordetection of infectious foci in patients with staphylococcusaureus bacteraemiardquo Contrast Media amp Molecular Imaging vol2017 p 8 2017
[81] L Fass ldquoImaging and cancer a reviewrdquoMolecular Oncology vol2 no 2 pp 115ndash152 2008
[82] A Chopra L Shan W C Eckelman et al ldquoMolecular imagingand contrast agent database (MICAD) Evolution and progressrdquoMolecular Imaging and Biology vol 14 no 1 pp 4ndash13 2012
[83] A Sanchez-Crespo P Andreo and S A Larsson ldquoPositronflight in human tissues and its influence on PET image spatialresolutionrdquo European Journal of Nuclear Medicine and Molecu-lar Imaging vol 31 no 1 pp 44ndash51 2004
[84] H W A M De Jong L Perk G W M Visser R Boellaard GAM S Van Dongen and A A Lammertsma ldquoHigh resolutionPET imaging characteristics of68Ga 124i and89Zr comparedto18Frdquo in Proceedings of the Nuclear Science Symposium Con-ference Record 2005 IEEE pp 1624ndash1627 Puerto Rico October2005
[85] I Velikyan A Sundin B Eriksson et al ldquoIn vivo bindingof [68Ga]-DOTATOC to somatostatin receptors in neuroen-docrine tumours - impact of peptide massrdquo Nuclear Medicineand Biology vol 37 no 3 pp 265ndash275 2010
[86] U Eberlein and M Lassmann ldquoDosimetry of [68Ga]-labeledcompoundsrdquo Applied Radiation and Isotopes vol 76 pp 70ndash742013
[87] C PettinatoA SarnelliMDiDonna et al ldquo68Ga-DOTANOCBiodistribution and dosimetry in patients affected by neuroen-docrine tumorsrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 35 no 1 pp 72ndash79 2008
[88] B P Burke G S Clemente and S J Archibald ldquoRecentadvances in chelator design and labelling methodology for68Ga radiopharmaceuticalsrdquo Journal of Labelled Compoundsand Radiopharmaceuticals vol 57 no 4 pp 239ndash243 2014
[89] I Velikyan U Rosenstrom S Estrada et al ldquoSynthesis andpreclinical evaluation of 68Ga-labeled collagelin analogs forimaging and quantification of fibrosisrdquo Nuclear Medicine andBiology vol 41 no 9 pp 728ndash736 2014
[90] M F Ferreira G Pereira J P Andre and etal C ldquoGa[NO2A-N-(120572-amino)propionate] chelates Synthesis and evaluation aspotential tracers for 68Ga PETrdquoDalton Transactions vol 43 no21 pp 8037ndash8047 2014
[91] J Notni J Simecek and H-J Wester ldquoPhosphinic acid func-tionalized polyazacycloalkane chelators for radiodiagnosticsand radiotherapeutics Unique characteristics and applicationsrdquoChemMedChem vol 9 no 6 pp 1107ndash1115 2014
[92] J Simecek O Zemek P Hermann J Notni and H J WesterldquoTailored gallium( III) chelator NOPO synthesis characteriza-tion bioconjugation and application in preclinical Ga-68-PETimagingrdquoMolecular Pharmaceutics 2013
[93] D Parker B P Waldron and D S Yufit ldquoCrystallographicand solution NMR structural analyses of four hexacoordinatedgallium(iii) complexes based on ligands derived from 6-amino-perhydro-14-diazepinerdquo Dalton Transactions vol 42 no 22pp 8001ndash8008 2013
[94] B P Waldron D Parker C Burchardt D S Yufit M ZimnyandF Roesch ldquoStructure and stability of hexadentate complexesof ligands based on AAZTA for efficient PET labelling withgallium-68rdquo Chemical Communications vol 49 no 6 pp 579ndash581 2013
[95] D Parker and B PWaldron ldquoConformational analysis and syn-thetic approaches to polydentate perhydro-diazepine ligandsfor the complexation of gallium(iii)rdquo Organic amp BiomolecularChemistry vol 11 no 17 pp 2827ndash2838 2013
[96] I Velikyan H Maecke and B Langstrom ldquoConvenient prepa-ration of 68Ga-based PET-radiopharmaceuticals at room tem-peraturerdquo Bioconjugate Chemistry vol 19 no 2 pp 569ndash5732008
[97] J Erchegyi R Cescato B Waser J E Rivier and J C ReubildquoN-Imidazolebenzyl-histidine substitution in somatostatin andin its octapeptide analogue modulates receptor selectivity andfunctionrdquo Journal of Medicinal Chemistry vol 54 no 17 pp5981ndash5987 2011
[98] R Saha N Saha R S Donofrio and L L Bestervelt ldquoMicrobialsiderophores Amini reviewrdquo Journal of Basic Microbiology vol53 no 4 pp 303ndash317 2013
[99] V Nikolova S Angelova N Markova and T Dudev ldquoGalliumas a Therapeutic Agent A Thermodynamic Evaluation of theCompetition between Ga3+ and Fe3+ Ions in MetalloproteinsrdquoThe Journal of Physical Chemistry B vol 120 no 9 pp 2241ndash2248 2016
[100] C R Chitambar ldquoGallium and its competing roles with ironin biological systemsrdquo Biochimica et Biophysica Acta (BBA) -Molecular Cell Research vol 1863 no 8 pp 2044ndash2053 2016
[101] J A Lessa M A Soares and R G dos Santos ldquoGallium(III)complexes with 2-acetylpyridine-derived thiosemicarbazonesantimicrobial and cytotoxic effects and investigation on theinteractions with tubulinrdquo BioMetals vol 26 pp 151ndash165 2013
Contrast Media amp Molecular Imaging 19
[102] M van Oosten M Hahn L M A Crane et al ldquoTargetedimaging of bacterial infections Advances hurdles and hopesrdquoFEMS Microbiology Reviews vol 39 no 6 pp 892ndash916 2015
[103] M Vorster AMaes C V DWiele andM Sathekge ldquoGallium-68 PET A Powerful Generator-based Alternative to Infectionand Inflammation Imagingrdquo Seminars in Nuclear Medicine vol46 no 5 pp 436ndash447 2016
[104] M Kircher and C Lapa ldquoNovel Noninvasive Nuclear MedicineImaging Techniques for Cardiac Inflammationrdquo Current Car-diovascular Imaging Reports vol 10 no 2 article no 6 2017
[105] D AHammoud ldquoMolecular imaging of inflammation Currentstatusrdquo Journal of Nuclear Medicine vol 57 no 8 pp 1161ndash11652016
[106] D R Brenner D Scherer K Muir et al ldquoA review of the appli-cation of inflammatory biomarkers in epidemiologic cancerresearchrdquo Cancer Epidemiology Biomarkers amp Prevention vol23 no 9 pp 1729ndash1751 2014
[107] M D Turner B Nedjai T Hurst and D J PenningtonldquoCytokines and chemokines at the crossroads of cell signallingand inflammatory diseaserdquo Biochimica et Biophysica Acta (BBA)- Molecular Cell Research vol 1843 no 11 pp 2563ndash2582 2014
[108] L Werner H Guzner-Gur and I Dotan ldquoInvolvement ofCXCR4CXCR7CXCL12 interactions in inflammatory boweldiseaserdquoTheranostics vol 3 no 1 pp 40ndash46 2013
[109] S Jalkanen and M Salmi ldquoVAP-1 and CD73 endothelial cellsurface enzymes in leukocyte extravasationrdquo ArteriosclerosisThrombosis and Vascular Biology vol 28 no 1 pp 18ndash26 2008
[110] G Malviya F Galli I Sonni and A Signore ldquoImaging T-lymphocytes in inflammatory diseases A nuclear medicineapproachrdquo The Quarterly Journal of Nuclear Medicine andMolecular Imaging vol 58 no 3 pp 237ndash257 2014
[111] S Gratz H J RennenO C BoermanW J Oyen and P Burmaldquo(99m)Tc-interleukin-8 for imaging acute osteomyelitisrdquo Jour-nal of Nuclear Medicine vol 42 no 8 pp 1257ndash1264 2001
[112] S Gratz H J Rennen O C Boerman W J Oyen andF H Corstens ldquoRapid imaging of experimental colitis with(99m)Tc-interleukin-8 in rabbitsrdquo Journal of Nuclear Medicnevol 42 no 6 pp 917ndash923 2001
[113] C Alkim H Alkim A R Koksal S Boga and I SenldquoAngiogenesis in inflammatory bowel diseaserdquo InternationalJournal of Inflammation vol 2015 Article ID 970890 2015
[114] I S Alam T H Witney G Tomasi et al ldquoRadiolabeled RGDtracer kinetics annotates differential 120572v1205733 integrin expressionlinked to cell intrinsic and vessel expressionrdquoMolecular Imagingand Biology vol 16 no 4 pp 558ndash566 2014
[115] J Notni K Pohle and H-J Wester ldquoBe spoilt for choice withradiolabelled RGD peptides Preclinical evaluation of 68Ga-TRAP(RGD)3rdquoNuclear Medicine and Biology vol 40 no 1 pp33ndash41 2013
[116] J Oxboel M Brandt-Larsen C Schjoeth-Eskesen et al ldquoCom-parison of two new angiogenesis PET tracers 68Ga-NODAGA-E[c(RGDyK)]2 and 64Cu-NODAGA-E[c(RGDyK)]2 in vivoimaging studies in human xenograft tumorsrdquo Nuclear Medicineand Biology vol 41 no 3 pp 259ndash267 2014
[117] J Simecek J Notni T G Kapp H Kessler and H-J WesterldquoBenefits of NOPO as chelator in gallium-68 peptides exempli-fied by preclinical characterization of 68Ga-NOPO-c(RGDfK)rdquoMolecular Pharmaceutics vol 11 no 5 pp 1687ndash1695 2014
[118] M Trajkovic-Arsic P Mohajerani A Sarantopoulos et alldquoMultimodal molecular imaging of integrin avb3 for in vivodetection of pancreatic cancerrdquo Journal of NuclearMedicine vol55 no 3 pp 446ndash451 2014
[119] H Cai and P S Conti ldquoRGD-based PET tracers for imagingreceptor integrin 120572 v1205733 expressionrdquo Journal of Labelled Com-pounds and Radiopharmaceuticals vol 56 no 5 pp 264ndash2792013
[120] I Dijkgraaf S Y A Terry W J Mcbride et al ldquoImagingintegrin alpha-v-beta-3 expression in tumors with an 18F-labeled dimeric RGD peptiderdquo Contrast Media amp MolecularImaging vol 8 no 3 pp 238ndash245 2013
[121] P A Knetsch M Petrik C Rangger et al ldquo[68Ga]NS3-RGD and [68Ga] Oxo-DO3A-RGD for imaging 120572v1205733 integrinexpression Synthesis evaluation and comparisonrdquo NuclearMedicine and Biology vol 40 no 1 pp 65ndash72 2013
[122] Z Liu and F Wang ldquoDevelopment of RGD-based radiotracersfor tumor imaging and therapy Translating from bench tobedsiderdquo Current Molecular Medicine vol 13 no 10 pp 1487ndash1505 2013
[123] H Choi J H Phi J C Paeng et al ldquoImaging of integrin 120572v1205733expression using 68Ga-RGD positron emission tomography inpediatric cerebral infarctrdquoMolecular Imaging vol 12 no 4 pp213ndash217 2013
[124] H-J Yoon K W Kang I K Chun et al ldquoCorrelation of breastcancer subtypes based on estrogen receptor progesteronereceptor and HER2 with functional imaging parameters from68Ga-RGD PETCT and 18F-FDG PETCTrdquo European Journalof Nuclear Medicine and Molecular Imaging vol 41 no 8 pp1534ndash1543 2014
[125] R P Baum H R Kulkarni D Muller et al ldquoFirst-in-human study demonstrating tumor-angiogenesis by PETCTimaging with 68Ga-NODAGA-THERANOST a high-affinitypeptidomimetic for 120572v1205733 integrin receptor targetingrdquo CancerBiotherapy andRadiopharmaceuticals vol 30 no 4 pp 152ndash1592015
[126] R Haubner A Finkenstedt A Stegmayr et alldquo[68Ga]NODAGA-RGD ndash Metabolic stability biodistributionand dosimetry data from patients with hepatocellularcarcinoma and liver cirrhosisrdquo European Journal of NuclearMedicine and Molecular Imaging vol 43 no 11 pp 2005ndash20132016
[127] V Lopez-Rodrıguez C Galindo-Sarco F O Garcıa-Perez GFerro-Flores O Arrieta and M A Avila-Rodrıguez ldquoPET-based human dosimetry of the dimeric 120572v1205733 integrin ligand68Ga-DOTA-E-[c(RGDfK)]2 a potential tracer for imagingtumor angiogenesisrdquo Journal of Nuclear Medicine vol 57 no 3pp 404ndash409 2016
[128] M V Backer Z Levashova V Patel et al ldquoMolecular imagingof VEGF receptors in angiogenic vasculature with single-chainVEGF-based probesrdquo Nature Medicine vol 13 no 4 pp 504ndash509 2007
[129] MV Backer Z Levashova R Levenson F G Blankenberg andJ M Backer ldquoCysteine-containing fusion tag for site-specificconjugation of therapeutic and imaging agents to targetingproteinsrdquoMethods in Molecular Biology (Clifton NJ) vol 494pp 275ndash294 2008
[130] M Eder A V Krivoshein M Backer J M Backer UHaberkorn and M Eisenhut ldquoScVEGF-PEG-HBED-CC andscVEGF-PEG-NOTA conjugates comparison of easy-to-labelrecombinant proteins for [68Ga]PET imaging of VEGF recep-tors in angiogenic vasculaturerdquo Nuclear Medicine and Biologyvol 37 no 4 pp 405ndash412 2010
[131] E Blom I Velikyan A Monazzam P Razifar et al ldquoSynthe-sis and characterization of scVEGF-PEG-[ 68Ga]NOTA andscVEGF-PEG-[ 68Ga]DOTA PET tracersrdquo Journal of Labelled
20 Contrast Media amp Molecular Imaging
Compounds and Radiopharmaceuticals vol 54 no 11 pp 685ndash692 2011
[132] S Gratz M Behe and O C Boerman ldquo 99119898Tc-E-selectinbinding peptide for imaging acute osteomyelitis in a novel ratmodelrdquo Nuclear Medicine Communications vol 22 no 9 pp1003ndash1013 2001
[133] S B Jensen M Kakela L Joslashdal et al ldquoExploring the radiosyn-thesis and in vitro characteristics of [68Ga]Ga-DOTA-Siglec-9rdquoJournal of Labelled Compounds and Radiopharmaceuticals vol60 no 9 pp 439ndash449 2017
[134] B A Teicher and S P Fricker ldquoCXCL12 (SDF-1)CXCR4pathway in cancerrdquo Clinical Cancer Research vol 16 no 11 pp2927ndash2931 2010
[135] O Jacobson I D Weiss D O Kiesewetter J M Farber andX Chen ldquoPET of tumor CXCR4 expression with 4-18F-T140rdquoJournal of Nuclear Medicine vol 51 no 11 pp 1796ndash1804 2010
[136] A Aghanejad A R Jalilian Y Fazaeli et al ldquoSynthesis andevaluation of [67Ga]-AMD3100 A novel imaging agent fortargeting the chemokine receptorCXCR4rdquo Scientia Pharmaceu-tica vol 82 no 1 pp 29ndash42 2014
[137] O Jacobson I D Weiss L P Szajek et al ldquoPET imaging ofCXCR4 using copper-64 labeled peptide antagonistrdquoTheranos-tics vol 1 pp 251ndash262 2011
[138] O Jacobson I D Weiss L P Szajek et al ldquoImprovement ofCXCR4 tracer specificity for PET imagingrdquo Journal of Con-trolled Release vol 157 no 2 pp 216ndash223 2012
[139] H J Wester U Keller M Schottelius et al ldquoDisclosing theCXCR4 expression in lymphoproliferative diseases by targetedmolecular imagingrdquo Theranostics vol 5 no 6 pp 618ndash6302015
[140] E Gourni O Demmer M Schottelius et al ldquoPET of CXCR4expression by a 68Ga-labeled highly specific targeted contrastagentrdquo Journal of NuclearMedicine vol 52 no 11 pp 1803ndash18102011
[141] O Demmer I Dijkgraaf U Schumacher et al ldquoDesignsynthesis and functionalization of dimeric peptides targetingchemokine receptor CXCR4rdquo Journal of Medicinal Chemistryvol 54 no 21 pp 7648ndash7662 2011
[142] O Demmer E Gourni U Schumacher H Kessler and H-JWester ldquoPET Imaging of CXCR4 Receptors in Cancer by a NewOptimized Ligandrdquo ChemMedChem vol 6 no 10 pp 1789ndash1791 2011
[143] U Hennrich L Seyler M Schafer et al ldquoSynthesis and invitro evaluation of 68Ga-DOTA-4-FBn-TN14003 a novel tracerfor the imaging of CXCR4 expressionrdquo Bioorganic amp MedicinalChemistry vol 20 no 4 pp 1502ndash1510 2012
[144] G P C George E Stevens O Aberg et al ldquoPreclinical evalua-tion of a CXCR4-specific 68Ga-labelled TN14003 derivative forcancer PET imagingrdquo Bioorganic amp Medicinal Chemistry vol22 no 2 pp 796ndash803 2014
[145] S Poty E Gourni P Desogere et al ldquoAMD3100 A VersatilePlatform for CXCR4 Targeting 68Ga-Based Radiopharmaceu-ticalsrdquo Bioconjugate Chemistry vol 27 no 3 pp 752ndash761 2016
[146] K Philipp-Abbrederis K Herrmann S Knop et al ldquoIn vivomolecular imaging of chemokine receptor CXCR4 expressionin patients with advancedmultiple myelomardquo EMBOMolecularMedicine vol 7 no 4 pp 477ndash487 2015
[147] Z Wang M Zhang L Wang et al ldquoProspective study of 68Ga-NOTA-NFB Radiation dosimetry in healthy volunteers andfirst application in glioma patientsrdquo Theranostics vol 5 no 8pp 882ndash889 2015
[148] I M Jackson P J Scott and S Thompson ldquoClinical Applica-tions of Radiolabeled Peptides for PETrdquo Seminars in NuclearMedicine vol 47 no 5 pp 493ndash523 2017
[149] C Lapa T Reiter R A Werner et al ldquo[68Ga]Pentixafor-PETCT for Imaging of Chemokine Receptor 4 Expression afterMyocardial Infarctionrdquo JACC Cardiovascular Imaging vol 8no 12 pp 1466ndash1468 2015
[150] C Rischpler S G Nekolla H Kossmann et al ldquoUpregu-lated myocardial CXCR4-expression after myocardial infarc-tion assessed by simultaneous GA-68 pentixafor PETMRIrdquoJournal of Nuclear Cardiology vol 23 no 1 pp 131ndash133 2016
[151] F Hyafil J Pelisek I Laitinen et al ldquoImaging the CytokineReceptorCXCR4 in atherosclerotic plaqueswith the radiotracer68Ga-Pentixafor for PETrdquo Journal of Nuclear Medicine vol 58no 3 pp 499ndash506 2017
[152] Y Yi ldquoFolate receptor-targeted diagnostics and therapeutics forinflammatory diseasesrdquo ImmuneNetwork vol 16 no 6 pp 337ndash343 2016
[153] C M Paulos M J Turk G J Breur and P S Low ldquoFolatereceptor-mediated targeting of therapeutic and imaging agentsto activated macrophages in rheumatoid arthritisrdquo AdvancedDrug Delivery Reviews vol 56 no 8 pp 1205ndash1217 2004
[154] W Han R Zaynagetdinov F E Yull et al ldquoMolecular imagingof folate receptor 120573-positive macrophages during acute lunginflammationrdquo American Journal of Respiratory Cell and Molec-ular Biology vol 53 no 1 pp 50ndash59 2015
[155] B Kuhle C Muller and T L Ross ldquoA Novel 68Ga-Labeledpteroic acid-based PET tracer for tumor imaging via the folatereceptorrdquo Recent Results in Cancer Research vol 194 pp 257ndash267 2013
[156] C Brand V A Longo M Groaning W A Weber and TReiner ldquoDevelopment of a New Folate-Derived Ga-68-BasedPET Imaging AgentrdquoMolecular Imaging and Biology vol 19 no5 pp 754ndash761 2017
[157] M Fani XWang G Nicolas et al ldquoDevelopment of new folate-based PET radiotracers Preclinical evaluation of 68Ga-DOTA-folate conjugatesrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 38 no 1 pp 108ndash119 2011
[158] C J Mathias M R Lewis D E Reichert et al ldquoPreparationof 66Ga- and 68Ga-labeled Ga(III)-deferoxamine-folate aspotential folate-receptor-targeted PET radiopharmaceuticalsrdquoNuclear Medicine and Biology vol 30 no 7 pp 725ndash731 2003
[159] S-M Kim N Choi S Hwang et al ldquoFolate receptor-specific positron emission tomography imaging with folic acid-conjugated tissue inhibitor of metalloproteinase-2rdquo Bulletin ofthe Korean Chemical Society vol 34 no 11 pp 3243ndash3248 2013
[160] M Fani M-L Tamma G P Nicolas et al ldquoIn vivo imagingof folate receptor positive tumor xenografts using novel 68Ga-NODAGA-folate conjugatesrdquo Molecular Pharmaceutics vol 9no 5 pp 1136ndash1145 2012
[161] C Muller and R Schibli ldquoProspects in folate receptor-targetedradionuclide therapyrdquo Frontiers in Oncology vol 3 Article IDArticle 249 2013
[162] A Jain A Mathur U Pandey et al ldquoSynthesis and evaluationof a 68Ga labeled folic acid derivative for targeting folatereceptorsrdquo Applied Radiation and Isotopes vol 116 pp 77ndash842016
[163] W Xia A R Hilgenbrink E L Matteson M B Lockwood J-X Cheng and P S Low ldquoA functional folate receptor is inducedduring macrophage activation and can be used to target drugsto activated macrophagesrdquo Blood vol 113 no 2 pp 438ndash4462009
Contrast Media amp Molecular Imaging 21
[164] E P Krenning W A P Breeman P P M Kooij et alldquoLocalisation of endocrine-related tumours with radioiodi-nated analogue of somatostatinrdquoThe Lancet vol 1 no 8632 pp242ndash244 1989
[165] E P Krenning D J KwekkeboomWH Bakker et al ldquoSomato-statin receptor scintigraphy with [111In-DTPA-d-Phe1]- and[123I-Tyr3]-octreotide the Rotterdam experience with morethan 1000 patientsrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 20 no 8 pp 716ndash731 1993
[166] A Stahl G Meisetschlager M Schottelius et al ldquo[123I]Mtr-TOCA a radioiodinated and carbohydrated analogue ofoctreotide Scintigraphic comparison with [111In]octreotiderdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 33 no 1 pp 45ndash52 2006
[167] R Lebtahi J le Cloirec C Houzard et al ldquoDetection of neu-roendocrine tumors 99mTc-P829 scintigraphy compared with111In-pentetreotide scintigraphyrdquo Journal of Nuclear Medicinevol 43 no 7 pp 889ndash895 2002
[168] C Decristoforo T Maina B Nock M Gabriel P Cordopatisand R Moncayo ldquo99mTc-demotate 1 First data in tumourpatients - Results of a pilotphase I studyrdquo European Journal ofNuclearMedicine andMolecular Imaging vol 30 no 9 pp 1211ndash1219 2003
[169] C Decristoforo S J Mather W Cholewinski E DonnemillerG Riccabona and R Moncayo ldquo(99m)Tc-EDDAHYNIC-TOC A new (99m)Tc-labelled radiopharmaceutical forimaging somatostatin receptor-positive tumours First clinicalresults and intra-patient comparison with 111In-labelledoctreotide derivativesrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 27 no 9 pp 1318ndash1325 2000
[170] A Hubalewska-Dydejczyk K Fross-Baron R Mikołajczak etal ldquo99mTc-EDDAHYNIC-octreotate scintigraphy an efficientmethod for the detection and staging of carcinoid tumoursResults of 3 yearsrsquo experiencerdquo European Journal of NuclearMedicine and Molecular Imaging vol 33 no 10 pp 1123ndash11332006
[171] M Bangard M Behe S Guhlke et al ldquoDetection of somato-statin receptor-positive tumours using the new 99mC-tricine-HYNIC-D-Phe1-Tyr3-octreotide First results in patients andcomparison with 111In-DTPA-D-Phe1-octreotiderdquo EuropeanJournal of Nuclear Medicine and Molecular Imaging vol 27 no6 pp 628ndash637 2000
[172] A Helisch G J Forster H Reber et al ldquoPre-therapeuticdosimetry and biodistribution of 86Y-DOTA- Phe1-Tyr3-octreotide versus 111In-pentetreotide in patients with advancedneuroendocrine tumoursrdquo European Journal of NuclearMedicine and Molecular Imaging vol 31 no 10 pp 1386ndash13922004
[173] M Henze J Schuhmacher P Hipp et al ldquoPET imaging ofsomatostatin receptors using [68GA]DOTA-D-Phe1-Tyr3-Octreotide First results in patients with meningiomasrdquo Journalof Nuclear Medicine vol 42 no 7 pp 1053ndash1056 2001
[174] I Kayani J B Bomanji A Groves et al ldquoFunctional imaging ofneuroendocrine tumors with combined PETCT using 68Ga-DOTATATE (Dota-DPhe1 Tyr3-octreotate) and 18F-FDGrdquoCancer vol 112 no 11 pp 2447ndash2455 2008
[175] A Al-Nahhas ldquoNuclear medicine imaging of neuroendocrinetumoursrdquo Clinical Medicine vol 12 no 4 pp 377ndash380 2012
[176] V Ambrosini S Nicolini P Caroli et al ldquoPETCT imaging indifferent types of lung cancer an overviewrdquo European Journal ofRadiology vol 81 no 5 pp 988ndash1001 2012
[177] V Ambrosini D Campana P Tomassetti and S Fanti ldquo68Ga-labelled peptides for diagnosis of gastroenteropancreatic NETrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 39 no 1 pp S52ndashS60 2012
[178] K E Oberg J-C Reubi D J Kwekkeboom and E P KrenningldquoRole of somatostatins in gastroenteropancreatic neuroen-docrine tumor development and therapyrdquoGastroenterology vol139 no 3 pp 753-753 2010
[179] K Oberg ldquoGallium-68 somatostatin receptor PETCT Is ittime to replace 111Indium DTPA octreotide for patients withneuroendocrine tumorsrdquo Endocrine Journal vol 42 no 1 pp3-4 2012
[180] R Srirajaskanthan I Kayani A M Quigley J Soh M ECaplin and J Bomanji ldquoThe role of 68Ga-DOTATATE PET inpatients with neuroendocrine tumors and negative or equivocalfindings on 111In-DTPA-octreotide scintigraphyrdquo Journal ofNuclear Medicine vol 51 no 6 pp 875ndash882 2010
[181] A Kroiss D Putzer and C Uprimny ldquoFunctional imag-ing in phaeochromocytoma and neuroblastoma with 68Ga-DOTA-Tyr3-octreotide positron emission tomography and123I-metaiodobenzylguanidinerdquo European Journal of NuclearMedicine and Molecular Imaging vol 38 no 5 pp 865ndash8732011
[182] M Naji C Zhao S J Welsh et al ldquo68Ga-DOTA-TATE PETvs 123I-MIBG in identifying malignant neural crest tumoursrdquoMolecular Imaging and Biology vol 13 no 4 pp 769ndash775 2011
[183] V Ambrosini P Tomassetti P Castellucci et al ldquoComparisonbetween 68Ga-DOTA-NOC and 18F-DOPA PET for the detec-tion of gastro-entero-pancreatic and lung neuro-endocrinetumoursrdquo European Journal of Nuclear Medicine and MolecularImaging vol 35 no 8 pp 1431ndash1438 2008
[184] D Putzer M Gabriel B Henninger et al ldquoBone metastasesin patients with neuroendocrine tumor 68Ga- DOTA-Tyr3-octreotide PET in comparison to CT and bone scintigraphyrdquoJournal of Nuclear Medicine vol 50 no 8 pp 1214ndash1221 2009
[185] L K Anzola-Fuentes M Chianelli F Galli et al ldquoSomatostatinreceptor scintigraphy in patients with rheumatoid arthritis andsecondary Sjogrenrsquos syndrome treated with Infliximab a pilotstudyrdquo EJNMMI Research vol 6 no 1 article no 49 2016
[186] T Nobashi Y Nakamoto T Kubo et al ldquoThe utility of PETCTwith 68Ga-DOTATOC in sarcoidosis comparison with 67Ga-scintigraphyrdquoAnnals ofNuclearMedicine vol 30 no 8 pp 544ndash552 2016
[187] C Boy T A Heusner T D Poeppel et al ldquo68Ga-DOTATOCPETCT and somatostatin receptor (sst1-sst5) expression innormal human tissue Correlation of sst2mRNAand SUVmaxrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 38 no 7 pp 1224ndash1236 2011
[188] P Rinne S Hellberg M Kiugel et al ldquoComparison of Somato-statin Receptor 2-Targeting PET Tracers in the Detection ofMouse Atherosclerotic Plaquesrdquo Molecular Imaging and Biol-ogy vol 18 no 1 pp 99ndash108 2016
[189] M Asti E Ferrari S Croci et al ldquoSynthesis and characteri-zation of 68Ga-labeled curcumin and curcuminoid complexesas potential radiotracers for imaging of cancer and alzheimersdiseaserdquo Inorganic Chemistry vol 53 no 10 pp 4922ndash49332014
[190] A Signore I Santino and A W J M Glaudemans ldquoIn vivoimaging of microorganismsrdquo Clinical and Translational Imag-ing vol 4 no 3 pp 161-162 2016
[191] S Auletta F Galli C Lauri D Martinelli I Santino andA Signore ldquoImaging bacteria with radiolabelled quinolones
22 Contrast Media amp Molecular Imaging
cephalosporins and siderophores for imaging infection a sys-tematic reviewrdquo Clinical and Translational Imaging vol 4 no 4pp 229ndash252 2016
[192] X Ning S Lee Z Wang et al ldquoMaltodextrin-based imagingprobes detect bacteria in vivo with high sensitivity and speci-ficityrdquo Nature Materials vol 10 no 8 pp 602ndash607 2011
[193] J Ady andY Fong ldquoImaging for infection Fromvisualization ofinflammation to visualization of microbesrdquo Surgical Infectionsvol 15 no 6 pp 700ndash707 2014
[194] J M Sierra D Rodriguez-Puig A Soriano J Mensa C Pieraand J Vila ldquoAccumulation of 99mTc-ciprofloxacin in Staphy-lococcus aureus and Pseudomonas aeruginosardquo AntimicrobialAgents and Chemotherapy vol 52 no 7 pp 2691-2692 2008
[195] D I Andersson and D Hughes ldquoMicrobiological effects ofsublethal levels of antibioticsrdquoNature ReviewsMicrobiology vol12 no 7 pp 465ndash478 2014
[196] N Dumarey D Blocklet T Appelboom L Tant and ASchoutens ldquoInfecton is not specific for bacterial osteo-articularinfective pathologyrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 29 no 4 pp 530ndash535 2002
[197] K E Britton D W Wareham S S Das et al ldquoImaging bacte-rial infection with 99mTc-ciprofloxacin (Infecton)rdquo Journal ofClinical Pathology vol 55 no 11 pp 817ndash823 2002
[198] G Ferro-Flores M A Avila-Rodrıguez and F O Garcıa-PerezldquoImaging of bacteria with radiolabeled ubiquicidin by SPECTand PET techniquesrdquo Clinical and Translational Imaging vol 4no 3 pp 175ndash182 2016
[199] P S Hiemstra M T van den Barselaar M Roest P H Nibber-ing and R van Furth ldquoUbiquicidin a novel murine microbi-cidal protein present in the cytosolic fraction of macrophagesrdquoJournal of Leukocyte Biology vol 66 no 3 pp 423ndash428 1999
[200] M S Akhtar A Qaisar J Irfanullah et al ldquoAntimicrobialpeptide 99mTc-ubiquicidin 29ndash41 as human infection-imagingagent clinical trialrdquo Journal of Nuclear Medicne vol 46 no 4pp 567ndash573 2005
[201] M Assadi K Vahdat I Nabipour et al ldquoDiagnostic value of99mTc-ubiquicidin scintigraphy for osteomyelitis and compar-isons with 99mTc-methylene diphosphonate scintigraphy andmagnetic resonance imagingrdquo Nuclear Medicine Communica-tions vol 32 no 8 pp 716ndash723 2011
[202] T Emery ldquoExchange of Iron by Gallium in SiderophoresrdquoBiochemistry vol 25 no 16 pp 4629ndash4633 1986
[203] M Petrik C Zhai H Haas and C Decristoforo ldquoSiderophoresfor molecular imaging applicationsrdquo Clinical and TranslationalImaging vol 5 no 1 pp 15ndash27 2017
[204] H J Flint E A BayerM T Rincon R Lamed and B AWhiteldquoPolysaccharide utilization by gut bacteria potential for newinsights from genomic analysisrdquo Nature Reviews Microbiologyvol 6 no 2 pp 121ndash131 2008
[205] GGowrishankarMNamavari E B Jouannot et al ldquoInvestiga-tion of 6-[18F]-fluoromaltose as a novel PET tracer for imagingbacterial infectionrdquo PLoS ONE vol 9 no 9 Article ID e1079512014
[206] N Gholipour M Akhlaghi A M Kheirabadi et al ldquoChelator-free radiolabeling of dextran with 68Ga for PET studiesrdquoJournal of Radioanalytical and Nuclear Chemistry vol 311 no3 pp 1811ndash1817 2017
[207] C Bettegowda C A Foss I Cheong et al ldquoImaging bac-terial infections with radiolabeled 1-(21015840-deoxy-21015840- fluoro-120573-D-arabinofuranosyl)-5-iodouracilrdquo Proceedings of the NationalAcadamy of Sciences of the United States of America vol 102 no4 pp 1145ndash1150 2005
[208] S A Soghomonyan M Doubrovin J Pike et al ldquoPositronemission tomography (PET) imaging of tumor-localizedSalmonella expressing HSV1-TKrdquo Cancer GeneTherapy vol 12no 1 pp 101ndash108 2005
[209] C Palestro K Nichols S Sheikh-Fayyaz S Dewey P Singhaland K Bhargava ldquoCan Gallium-68 PET differentiate acuteinterstitial nephritis from acute tubular necrosisrdquo Journal ofNuclear Medicne vol 57 Supplement 2 p 551 2016
[210] A J Morguet D L Munz V Ivancevic et al ldquoImmunoscintig-raphy using technetium-99m-labeled anti-NCA-95 antigranu-locyte antibodies as an adjunct to echocardiography in subacuteinfective endocarditisrdquo Journal of the American College ofCardiology vol 23 no 5 pp 1171ndash1178 1994
[211] C van der Laken O Boerman W Oyen et al ldquoIn Vivo Expres-sion of Interleukin-1 Receptors during Various ExperimentallyInduced Inflammatory Conditionsrdquo The Journal of InfectiousDiseases vol 177 no 5 pp 1398ndash1401 1998
[212] C J Van Der Laken O C Boerman W J G Oyen M T PVan De Ven J W M Van Der Meer and F H M CorstensldquoScintigraphic detection of infection and inflammation Newdevelopments with special emphasis on receptor interactionrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 25 no 5 pp 535ndash546 1998
[213] C J van der LakenOC BoermanW J GOyenM T P van deVen J W M van der Meer and F H M Corstens ldquoImaging ofinfection in rabbits with radioiodinated interleukin-1 (120572 and 120573)its receptor antagonist and a chemotactic peptide a comparativestudyrdquo European Journal of Nuclear Medicine and MolecularImaging vol 25 no 4 pp 347ndash352 1998
[214] C J Van Der Laken O C BoermanW J G Oyen M T P VanDe Ven F H M Corstens and J W M Ven Der Meer ldquoThekinetics of radiolabelled interleukin-8 in infection and sterileinflammationrdquo Nuclear Medicine Communications vol 19 no3 pp 271ndash282 1998
[215] E Lazzeri P Erba M Perri et al ldquoScintigraphic imaging ofvertebral osteomyelitis with 111in-biotinrdquoThe Spine Journal vol33 no 7 pp E198ndashE204 2008
[216] E Blom B Langstrom and I Velikyan ldquo68Ga-labeling of biotinanalogues and their characterizationrdquo Bioconjugate Chemistryvol 20 no 6 pp 1146ndash1151 2009
[217] O Eriksson F Carlsson E Blom et al ldquoPreclinical evaluationof a 68Ga-labeled biotin analogue for applications in islettransplantationrdquo Nuclear Medicine and Biology vol 39 no 3pp 415ndash421 2012
[218] E A Weinstein A A Ordonez V P DeMarco et alldquoImaging Enterobacteriaceae infection in vivo with 18F-fluoro-deoxysorbitol positron emission tomographyrdquo Science Transla-tional Medicine vol 6 no 259 p 259ra146 2014
[219] K M Nielsen M H Kyneb A K O Alstrup et alldquo68Ga-labeled phage-display selected peptides as tracers forpositron emission tomography imaging of Staphylococcusaureus biofilm-associated infections Selection radiolabellingand preliminary biological evaluationrdquo Nuclear Medicine andBiology vol 43 no 10 pp 593ndash605 2016
[220] T J Makinen P Lankinen T Poyhonen J Jalava H T Aroand A Roivainen ldquoComparison of 18F-FDG and 68Ga PETimaging in the assessment of experimental osteomyelitis due toStaphylococcus aureusrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 32 no 11 pp 1259ndash1268 2005
[221] JMU Silvola I LaitinenH J Sipila et al ldquoUptake of 68galliumin atherosclerotic plaques in LDLRminusminusApoB100100micerdquo EJN-MMI Research vol 1 no 1 pp 1ndash8 2011
Contrast Media amp Molecular Imaging 23
[222] T A Wynn ldquoCellular and molecular mechanisms of fibrosisrdquoThe Journal of Pathology vol 214 no 2 pp 199ndash210 2008
[223] T Derlin D Jonigk J Bauersachs and FM Bengel ldquoMolecularImaging of Chemokine Receptor CXCR4 in NonndashSmall CellLung Cancer Using 68Ga-Pentixafor PETCT ComparisonWith 18F-FDGrdquo Clinical Nuclear Medicine 2016
[224] I Velikyan U Rosenstrom T N Bulenga O Eriksson andG Antoni ldquoFeasibility of multiple examinations using68ga-labelled collagelin analogues Organ distribution in rat forextrapolation to human organ and whole-body radiationdosimetryrdquo Pharmaceuticals vol 9 no 2 article no 31 2016
[225] S Jadhav M Kakela J Makila et al ldquoSynthesis and in VivoPET Imaging of Hyaluronan Conjugates of OligonucleotidesrdquoBioconjugate Chemistry vol 27 no 2 pp 391ndash403 2016
[226] A Autio A Saraste N Kudomi et al ldquoAssessment of bloodflow with (68) Ga-DOTA PET in experimental inflammation avalidation study using (15) O-waterrdquo American Journal ofNuclear Medicine and Molecular Imaging vol 4 no 6 pp 571ndash579 2014
[227] G Davies A Rolle A Maurer et al ldquoTowards translationalimmunoPETMR imaging of invasive pulmonary aspergillosisthe Humanised Monoclonal Antibody JF5 detects in vivordquoTheranostics vol 7 no 14 pp 3398ndash3414 2017
[228] DGoodwin CMeares GDavid et al ldquoMonoclonal antibodiesas reversible equilibrium carriers of radiopharmaceuticalsrdquoInternational Journal of Radiation Applications and Instrumen-tation Part B Nuclear Medicine and Biology vol 13 no 4 pp383ndash391 1986
[229] D A Goodwin C F Mears M McTigue and G S DavidldquoMonoclonal antibody hapten radiopharmaceutical deliveryrdquoNuclear Medicine Communications vol 7 no 8 pp 569ndash5801986
[230] S E Halpern and R O Dillman ldquoProblems associated withradioimmunodetection and possibilities for future solutionsrdquo JBiol Response Mod vol 6 no 3 pp 235ndash262 1987
[231] H Hong J Sun and W Cai ldquoRadionuclide-based cancerimaging targeting the carcinoembryonic antigenrdquo BiomarkerInsights vol 3 pp 435ndash451 2008
[232] G J Forster E B Santos P M Smith-Jones P Zanzonico andS M Larson ldquoPretargeted radioimmunotherapy with a single-chain antibodystreptavidin construct and radiolabeledDOTA-biotin Strategies for reduction of the renal doserdquo Journal ofNuclear Medicine vol 47 no 1 pp 140ndash149 2006
[233] Z Yao M Zhang H Kobayashi et al ldquoImproved targeting ofradiolabeled streptavidin in tumors pretargeted with biotiny-lated monoclonal antibodies through an avidin chaserdquo Journalof Nuclear Medicine vol 36 no 5 pp 837ndash841 1995
[234] C-H Chang R M Sharkey E A Rossi et al ldquoMolecularAdvances in Pretargeting Radioimunotherapy with BispecificAntibodies 1 Supported in part by USPHS Grant R01-CA-84379from the NIH and Department of Energy Grant DE-FG01-00NE22941 (both to R M S)1rdquo Mol Cancer Ther vol 1 no 7pp 553ndash563 2002
[235] R M Sharkey E A Rossi W J McBride C-H Chang andD M Goldenberg ldquoRecombinant Bispecific Monoclonal Anti-bodies Prepared by theDock-and-Lock Strategy for PretargetedRadioimmunotherapyrdquo Seminars in Nuclear Medicine vol 40no 3 pp 190ndash203 2010
[236] R M Sharkey E A Rossi C-H Chang and D M Golden-berg ldquoImproved cancer therapy and molecular imaging withmultivalent multispecific antibodiesrdquo Cancer Biotherapy andRadiopharmaceuticals vol 25 no 1 pp 1ndash12 2010
[237] D M Goldenberg R M Sharkey G Paganelli J Barbet andJ Chatal ldquoAntibody pretargeting advances cancer radioim-munodetection and radioimmunotherapyrdquo Journal of ClinicalOncology vol 24 no 5 pp 823ndash834 2006
[238] O C Boerman F G van Schaijk W J G Oyen and FH M Corstens ldquoPretargeted radioimmunotherapy of cancerprogress step by steprdquo Journal of Nuclear Medicine vol 44 no3 pp 400ndash411 2003
[239] J Schuhmacher S Kaul G Klivenyi et al ldquoImmunoscintigra-phy with positron emission tomography Gallium-68 chelateimaging of breast cancer pretargeted with bispecific anti-MUC1anti-Ga chelate antibodiesrdquo Cancer Research vol 61 no9 pp 3712ndash3717 2001
[240] J Schuhmacher G Klivenyi S Kaul et al ldquoPretargeting ofhuman mammary carcinoma xenografts with bispecific anti-MUC1anti-Ga chelate antibodies and immunoscintigraphywith PETrdquo Nuclear Medicine and Biology vol 28 no 7 pp 821ndash828 2001
[241] C Somasundaram S Matzku J Schuhmacher and M ZollerldquoDevelopment of a bispecific monoclonal antibody against agallium-67 chelate and the human melanoma-associated anti-gen p97 for potential use in pretargeted immunoscintigraphyrdquoCancer Immunology Immunotherapy vol 36 no 5 pp 337ndash3451993
[242] E A Rossi D L Rossi R Stein D M Goldenberg and C-H Chang ldquoA bispecific antibody-IFN1205722b immunocytokine tar-geting CD20 and HLA-DR is highly toxic to human lymphomaandmultiplemyeloma cellsrdquoCancer Research vol 70 no 19 pp7600ndash7609 2010
[243] R M Sharkey H Karacay S Litwin et al ldquoImproved ther-apeutic results by pretargeted radioimmunotherapy of non-Hodgkinrsquos lymphoma with a new recombinant trivalent anti-CD20 bispecific antibodyrdquo Cancer Research vol 68 no 13 pp5282ndash5290 2008
[244] G L Griffiths C-H Chang W J McBride et al ldquoReagentsandmethods for PETusing bispecific antibody pretargeting and68Ga-radiolabeled bivalent hapten-peptide-chelate conjugatesrdquoJournal of Nuclear Medicine vol 45 no 1 pp 30ndash39 2004
[245] J Watine M Miedouge and B Friedberg ldquoCarcinoembryonicantigen as an independent prognostic factor of recurrence andsurvival in patients resected for colorectal liver metastases Asystematic reviewrdquo Diseases of the Colon amp Rectum vol 44 no12 pp 1791ndash1799 2001
[246] M J Goldstein and E P Mitchell ldquoCarcinoembryonic antigenin the staging and follow-up of patients with colorectal cancerrdquoCancer Investigation vol 23 no 4 pp 338ndash351 2005
[247] D V Gold D M Goldenberg H Karacay et al ldquoA novelbispecific trivalent antibody construct for targeting pancreaticcarcinomardquo Cancer Research vol 68 no 12 pp 4819ndash48262008
[248] J Schuhmacher G Klivenyi R Matys et al ldquoMultistep tumortargeting in nudemice using bispecific antibodies and a galliumchelate suitable for immunoscintigraphy with positron emis-sion tomographyrdquo Cancer Research vol 55 no 1 pp 115ndash1231995
[249] G Klivenyi J Schuhmacher E Patzelt et al ldquoGallium-68chelate imaging of human colon carcinoma xenografts pre-targeted with bispecific anti-CD44(V6)anti-gallium chelateantibodiesrdquo Journal ofNuclearMedicine vol 39 no 10 pp 1769ndash1776 1998
[250] M Zoller J Schuhmacher J Reed W Maier-Borst and SMatzku ldquoEstablishment and characterization of monoclonal
24 Contrast Media amp Molecular Imaging
antibodies against an octahedral gallium chelate suitable forimmunoscintigraphy with PETrdquo Journal of Nuclear Medicinevol 33 no 7 pp 1366ndash1372 1992
[251] R M Sharkey T M Cardillo E A Rossi et al ldquoSignal ampli-fication in molecular imaging by pretargeting a multivalentbispecific antibodyrdquo Nature Medicine vol 11 no 11 pp 1250ndash1255 2005
[252] D M Goldenberg and R M Sharkey ldquoNovel radiolabeledantibody conjugatesrdquo Oncogene vol 26 no 25 pp 3734ndash37442007
[253] D M Goldenberg E A Rossi R M Sharkey W J McBrideand C-H Chang ldquoMultifunctional antibodies by the dock-and-lock method for improved cancer imaging and therapy bypretargetingrdquo Journal of NuclearMedicine vol 49 no 1 pp 158ndash163 2008
[254] R Schoffelen R M Sharkey D M Goldenberg et al ldquoPre-targeted immuno-positron emission tomography imaging ofcarcinoembryonic antigen-expressing tumors with a bispecificantibody and a68Ga- And18F-labeled hapten peptide in micewith human tumor xenograftsrdquoMolecular Cancer Therapeuticsvol 9 no 4 pp 1019ndash1027 2010
[255] E S Bos W H Kuijpers M Meesters-Winters et al ldquoIn vitroevaluation of DNA-DNA hybridization as a two-step approachin radioimmunotherapy of cancerrdquoCancer Research vol 54 no13 pp 3479ndash3486 1994
[256] G Paganelli M Bartolomei M Ferrari et al ldquoPre-TargetedLocoregional Radioimmunotherapy withrdquo Cancer biotherapyand radiopharmaceuticals vol 16 no 3 pp 227ndash235 2001
[257] A Forero P L Weiden J M Vose et al ldquoPhase 1 trial of a novelanti-CD20 fusion protein in pretargeted radioimmunotherapyfor B-cell non-Hodgkin lymphomardquo Blood vol 104 no 1 pp227ndash236 2004
[258] DM Goldenberg C-H Chang E A RossiW J McBride andR M Sharkey ldquoPretargeted molecular imaging and radioim-munotherapyrdquoTheranostics vol 2 no 5 pp 523ndash540 2012
[259] H Karacay R M Sharkey W J McBride E A Rossi C-HChang and D M Goldenberg ldquoOptimization of hapten-peptide labeling for pretargeted immunoPET of bispecificantibody using generator-produced 68Gardquo Journal of NuclearMedicine vol 52 no 4 pp 555ndash559 2011
[260] J R Oh and B C Ahn ldquoFalse-positive uptake on radioiodinewhole-body scintigraphy physiologic and pathologic variantsunrelated to thyroid cancerrdquo American Journal of NuclearMedicine and Molecular Imaging vol 2 no 2 pp 141ndash150 2012
[261] E Frampas C Rousseau C Bodet-Milin J Barbet J-F Chataland F Kraeber-Bodere ldquoImprovement of radioimmunotherapyusing pretargetingrdquo Frontiers in Oncology vol 3 Article ID00159 2013
[262] C S McKay and M G Finn ldquoClick chemistry in complexmixtures Bioorthogonal bioconjugationrdquo Chemistry amp Biologyvol 21 no 9 pp 1075ndash1101 2014
[263] B L Oliveira Z Guo and G J Bernardes ldquoInverse electrondemand DielsndashAlder reactions in chemical biologyrdquo ChemicalSociety Reviews vol 46 no 16 pp 4895ndash4950 2017
[264] B Nichols Z Qin J Yang D R Vera and N K Devaraj ldquo68Gachelating bioorthogonal tetrazine polymers for the multisteplabeling of cancer biomarkersrdquo Chemical Communications vol50 no 40 pp 5215ndash5217 2014
[265] R Rossin P R Verkerk S M van den Bosch et al ldquoInvivo chemistry for pretargeted tumor imaging in live micerdquoAngewandte Chemie International Edition vol 49 no 19 pp3375ndash3378 2010
[266] B M Zeglis K K Sevak T Reiner et al ldquoA pretargetedPET imaging strategy based on bioorthogonal diels-alder clickchemistryrdquo Journal of Nuclear Medicine vol 54 no 8 pp 1389ndash1396 2013
[267] J L Houghton R Membreno D Abdel-Atti et al ldquoEstablish-ment of the invivo efficacy of pretargeted radioimmunotherapyutilizing inverse electron demand diels-alder click chemistryrdquoMolecular Cancer Therapeutics vol 16 no 1 pp 124ndash133 2017
[268] J Funkhouser ldquoReinventing pharma the theranostic revolu-tionrdquo Current Drug Discovery pp 17ndash19 2002
[269] J Sorensen I Velikyan A Wennborg et al ldquoMeasuring HER2-expression in metastatic breast cancer using 68Ga-ABY025PETCTrdquo European Journal of Nuclear Medicine and MolecularImaging vol 41 pp S226ndashS226 2014
[270] I Velikyan A Wennborg J Feldwisch et al ldquoGMP compliantpreparation of a 68Gallium-labeled Affibody analogue forbreast cancer patient examination first-in-manrdquoEur JNuclMedMol Imaging vol 41 pp S228ndashS229 2014
[271] K Oberg ldquoMolecular imaging radiotherapy Theranostics forpersonalized patient management of neuroendocrine tumors(NETs)rdquoTheranostics vol 2 no 5 pp 448ndash458 2012
[272] I Velikyan AWennborg J FeldwischH Lindman J Carlssonand J Sorensen ldquoGood manufacturing practice production of [(68) Ga]Ga-ABY-025 for HER2 specific breast cancer imagingrdquoAmerican Journal of Nuclear Medicine and Molecular Imagingvol 6 no 2 pp 135ndash153 2016
[273] M Sandstrom K Lindskog I Velikyan et al ldquoBiodistributionand radiation dosimetry of the anti-HER2 Affibody molecule68Ga-ABY-025 in breast cancer patientsrdquo Journal of NuclearMedicine vol 57 no 6 pp 867ndash871 2016
[274] D Sandberg V Tolmachev I Velikyan et al ldquoIntra-imagereferencing for simplified assessment of HER2-expression inbreast cancer metastases using the Affibody molecule ABY-025with PET and SPECTrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 44 no 8 pp 1337ndash1346 2017
[275] H ZhangM AMoroz I Serganova et al ldquoImaging expressionof the human somatostatin receptor subtype-2 reporter genewith 68Ga-DOTATOCrdquo Journal ofNuclearMedicine vol 52 no1 pp 123ndash131 2011
[276] M Naji and A Al-Nahhas ldquo68Ga-labelled peptides in themanagement of neuroectodermal tumoursrdquo European Journalof Nuclear Medicine and Molecular Imaging vol 39 no 1 ppS61ndashS67 2012
[277] I Velikyan ldquoThe diversity of 68Ga-Based imaging agentsrdquoRecent Results in Cancer Research vol 194 pp 101ndash131 2013
[278] K Ferreira H-Y Hu V Fetz et al ldquoMultivalent siderophore-dotam conjugates as theranostics for imaging and treatment ofbacterial infectionsrdquo Angewandte Chemie International Editionvol 56 no 28 pp 8272ndash8276 2017
Computational and Mathematical Methods in Medicine
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Submit your manuscripts atwwwhindawicom
Contrast Media amp Molecular Imaging 17
[43] A W J M Glaudemans R H J A Slart J M Van Dijl MVan Oosten and G M Van Dam ldquoMolecular imaging of infec-tious and inflammatory diseases A terra incognitardquo Journal ofNuclear Medicine vol 56 no 5 pp 659ndash661 2015
[44] X Li W Bauer I Israel et al ldquoTargeting p-selectin by gallium-68-labeled fucoidan positron emission tomography for nonin-vasive characterization of vulnerable plaques Correlation within vivo 176t mrirdquo Arteriosclerosis Thrombosis and VascularBiology vol 34 no 8 pp 1661ndash1667 2014
[45] S Eichendorff P Svendsen D Bender et al ldquoBiodistributionand PET Imaging of a Novel [68Ga]-Anti-CD163-AntibodyConjugate in Rats with Collagen-Induced Arthritis and inControlsrdquoMolecular Imaging and Biology vol 17 no 1 pp 87ndash93 2014
[46] Z Zhu Y Yin K Zheng et al ldquoEvaluation of synovial angiogen-esis in patients with rheumatoid arthritis using 68Ga-PRGD2PETCT A prospective proof-of-concept cohort studyrdquo Annalsof the Rheumatic Diseases vol 73 no 6 pp 1269ndash1272 2014
[47] J S Eo J C Paeng S Lee et al ldquoAngiogenesis imaging inmyocardial infarction using 68Ga-NOTA- RGD PET Charac-terization and application to therapeutic efficacy monitoring inratsrdquo Coronary Artery Disease vol 24 no 4 pp 303ndash311 2013
[48] J H Kim Y-H Kim Y J Kim et al ldquoQuantitative positronemission tomography imaging of angiogenesis in rats with fore-limb ischemia using 68Ga-NOTA-c(RGDyK)rdquo Angiogenesisvol 16 no 4 pp 837ndash846 2013
[49] I Laitinen J Notni K Pohle et al ldquoComparison of cyclicRGD peptides for 120572v1205733 integrin detection in a rat model ofmyocardial infarctionrdquo EJNMMI Research vol 3 no 1 pp 1ndash9 2013
[50] M Kiugel I Dijkgraaf V Kyto et al ldquoDimeric [68Ga]DOTA-RGD Peptide Targeting 120572 ltinfgtvltinfgt 120573 ltinfgt3ltinfgt Inte-grin Reveals Extracellular Matrix Alterations after MyocardialInfarctionrdquo Molecular Imaging and Biology vol 16 no 6 pp793ndash801 2014
[51] M Gronman M Tarkia T Kiviniemi et al ldquoImaging of 120572v1205733integrin expression in experimental myocardial ischemia with[68Ga]NODAGA-RGD positron emission tomographyrdquo Jour-nal of Translational Medicine vol 15 no 1 p 144 2017
[52] J Haukkala I Laitinen P Luoto et al ldquo68Ga-DOTA-RGDpep-tide Biodistribution and binding into atherosclerotic plaquesin micerdquo European Journal of Nuclear Medicine and MolecularImaging vol 36 no 12 pp 2058ndash2067 2009
[53] H Virtanen A Autio R Siitonen et al ldquo68Ga-DOTA-Siglec-9- a new imaging tool to detect synovitisrdquo Arthritis Research ampTherapy vol 17 no 1 article no 308 2015
[54] J Retamal J Sorensen M Lubberink et al ldquoFeasibility of(68) Ga-labeled Siglec-9 peptide for the imaging of acutelung inflammation a pilot study in a porcine model of acuterespiratory distress syndromerdquoAm JNuclMedMol Imaging vol6 no 1 pp 18ndash31 2016
[55] J M U Silvola H Virtanen R Siitonen et al ldquoLeukocytetrafficking-associated vascular adhesion protein 1 is expressedand functionally active in atherosclerotic plaquesrdquo ScientificReports vol 6 Article ID 35089 2016
[56] H Ahtinen J Kulkova L Lindholm et al ldquo68Ga-DOTA-Siglec-9 PETCT imaging of peri-implant tissue responses andstaphylococcal infectionsrdquo EJNMMI Research vol 4 no 1article no 45 pp 1ndash11 2014
[57] A Autio S Jalkanen and A Roivainen ldquoNuclear imaging ofinflammation Homing-associated molecules as targetsrdquo EJN-MMI Research vol 3 no 1 pp 1ndash7 2013
[58] J TThackeray T Derlin AHaghikia et al ldquoMolecular Imagingof the Chemokine Receptor CXCR4 after Acute MyocardialInfarctionrdquo JACC Cardiovascular Imaging vol 8 no 12 pp1417ndash1426 2015
[59] J S Schmid A Schirbel A K Buck S Kropf H-J Westerand C Lapa ldquoPentixafor-Positron Emission TomographyComputed Tomography Detects Chemokine Receptor CXCR4Expression after Ischemic Strokerdquo Circulation CardiovascularImaging vol 9 no 9 Article ID e005217 2016
[60] J Zhou G Hao H Weng et al ldquoIn vivo evaluation ofmedical device-associated inflammation using a macrophage-specific positron emission tomography (PET) imaging proberdquoBioorganic amp Medicinal Chemistry Letters vol 23 no 7 pp2044ndash2047 2013
[61] S A Kularatne M-J Belanger X Meng et al ldquoComparativeanalysis of folate derived PET imaging agents with [ 18F]-2-fluoro-2-deoxy-d-glucose using a rodent inflammatory pawmodelrdquo Molecular Pharmaceutics vol 10 no 8 pp 3103ndash31112013
[62] V Ambrosini M Zompatori F De Luca et al ldquo68Ga-DOTANOCPETCTAllows Somatostatin Receptor Imaging inIdiopathic Pulmonary Fibrosis Preliminary Resultsrdquo Journal ofNuclear Medicine vol 51 no 12 pp 1950ndash1955 2010
[63] T Lincke J Singer R Kluge O Sabri and R Paschke ldquoRela-tive quantification of indium-111 pentetreotide and gallium-68DOTATOC uptake in the thyroid gland and association withthyroid pathologiesrdquoThyroid vol 19 no 4 pp 381ndash389 2009
[64] A Rominger T Saam E Vogl et al ldquoIn vivo imaging ofmacrophage activity in the coronary arteries using 68Ga-DOTATATE PETCT correlation with coronary calcium bur-den and risk factorsrdquo Journal of Nuclear Medicine vol 51 no 2pp 193ndash197 2010
[65] J M Tarkin F R Joshi N R Evans et al ldquoDetection ofAtherosclerotic Inflammation by 68Ga-DOTATATE PET Com-pared to [18F]FDG PET Imagingrdquo Journal of the AmericanCollege of Cardiology vol 69 no 14 pp 1774ndash1791 2017
[66] S-P Lee H-J Im S Kang et al ldquoNoninvasive imaging ofmyocardial inflammation in myocarditis using 68Ga-taggedmannosylated human serum albumin positron emissiontomographyrdquoTheranostics vol 7 no 2 pp 413ndash424 2017
[67] Z Zha J Song S R Choi et al ldquo68Ga-Bivalent PolypegylatedStyrylpyridine Conjugates for Imaging A120573 Plaques in CerebralAmyloid Angiopathyrdquo Bioconjugate Chemistry vol 27 no 5 pp1314ndash1323 2016
[68] H Watanabe M Ono S Iikuni et al ldquoA 68Ga complex basedon benzofuran scaffold for the detection of 120573-amyloid plaquesrdquoBioorganic amp Medicinal Chemistry Letters vol 24 no 20 pp4834ndash4837 2014
[69] D Cressier M Dhilly T T Cao Pham et al ldquoGallium-68 Com-plexes Conjugated to Pittsburgh Compound B Radiolabelingand Biological EvaluationrdquoMolecular Imaging and Biology vol18 no 3 pp 334ndash343 2016
[70] D Satpati CArjun R KrishnamohanG Samuel and S Baner-jee ldquo68Ga-labeledCiprofloxacinConjugates as Radiotracers forTargeting Bacterial InfectionrdquoChemical Biology ampDrug Designvol 87 no 5 pp 680ndash686 2016
[71] T Ebenhan N Chadwick and M M Sathekge ldquoPeptidesynthesis characterization and 68Ga-radiolabeling of NOTA-conjugated ubiquicidin fragments for prospective infectionimaging with PETCTrdquo Nuclear Medicine and Biology vol 41no 5 pp 390ndash400 2014
18 Contrast Media amp Molecular Imaging
[72] T Ebenhan J R Zeevaart and J D Venter ldquoPreclinicalevaluation of 68Ga-labeled 1 4 7-triazacyclononane-1 4 7-triacetic acid-ubiquicidin as a radioligand for PET infectionimagingrdquo Journal of Nuclear Medicine vol 55 no 2 pp 308ndash314 2014
[73] B B Mokaleng T Ebenhan S Ramesh et al ldquoSynthesis 68Ga-radiolabeling and preliminary in vivo assessment of adepsipeptide-derived compound as a potential PETCTinfection imaging agentrdquo BioMed Research International vol2015 Article ID 284354 2015
[74] T Ebenhan B Mokaleng J Venter H Kruger J Zeevaart andM Sathekge ldquoPreclinical Assessment of a 68Ga-DOTA-Functionalized Depsipeptide as a Radiodiagnostic InfectionImaging AgentrdquoMolecules vol 22 no 9 p 1403 2017
[75] S Chopra B Singh A Koul A Mishra and H Wester ldquoSyn-thesis of DOTA conjugated GF-17 and RAWVAWR-NH2 andradiolabeling with 68Ga as a potential PET tracer for infectionimagingrdquo J Nucl Med vol 57 Supplement 2 p 1115 2016
[76] M Petrik HHaas P Laverman et al ldquo 68Ga-triacetylfusarinineC and 68Ga-ferrioxamine e for aspergillus infection imaginguptake specificity in various microorganismsrdquoMolecular Imag-ing and Biology vol 16 no 1 pp 102ndash108 2014
[77] V Kumar and D K Boddeti ldquo 68Ga-radiopharmaceuticals forPET imaging of infection and inflammationrdquo Recent Results inCancer Research vol 194 pp 189ndash219 2013
[78] M Vorster A Maes A Jacobs et al ldquoEvaluating the possiblerole of 68Ga-citrate PETCT in the characterization of indeter-minate lung lesionsrdquo Annals of Nuclear Medicine vol 28 no 6pp 523ndash530 2014
[79] M Vorster B Mokaleng M M Sathekge and T Ebenhan ldquoAmodified technique for efficient radiolabeling of 68Ga-citratefrom a SnO2-based 68Ge68Ga generator for better infectionimagingrdquoHellenic Journal of Nuclear Medicine vol 16 no 3 pp193ndash198 2013
[80] S Salomaeki J Kemppainen U Hohenthal et al ldquoHead-to-head comparison of 68Ga-Citrate and 18F-FDG PETCT fordetection of infectious foci in patients with staphylococcusaureus bacteraemiardquo Contrast Media amp Molecular Imaging vol2017 p 8 2017
[81] L Fass ldquoImaging and cancer a reviewrdquoMolecular Oncology vol2 no 2 pp 115ndash152 2008
[82] A Chopra L Shan W C Eckelman et al ldquoMolecular imagingand contrast agent database (MICAD) Evolution and progressrdquoMolecular Imaging and Biology vol 14 no 1 pp 4ndash13 2012
[83] A Sanchez-Crespo P Andreo and S A Larsson ldquoPositronflight in human tissues and its influence on PET image spatialresolutionrdquo European Journal of Nuclear Medicine and Molecu-lar Imaging vol 31 no 1 pp 44ndash51 2004
[84] H W A M De Jong L Perk G W M Visser R Boellaard GAM S Van Dongen and A A Lammertsma ldquoHigh resolutionPET imaging characteristics of68Ga 124i and89Zr comparedto18Frdquo in Proceedings of the Nuclear Science Symposium Con-ference Record 2005 IEEE pp 1624ndash1627 Puerto Rico October2005
[85] I Velikyan A Sundin B Eriksson et al ldquoIn vivo bindingof [68Ga]-DOTATOC to somatostatin receptors in neuroen-docrine tumours - impact of peptide massrdquo Nuclear Medicineand Biology vol 37 no 3 pp 265ndash275 2010
[86] U Eberlein and M Lassmann ldquoDosimetry of [68Ga]-labeledcompoundsrdquo Applied Radiation and Isotopes vol 76 pp 70ndash742013
[87] C PettinatoA SarnelliMDiDonna et al ldquo68Ga-DOTANOCBiodistribution and dosimetry in patients affected by neuroen-docrine tumorsrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 35 no 1 pp 72ndash79 2008
[88] B P Burke G S Clemente and S J Archibald ldquoRecentadvances in chelator design and labelling methodology for68Ga radiopharmaceuticalsrdquo Journal of Labelled Compoundsand Radiopharmaceuticals vol 57 no 4 pp 239ndash243 2014
[89] I Velikyan U Rosenstrom S Estrada et al ldquoSynthesis andpreclinical evaluation of 68Ga-labeled collagelin analogs forimaging and quantification of fibrosisrdquo Nuclear Medicine andBiology vol 41 no 9 pp 728ndash736 2014
[90] M F Ferreira G Pereira J P Andre and etal C ldquoGa[NO2A-N-(120572-amino)propionate] chelates Synthesis and evaluation aspotential tracers for 68Ga PETrdquoDalton Transactions vol 43 no21 pp 8037ndash8047 2014
[91] J Notni J Simecek and H-J Wester ldquoPhosphinic acid func-tionalized polyazacycloalkane chelators for radiodiagnosticsand radiotherapeutics Unique characteristics and applicationsrdquoChemMedChem vol 9 no 6 pp 1107ndash1115 2014
[92] J Simecek O Zemek P Hermann J Notni and H J WesterldquoTailored gallium( III) chelator NOPO synthesis characteriza-tion bioconjugation and application in preclinical Ga-68-PETimagingrdquoMolecular Pharmaceutics 2013
[93] D Parker B P Waldron and D S Yufit ldquoCrystallographicand solution NMR structural analyses of four hexacoordinatedgallium(iii) complexes based on ligands derived from 6-amino-perhydro-14-diazepinerdquo Dalton Transactions vol 42 no 22pp 8001ndash8008 2013
[94] B P Waldron D Parker C Burchardt D S Yufit M ZimnyandF Roesch ldquoStructure and stability of hexadentate complexesof ligands based on AAZTA for efficient PET labelling withgallium-68rdquo Chemical Communications vol 49 no 6 pp 579ndash581 2013
[95] D Parker and B PWaldron ldquoConformational analysis and syn-thetic approaches to polydentate perhydro-diazepine ligandsfor the complexation of gallium(iii)rdquo Organic amp BiomolecularChemistry vol 11 no 17 pp 2827ndash2838 2013
[96] I Velikyan H Maecke and B Langstrom ldquoConvenient prepa-ration of 68Ga-based PET-radiopharmaceuticals at room tem-peraturerdquo Bioconjugate Chemistry vol 19 no 2 pp 569ndash5732008
[97] J Erchegyi R Cescato B Waser J E Rivier and J C ReubildquoN-Imidazolebenzyl-histidine substitution in somatostatin andin its octapeptide analogue modulates receptor selectivity andfunctionrdquo Journal of Medicinal Chemistry vol 54 no 17 pp5981ndash5987 2011
[98] R Saha N Saha R S Donofrio and L L Bestervelt ldquoMicrobialsiderophores Amini reviewrdquo Journal of Basic Microbiology vol53 no 4 pp 303ndash317 2013
[99] V Nikolova S Angelova N Markova and T Dudev ldquoGalliumas a Therapeutic Agent A Thermodynamic Evaluation of theCompetition between Ga3+ and Fe3+ Ions in MetalloproteinsrdquoThe Journal of Physical Chemistry B vol 120 no 9 pp 2241ndash2248 2016
[100] C R Chitambar ldquoGallium and its competing roles with ironin biological systemsrdquo Biochimica et Biophysica Acta (BBA) -Molecular Cell Research vol 1863 no 8 pp 2044ndash2053 2016
[101] J A Lessa M A Soares and R G dos Santos ldquoGallium(III)complexes with 2-acetylpyridine-derived thiosemicarbazonesantimicrobial and cytotoxic effects and investigation on theinteractions with tubulinrdquo BioMetals vol 26 pp 151ndash165 2013
Contrast Media amp Molecular Imaging 19
[102] M van Oosten M Hahn L M A Crane et al ldquoTargetedimaging of bacterial infections Advances hurdles and hopesrdquoFEMS Microbiology Reviews vol 39 no 6 pp 892ndash916 2015
[103] M Vorster AMaes C V DWiele andM Sathekge ldquoGallium-68 PET A Powerful Generator-based Alternative to Infectionand Inflammation Imagingrdquo Seminars in Nuclear Medicine vol46 no 5 pp 436ndash447 2016
[104] M Kircher and C Lapa ldquoNovel Noninvasive Nuclear MedicineImaging Techniques for Cardiac Inflammationrdquo Current Car-diovascular Imaging Reports vol 10 no 2 article no 6 2017
[105] D AHammoud ldquoMolecular imaging of inflammation Currentstatusrdquo Journal of Nuclear Medicine vol 57 no 8 pp 1161ndash11652016
[106] D R Brenner D Scherer K Muir et al ldquoA review of the appli-cation of inflammatory biomarkers in epidemiologic cancerresearchrdquo Cancer Epidemiology Biomarkers amp Prevention vol23 no 9 pp 1729ndash1751 2014
[107] M D Turner B Nedjai T Hurst and D J PenningtonldquoCytokines and chemokines at the crossroads of cell signallingand inflammatory diseaserdquo Biochimica et Biophysica Acta (BBA)- Molecular Cell Research vol 1843 no 11 pp 2563ndash2582 2014
[108] L Werner H Guzner-Gur and I Dotan ldquoInvolvement ofCXCR4CXCR7CXCL12 interactions in inflammatory boweldiseaserdquoTheranostics vol 3 no 1 pp 40ndash46 2013
[109] S Jalkanen and M Salmi ldquoVAP-1 and CD73 endothelial cellsurface enzymes in leukocyte extravasationrdquo ArteriosclerosisThrombosis and Vascular Biology vol 28 no 1 pp 18ndash26 2008
[110] G Malviya F Galli I Sonni and A Signore ldquoImaging T-lymphocytes in inflammatory diseases A nuclear medicineapproachrdquo The Quarterly Journal of Nuclear Medicine andMolecular Imaging vol 58 no 3 pp 237ndash257 2014
[111] S Gratz H J RennenO C BoermanW J Oyen and P Burmaldquo(99m)Tc-interleukin-8 for imaging acute osteomyelitisrdquo Jour-nal of Nuclear Medicine vol 42 no 8 pp 1257ndash1264 2001
[112] S Gratz H J Rennen O C Boerman W J Oyen andF H Corstens ldquoRapid imaging of experimental colitis with(99m)Tc-interleukin-8 in rabbitsrdquo Journal of Nuclear Medicnevol 42 no 6 pp 917ndash923 2001
[113] C Alkim H Alkim A R Koksal S Boga and I SenldquoAngiogenesis in inflammatory bowel diseaserdquo InternationalJournal of Inflammation vol 2015 Article ID 970890 2015
[114] I S Alam T H Witney G Tomasi et al ldquoRadiolabeled RGDtracer kinetics annotates differential 120572v1205733 integrin expressionlinked to cell intrinsic and vessel expressionrdquoMolecular Imagingand Biology vol 16 no 4 pp 558ndash566 2014
[115] J Notni K Pohle and H-J Wester ldquoBe spoilt for choice withradiolabelled RGD peptides Preclinical evaluation of 68Ga-TRAP(RGD)3rdquoNuclear Medicine and Biology vol 40 no 1 pp33ndash41 2013
[116] J Oxboel M Brandt-Larsen C Schjoeth-Eskesen et al ldquoCom-parison of two new angiogenesis PET tracers 68Ga-NODAGA-E[c(RGDyK)]2 and 64Cu-NODAGA-E[c(RGDyK)]2 in vivoimaging studies in human xenograft tumorsrdquo Nuclear Medicineand Biology vol 41 no 3 pp 259ndash267 2014
[117] J Simecek J Notni T G Kapp H Kessler and H-J WesterldquoBenefits of NOPO as chelator in gallium-68 peptides exempli-fied by preclinical characterization of 68Ga-NOPO-c(RGDfK)rdquoMolecular Pharmaceutics vol 11 no 5 pp 1687ndash1695 2014
[118] M Trajkovic-Arsic P Mohajerani A Sarantopoulos et alldquoMultimodal molecular imaging of integrin avb3 for in vivodetection of pancreatic cancerrdquo Journal of NuclearMedicine vol55 no 3 pp 446ndash451 2014
[119] H Cai and P S Conti ldquoRGD-based PET tracers for imagingreceptor integrin 120572 v1205733 expressionrdquo Journal of Labelled Com-pounds and Radiopharmaceuticals vol 56 no 5 pp 264ndash2792013
[120] I Dijkgraaf S Y A Terry W J Mcbride et al ldquoImagingintegrin alpha-v-beta-3 expression in tumors with an 18F-labeled dimeric RGD peptiderdquo Contrast Media amp MolecularImaging vol 8 no 3 pp 238ndash245 2013
[121] P A Knetsch M Petrik C Rangger et al ldquo[68Ga]NS3-RGD and [68Ga] Oxo-DO3A-RGD for imaging 120572v1205733 integrinexpression Synthesis evaluation and comparisonrdquo NuclearMedicine and Biology vol 40 no 1 pp 65ndash72 2013
[122] Z Liu and F Wang ldquoDevelopment of RGD-based radiotracersfor tumor imaging and therapy Translating from bench tobedsiderdquo Current Molecular Medicine vol 13 no 10 pp 1487ndash1505 2013
[123] H Choi J H Phi J C Paeng et al ldquoImaging of integrin 120572v1205733expression using 68Ga-RGD positron emission tomography inpediatric cerebral infarctrdquoMolecular Imaging vol 12 no 4 pp213ndash217 2013
[124] H-J Yoon K W Kang I K Chun et al ldquoCorrelation of breastcancer subtypes based on estrogen receptor progesteronereceptor and HER2 with functional imaging parameters from68Ga-RGD PETCT and 18F-FDG PETCTrdquo European Journalof Nuclear Medicine and Molecular Imaging vol 41 no 8 pp1534ndash1543 2014
[125] R P Baum H R Kulkarni D Muller et al ldquoFirst-in-human study demonstrating tumor-angiogenesis by PETCTimaging with 68Ga-NODAGA-THERANOST a high-affinitypeptidomimetic for 120572v1205733 integrin receptor targetingrdquo CancerBiotherapy andRadiopharmaceuticals vol 30 no 4 pp 152ndash1592015
[126] R Haubner A Finkenstedt A Stegmayr et alldquo[68Ga]NODAGA-RGD ndash Metabolic stability biodistributionand dosimetry data from patients with hepatocellularcarcinoma and liver cirrhosisrdquo European Journal of NuclearMedicine and Molecular Imaging vol 43 no 11 pp 2005ndash20132016
[127] V Lopez-Rodrıguez C Galindo-Sarco F O Garcıa-Perez GFerro-Flores O Arrieta and M A Avila-Rodrıguez ldquoPET-based human dosimetry of the dimeric 120572v1205733 integrin ligand68Ga-DOTA-E-[c(RGDfK)]2 a potential tracer for imagingtumor angiogenesisrdquo Journal of Nuclear Medicine vol 57 no 3pp 404ndash409 2016
[128] M V Backer Z Levashova V Patel et al ldquoMolecular imagingof VEGF receptors in angiogenic vasculature with single-chainVEGF-based probesrdquo Nature Medicine vol 13 no 4 pp 504ndash509 2007
[129] MV Backer Z Levashova R Levenson F G Blankenberg andJ M Backer ldquoCysteine-containing fusion tag for site-specificconjugation of therapeutic and imaging agents to targetingproteinsrdquoMethods in Molecular Biology (Clifton NJ) vol 494pp 275ndash294 2008
[130] M Eder A V Krivoshein M Backer J M Backer UHaberkorn and M Eisenhut ldquoScVEGF-PEG-HBED-CC andscVEGF-PEG-NOTA conjugates comparison of easy-to-labelrecombinant proteins for [68Ga]PET imaging of VEGF recep-tors in angiogenic vasculaturerdquo Nuclear Medicine and Biologyvol 37 no 4 pp 405ndash412 2010
[131] E Blom I Velikyan A Monazzam P Razifar et al ldquoSynthe-sis and characterization of scVEGF-PEG-[ 68Ga]NOTA andscVEGF-PEG-[ 68Ga]DOTA PET tracersrdquo Journal of Labelled
20 Contrast Media amp Molecular Imaging
Compounds and Radiopharmaceuticals vol 54 no 11 pp 685ndash692 2011
[132] S Gratz M Behe and O C Boerman ldquo 99119898Tc-E-selectinbinding peptide for imaging acute osteomyelitis in a novel ratmodelrdquo Nuclear Medicine Communications vol 22 no 9 pp1003ndash1013 2001
[133] S B Jensen M Kakela L Joslashdal et al ldquoExploring the radiosyn-thesis and in vitro characteristics of [68Ga]Ga-DOTA-Siglec-9rdquoJournal of Labelled Compounds and Radiopharmaceuticals vol60 no 9 pp 439ndash449 2017
[134] B A Teicher and S P Fricker ldquoCXCL12 (SDF-1)CXCR4pathway in cancerrdquo Clinical Cancer Research vol 16 no 11 pp2927ndash2931 2010
[135] O Jacobson I D Weiss D O Kiesewetter J M Farber andX Chen ldquoPET of tumor CXCR4 expression with 4-18F-T140rdquoJournal of Nuclear Medicine vol 51 no 11 pp 1796ndash1804 2010
[136] A Aghanejad A R Jalilian Y Fazaeli et al ldquoSynthesis andevaluation of [67Ga]-AMD3100 A novel imaging agent fortargeting the chemokine receptorCXCR4rdquo Scientia Pharmaceu-tica vol 82 no 1 pp 29ndash42 2014
[137] O Jacobson I D Weiss L P Szajek et al ldquoPET imaging ofCXCR4 using copper-64 labeled peptide antagonistrdquoTheranos-tics vol 1 pp 251ndash262 2011
[138] O Jacobson I D Weiss L P Szajek et al ldquoImprovement ofCXCR4 tracer specificity for PET imagingrdquo Journal of Con-trolled Release vol 157 no 2 pp 216ndash223 2012
[139] H J Wester U Keller M Schottelius et al ldquoDisclosing theCXCR4 expression in lymphoproliferative diseases by targetedmolecular imagingrdquo Theranostics vol 5 no 6 pp 618ndash6302015
[140] E Gourni O Demmer M Schottelius et al ldquoPET of CXCR4expression by a 68Ga-labeled highly specific targeted contrastagentrdquo Journal of NuclearMedicine vol 52 no 11 pp 1803ndash18102011
[141] O Demmer I Dijkgraaf U Schumacher et al ldquoDesignsynthesis and functionalization of dimeric peptides targetingchemokine receptor CXCR4rdquo Journal of Medicinal Chemistryvol 54 no 21 pp 7648ndash7662 2011
[142] O Demmer E Gourni U Schumacher H Kessler and H-JWester ldquoPET Imaging of CXCR4 Receptors in Cancer by a NewOptimized Ligandrdquo ChemMedChem vol 6 no 10 pp 1789ndash1791 2011
[143] U Hennrich L Seyler M Schafer et al ldquoSynthesis and invitro evaluation of 68Ga-DOTA-4-FBn-TN14003 a novel tracerfor the imaging of CXCR4 expressionrdquo Bioorganic amp MedicinalChemistry vol 20 no 4 pp 1502ndash1510 2012
[144] G P C George E Stevens O Aberg et al ldquoPreclinical evalua-tion of a CXCR4-specific 68Ga-labelled TN14003 derivative forcancer PET imagingrdquo Bioorganic amp Medicinal Chemistry vol22 no 2 pp 796ndash803 2014
[145] S Poty E Gourni P Desogere et al ldquoAMD3100 A VersatilePlatform for CXCR4 Targeting 68Ga-Based Radiopharmaceu-ticalsrdquo Bioconjugate Chemistry vol 27 no 3 pp 752ndash761 2016
[146] K Philipp-Abbrederis K Herrmann S Knop et al ldquoIn vivomolecular imaging of chemokine receptor CXCR4 expressionin patients with advancedmultiple myelomardquo EMBOMolecularMedicine vol 7 no 4 pp 477ndash487 2015
[147] Z Wang M Zhang L Wang et al ldquoProspective study of 68Ga-NOTA-NFB Radiation dosimetry in healthy volunteers andfirst application in glioma patientsrdquo Theranostics vol 5 no 8pp 882ndash889 2015
[148] I M Jackson P J Scott and S Thompson ldquoClinical Applica-tions of Radiolabeled Peptides for PETrdquo Seminars in NuclearMedicine vol 47 no 5 pp 493ndash523 2017
[149] C Lapa T Reiter R A Werner et al ldquo[68Ga]Pentixafor-PETCT for Imaging of Chemokine Receptor 4 Expression afterMyocardial Infarctionrdquo JACC Cardiovascular Imaging vol 8no 12 pp 1466ndash1468 2015
[150] C Rischpler S G Nekolla H Kossmann et al ldquoUpregu-lated myocardial CXCR4-expression after myocardial infarc-tion assessed by simultaneous GA-68 pentixafor PETMRIrdquoJournal of Nuclear Cardiology vol 23 no 1 pp 131ndash133 2016
[151] F Hyafil J Pelisek I Laitinen et al ldquoImaging the CytokineReceptorCXCR4 in atherosclerotic plaqueswith the radiotracer68Ga-Pentixafor for PETrdquo Journal of Nuclear Medicine vol 58no 3 pp 499ndash506 2017
[152] Y Yi ldquoFolate receptor-targeted diagnostics and therapeutics forinflammatory diseasesrdquo ImmuneNetwork vol 16 no 6 pp 337ndash343 2016
[153] C M Paulos M J Turk G J Breur and P S Low ldquoFolatereceptor-mediated targeting of therapeutic and imaging agentsto activated macrophages in rheumatoid arthritisrdquo AdvancedDrug Delivery Reviews vol 56 no 8 pp 1205ndash1217 2004
[154] W Han R Zaynagetdinov F E Yull et al ldquoMolecular imagingof folate receptor 120573-positive macrophages during acute lunginflammationrdquo American Journal of Respiratory Cell and Molec-ular Biology vol 53 no 1 pp 50ndash59 2015
[155] B Kuhle C Muller and T L Ross ldquoA Novel 68Ga-Labeledpteroic acid-based PET tracer for tumor imaging via the folatereceptorrdquo Recent Results in Cancer Research vol 194 pp 257ndash267 2013
[156] C Brand V A Longo M Groaning W A Weber and TReiner ldquoDevelopment of a New Folate-Derived Ga-68-BasedPET Imaging AgentrdquoMolecular Imaging and Biology vol 19 no5 pp 754ndash761 2017
[157] M Fani XWang G Nicolas et al ldquoDevelopment of new folate-based PET radiotracers Preclinical evaluation of 68Ga-DOTA-folate conjugatesrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 38 no 1 pp 108ndash119 2011
[158] C J Mathias M R Lewis D E Reichert et al ldquoPreparationof 66Ga- and 68Ga-labeled Ga(III)-deferoxamine-folate aspotential folate-receptor-targeted PET radiopharmaceuticalsrdquoNuclear Medicine and Biology vol 30 no 7 pp 725ndash731 2003
[159] S-M Kim N Choi S Hwang et al ldquoFolate receptor-specific positron emission tomography imaging with folic acid-conjugated tissue inhibitor of metalloproteinase-2rdquo Bulletin ofthe Korean Chemical Society vol 34 no 11 pp 3243ndash3248 2013
[160] M Fani M-L Tamma G P Nicolas et al ldquoIn vivo imagingof folate receptor positive tumor xenografts using novel 68Ga-NODAGA-folate conjugatesrdquo Molecular Pharmaceutics vol 9no 5 pp 1136ndash1145 2012
[161] C Muller and R Schibli ldquoProspects in folate receptor-targetedradionuclide therapyrdquo Frontiers in Oncology vol 3 Article IDArticle 249 2013
[162] A Jain A Mathur U Pandey et al ldquoSynthesis and evaluationof a 68Ga labeled folic acid derivative for targeting folatereceptorsrdquo Applied Radiation and Isotopes vol 116 pp 77ndash842016
[163] W Xia A R Hilgenbrink E L Matteson M B Lockwood J-X Cheng and P S Low ldquoA functional folate receptor is inducedduring macrophage activation and can be used to target drugsto activated macrophagesrdquo Blood vol 113 no 2 pp 438ndash4462009
Contrast Media amp Molecular Imaging 21
[164] E P Krenning W A P Breeman P P M Kooij et alldquoLocalisation of endocrine-related tumours with radioiodi-nated analogue of somatostatinrdquoThe Lancet vol 1 no 8632 pp242ndash244 1989
[165] E P Krenning D J KwekkeboomWH Bakker et al ldquoSomato-statin receptor scintigraphy with [111In-DTPA-d-Phe1]- and[123I-Tyr3]-octreotide the Rotterdam experience with morethan 1000 patientsrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 20 no 8 pp 716ndash731 1993
[166] A Stahl G Meisetschlager M Schottelius et al ldquo[123I]Mtr-TOCA a radioiodinated and carbohydrated analogue ofoctreotide Scintigraphic comparison with [111In]octreotiderdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 33 no 1 pp 45ndash52 2006
[167] R Lebtahi J le Cloirec C Houzard et al ldquoDetection of neu-roendocrine tumors 99mTc-P829 scintigraphy compared with111In-pentetreotide scintigraphyrdquo Journal of Nuclear Medicinevol 43 no 7 pp 889ndash895 2002
[168] C Decristoforo T Maina B Nock M Gabriel P Cordopatisand R Moncayo ldquo99mTc-demotate 1 First data in tumourpatients - Results of a pilotphase I studyrdquo European Journal ofNuclearMedicine andMolecular Imaging vol 30 no 9 pp 1211ndash1219 2003
[169] C Decristoforo S J Mather W Cholewinski E DonnemillerG Riccabona and R Moncayo ldquo(99m)Tc-EDDAHYNIC-TOC A new (99m)Tc-labelled radiopharmaceutical forimaging somatostatin receptor-positive tumours First clinicalresults and intra-patient comparison with 111In-labelledoctreotide derivativesrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 27 no 9 pp 1318ndash1325 2000
[170] A Hubalewska-Dydejczyk K Fross-Baron R Mikołajczak etal ldquo99mTc-EDDAHYNIC-octreotate scintigraphy an efficientmethod for the detection and staging of carcinoid tumoursResults of 3 yearsrsquo experiencerdquo European Journal of NuclearMedicine and Molecular Imaging vol 33 no 10 pp 1123ndash11332006
[171] M Bangard M Behe S Guhlke et al ldquoDetection of somato-statin receptor-positive tumours using the new 99mC-tricine-HYNIC-D-Phe1-Tyr3-octreotide First results in patients andcomparison with 111In-DTPA-D-Phe1-octreotiderdquo EuropeanJournal of Nuclear Medicine and Molecular Imaging vol 27 no6 pp 628ndash637 2000
[172] A Helisch G J Forster H Reber et al ldquoPre-therapeuticdosimetry and biodistribution of 86Y-DOTA- Phe1-Tyr3-octreotide versus 111In-pentetreotide in patients with advancedneuroendocrine tumoursrdquo European Journal of NuclearMedicine and Molecular Imaging vol 31 no 10 pp 1386ndash13922004
[173] M Henze J Schuhmacher P Hipp et al ldquoPET imaging ofsomatostatin receptors using [68GA]DOTA-D-Phe1-Tyr3-Octreotide First results in patients with meningiomasrdquo Journalof Nuclear Medicine vol 42 no 7 pp 1053ndash1056 2001
[174] I Kayani J B Bomanji A Groves et al ldquoFunctional imaging ofneuroendocrine tumors with combined PETCT using 68Ga-DOTATATE (Dota-DPhe1 Tyr3-octreotate) and 18F-FDGrdquoCancer vol 112 no 11 pp 2447ndash2455 2008
[175] A Al-Nahhas ldquoNuclear medicine imaging of neuroendocrinetumoursrdquo Clinical Medicine vol 12 no 4 pp 377ndash380 2012
[176] V Ambrosini S Nicolini P Caroli et al ldquoPETCT imaging indifferent types of lung cancer an overviewrdquo European Journal ofRadiology vol 81 no 5 pp 988ndash1001 2012
[177] V Ambrosini D Campana P Tomassetti and S Fanti ldquo68Ga-labelled peptides for diagnosis of gastroenteropancreatic NETrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 39 no 1 pp S52ndashS60 2012
[178] K E Oberg J-C Reubi D J Kwekkeboom and E P KrenningldquoRole of somatostatins in gastroenteropancreatic neuroen-docrine tumor development and therapyrdquoGastroenterology vol139 no 3 pp 753-753 2010
[179] K Oberg ldquoGallium-68 somatostatin receptor PETCT Is ittime to replace 111Indium DTPA octreotide for patients withneuroendocrine tumorsrdquo Endocrine Journal vol 42 no 1 pp3-4 2012
[180] R Srirajaskanthan I Kayani A M Quigley J Soh M ECaplin and J Bomanji ldquoThe role of 68Ga-DOTATATE PET inpatients with neuroendocrine tumors and negative or equivocalfindings on 111In-DTPA-octreotide scintigraphyrdquo Journal ofNuclear Medicine vol 51 no 6 pp 875ndash882 2010
[181] A Kroiss D Putzer and C Uprimny ldquoFunctional imag-ing in phaeochromocytoma and neuroblastoma with 68Ga-DOTA-Tyr3-octreotide positron emission tomography and123I-metaiodobenzylguanidinerdquo European Journal of NuclearMedicine and Molecular Imaging vol 38 no 5 pp 865ndash8732011
[182] M Naji C Zhao S J Welsh et al ldquo68Ga-DOTA-TATE PETvs 123I-MIBG in identifying malignant neural crest tumoursrdquoMolecular Imaging and Biology vol 13 no 4 pp 769ndash775 2011
[183] V Ambrosini P Tomassetti P Castellucci et al ldquoComparisonbetween 68Ga-DOTA-NOC and 18F-DOPA PET for the detec-tion of gastro-entero-pancreatic and lung neuro-endocrinetumoursrdquo European Journal of Nuclear Medicine and MolecularImaging vol 35 no 8 pp 1431ndash1438 2008
[184] D Putzer M Gabriel B Henninger et al ldquoBone metastasesin patients with neuroendocrine tumor 68Ga- DOTA-Tyr3-octreotide PET in comparison to CT and bone scintigraphyrdquoJournal of Nuclear Medicine vol 50 no 8 pp 1214ndash1221 2009
[185] L K Anzola-Fuentes M Chianelli F Galli et al ldquoSomatostatinreceptor scintigraphy in patients with rheumatoid arthritis andsecondary Sjogrenrsquos syndrome treated with Infliximab a pilotstudyrdquo EJNMMI Research vol 6 no 1 article no 49 2016
[186] T Nobashi Y Nakamoto T Kubo et al ldquoThe utility of PETCTwith 68Ga-DOTATOC in sarcoidosis comparison with 67Ga-scintigraphyrdquoAnnals ofNuclearMedicine vol 30 no 8 pp 544ndash552 2016
[187] C Boy T A Heusner T D Poeppel et al ldquo68Ga-DOTATOCPETCT and somatostatin receptor (sst1-sst5) expression innormal human tissue Correlation of sst2mRNAand SUVmaxrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 38 no 7 pp 1224ndash1236 2011
[188] P Rinne S Hellberg M Kiugel et al ldquoComparison of Somato-statin Receptor 2-Targeting PET Tracers in the Detection ofMouse Atherosclerotic Plaquesrdquo Molecular Imaging and Biol-ogy vol 18 no 1 pp 99ndash108 2016
[189] M Asti E Ferrari S Croci et al ldquoSynthesis and characteri-zation of 68Ga-labeled curcumin and curcuminoid complexesas potential radiotracers for imaging of cancer and alzheimersdiseaserdquo Inorganic Chemistry vol 53 no 10 pp 4922ndash49332014
[190] A Signore I Santino and A W J M Glaudemans ldquoIn vivoimaging of microorganismsrdquo Clinical and Translational Imag-ing vol 4 no 3 pp 161-162 2016
[191] S Auletta F Galli C Lauri D Martinelli I Santino andA Signore ldquoImaging bacteria with radiolabelled quinolones
22 Contrast Media amp Molecular Imaging
cephalosporins and siderophores for imaging infection a sys-tematic reviewrdquo Clinical and Translational Imaging vol 4 no 4pp 229ndash252 2016
[192] X Ning S Lee Z Wang et al ldquoMaltodextrin-based imagingprobes detect bacteria in vivo with high sensitivity and speci-ficityrdquo Nature Materials vol 10 no 8 pp 602ndash607 2011
[193] J Ady andY Fong ldquoImaging for infection Fromvisualization ofinflammation to visualization of microbesrdquo Surgical Infectionsvol 15 no 6 pp 700ndash707 2014
[194] J M Sierra D Rodriguez-Puig A Soriano J Mensa C Pieraand J Vila ldquoAccumulation of 99mTc-ciprofloxacin in Staphy-lococcus aureus and Pseudomonas aeruginosardquo AntimicrobialAgents and Chemotherapy vol 52 no 7 pp 2691-2692 2008
[195] D I Andersson and D Hughes ldquoMicrobiological effects ofsublethal levels of antibioticsrdquoNature ReviewsMicrobiology vol12 no 7 pp 465ndash478 2014
[196] N Dumarey D Blocklet T Appelboom L Tant and ASchoutens ldquoInfecton is not specific for bacterial osteo-articularinfective pathologyrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 29 no 4 pp 530ndash535 2002
[197] K E Britton D W Wareham S S Das et al ldquoImaging bacte-rial infection with 99mTc-ciprofloxacin (Infecton)rdquo Journal ofClinical Pathology vol 55 no 11 pp 817ndash823 2002
[198] G Ferro-Flores M A Avila-Rodrıguez and F O Garcıa-PerezldquoImaging of bacteria with radiolabeled ubiquicidin by SPECTand PET techniquesrdquo Clinical and Translational Imaging vol 4no 3 pp 175ndash182 2016
[199] P S Hiemstra M T van den Barselaar M Roest P H Nibber-ing and R van Furth ldquoUbiquicidin a novel murine microbi-cidal protein present in the cytosolic fraction of macrophagesrdquoJournal of Leukocyte Biology vol 66 no 3 pp 423ndash428 1999
[200] M S Akhtar A Qaisar J Irfanullah et al ldquoAntimicrobialpeptide 99mTc-ubiquicidin 29ndash41 as human infection-imagingagent clinical trialrdquo Journal of Nuclear Medicne vol 46 no 4pp 567ndash573 2005
[201] M Assadi K Vahdat I Nabipour et al ldquoDiagnostic value of99mTc-ubiquicidin scintigraphy for osteomyelitis and compar-isons with 99mTc-methylene diphosphonate scintigraphy andmagnetic resonance imagingrdquo Nuclear Medicine Communica-tions vol 32 no 8 pp 716ndash723 2011
[202] T Emery ldquoExchange of Iron by Gallium in SiderophoresrdquoBiochemistry vol 25 no 16 pp 4629ndash4633 1986
[203] M Petrik C Zhai H Haas and C Decristoforo ldquoSiderophoresfor molecular imaging applicationsrdquo Clinical and TranslationalImaging vol 5 no 1 pp 15ndash27 2017
[204] H J Flint E A BayerM T Rincon R Lamed and B AWhiteldquoPolysaccharide utilization by gut bacteria potential for newinsights from genomic analysisrdquo Nature Reviews Microbiologyvol 6 no 2 pp 121ndash131 2008
[205] GGowrishankarMNamavari E B Jouannot et al ldquoInvestiga-tion of 6-[18F]-fluoromaltose as a novel PET tracer for imagingbacterial infectionrdquo PLoS ONE vol 9 no 9 Article ID e1079512014
[206] N Gholipour M Akhlaghi A M Kheirabadi et al ldquoChelator-free radiolabeling of dextran with 68Ga for PET studiesrdquoJournal of Radioanalytical and Nuclear Chemistry vol 311 no3 pp 1811ndash1817 2017
[207] C Bettegowda C A Foss I Cheong et al ldquoImaging bac-terial infections with radiolabeled 1-(21015840-deoxy-21015840- fluoro-120573-D-arabinofuranosyl)-5-iodouracilrdquo Proceedings of the NationalAcadamy of Sciences of the United States of America vol 102 no4 pp 1145ndash1150 2005
[208] S A Soghomonyan M Doubrovin J Pike et al ldquoPositronemission tomography (PET) imaging of tumor-localizedSalmonella expressing HSV1-TKrdquo Cancer GeneTherapy vol 12no 1 pp 101ndash108 2005
[209] C Palestro K Nichols S Sheikh-Fayyaz S Dewey P Singhaland K Bhargava ldquoCan Gallium-68 PET differentiate acuteinterstitial nephritis from acute tubular necrosisrdquo Journal ofNuclear Medicne vol 57 Supplement 2 p 551 2016
[210] A J Morguet D L Munz V Ivancevic et al ldquoImmunoscintig-raphy using technetium-99m-labeled anti-NCA-95 antigranu-locyte antibodies as an adjunct to echocardiography in subacuteinfective endocarditisrdquo Journal of the American College ofCardiology vol 23 no 5 pp 1171ndash1178 1994
[211] C van der Laken O Boerman W Oyen et al ldquoIn Vivo Expres-sion of Interleukin-1 Receptors during Various ExperimentallyInduced Inflammatory Conditionsrdquo The Journal of InfectiousDiseases vol 177 no 5 pp 1398ndash1401 1998
[212] C J Van Der Laken O C Boerman W J G Oyen M T PVan De Ven J W M Van Der Meer and F H M CorstensldquoScintigraphic detection of infection and inflammation Newdevelopments with special emphasis on receptor interactionrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 25 no 5 pp 535ndash546 1998
[213] C J van der LakenOC BoermanW J GOyenM T P van deVen J W M van der Meer and F H M Corstens ldquoImaging ofinfection in rabbits with radioiodinated interleukin-1 (120572 and 120573)its receptor antagonist and a chemotactic peptide a comparativestudyrdquo European Journal of Nuclear Medicine and MolecularImaging vol 25 no 4 pp 347ndash352 1998
[214] C J Van Der Laken O C BoermanW J G Oyen M T P VanDe Ven F H M Corstens and J W M Ven Der Meer ldquoThekinetics of radiolabelled interleukin-8 in infection and sterileinflammationrdquo Nuclear Medicine Communications vol 19 no3 pp 271ndash282 1998
[215] E Lazzeri P Erba M Perri et al ldquoScintigraphic imaging ofvertebral osteomyelitis with 111in-biotinrdquoThe Spine Journal vol33 no 7 pp E198ndashE204 2008
[216] E Blom B Langstrom and I Velikyan ldquo68Ga-labeling of biotinanalogues and their characterizationrdquo Bioconjugate Chemistryvol 20 no 6 pp 1146ndash1151 2009
[217] O Eriksson F Carlsson E Blom et al ldquoPreclinical evaluationof a 68Ga-labeled biotin analogue for applications in islettransplantationrdquo Nuclear Medicine and Biology vol 39 no 3pp 415ndash421 2012
[218] E A Weinstein A A Ordonez V P DeMarco et alldquoImaging Enterobacteriaceae infection in vivo with 18F-fluoro-deoxysorbitol positron emission tomographyrdquo Science Transla-tional Medicine vol 6 no 259 p 259ra146 2014
[219] K M Nielsen M H Kyneb A K O Alstrup et alldquo68Ga-labeled phage-display selected peptides as tracers forpositron emission tomography imaging of Staphylococcusaureus biofilm-associated infections Selection radiolabellingand preliminary biological evaluationrdquo Nuclear Medicine andBiology vol 43 no 10 pp 593ndash605 2016
[220] T J Makinen P Lankinen T Poyhonen J Jalava H T Aroand A Roivainen ldquoComparison of 18F-FDG and 68Ga PETimaging in the assessment of experimental osteomyelitis due toStaphylococcus aureusrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 32 no 11 pp 1259ndash1268 2005
[221] JMU Silvola I LaitinenH J Sipila et al ldquoUptake of 68galliumin atherosclerotic plaques in LDLRminusminusApoB100100micerdquo EJN-MMI Research vol 1 no 1 pp 1ndash8 2011
Contrast Media amp Molecular Imaging 23
[222] T A Wynn ldquoCellular and molecular mechanisms of fibrosisrdquoThe Journal of Pathology vol 214 no 2 pp 199ndash210 2008
[223] T Derlin D Jonigk J Bauersachs and FM Bengel ldquoMolecularImaging of Chemokine Receptor CXCR4 in NonndashSmall CellLung Cancer Using 68Ga-Pentixafor PETCT ComparisonWith 18F-FDGrdquo Clinical Nuclear Medicine 2016
[224] I Velikyan U Rosenstrom T N Bulenga O Eriksson andG Antoni ldquoFeasibility of multiple examinations using68ga-labelled collagelin analogues Organ distribution in rat forextrapolation to human organ and whole-body radiationdosimetryrdquo Pharmaceuticals vol 9 no 2 article no 31 2016
[225] S Jadhav M Kakela J Makila et al ldquoSynthesis and in VivoPET Imaging of Hyaluronan Conjugates of OligonucleotidesrdquoBioconjugate Chemistry vol 27 no 2 pp 391ndash403 2016
[226] A Autio A Saraste N Kudomi et al ldquoAssessment of bloodflow with (68) Ga-DOTA PET in experimental inflammation avalidation study using (15) O-waterrdquo American Journal ofNuclear Medicine and Molecular Imaging vol 4 no 6 pp 571ndash579 2014
[227] G Davies A Rolle A Maurer et al ldquoTowards translationalimmunoPETMR imaging of invasive pulmonary aspergillosisthe Humanised Monoclonal Antibody JF5 detects in vivordquoTheranostics vol 7 no 14 pp 3398ndash3414 2017
[228] DGoodwin CMeares GDavid et al ldquoMonoclonal antibodiesas reversible equilibrium carriers of radiopharmaceuticalsrdquoInternational Journal of Radiation Applications and Instrumen-tation Part B Nuclear Medicine and Biology vol 13 no 4 pp383ndash391 1986
[229] D A Goodwin C F Mears M McTigue and G S DavidldquoMonoclonal antibody hapten radiopharmaceutical deliveryrdquoNuclear Medicine Communications vol 7 no 8 pp 569ndash5801986
[230] S E Halpern and R O Dillman ldquoProblems associated withradioimmunodetection and possibilities for future solutionsrdquo JBiol Response Mod vol 6 no 3 pp 235ndash262 1987
[231] H Hong J Sun and W Cai ldquoRadionuclide-based cancerimaging targeting the carcinoembryonic antigenrdquo BiomarkerInsights vol 3 pp 435ndash451 2008
[232] G J Forster E B Santos P M Smith-Jones P Zanzonico andS M Larson ldquoPretargeted radioimmunotherapy with a single-chain antibodystreptavidin construct and radiolabeledDOTA-biotin Strategies for reduction of the renal doserdquo Journal ofNuclear Medicine vol 47 no 1 pp 140ndash149 2006
[233] Z Yao M Zhang H Kobayashi et al ldquoImproved targeting ofradiolabeled streptavidin in tumors pretargeted with biotiny-lated monoclonal antibodies through an avidin chaserdquo Journalof Nuclear Medicine vol 36 no 5 pp 837ndash841 1995
[234] C-H Chang R M Sharkey E A Rossi et al ldquoMolecularAdvances in Pretargeting Radioimunotherapy with BispecificAntibodies 1 Supported in part by USPHS Grant R01-CA-84379from the NIH and Department of Energy Grant DE-FG01-00NE22941 (both to R M S)1rdquo Mol Cancer Ther vol 1 no 7pp 553ndash563 2002
[235] R M Sharkey E A Rossi W J McBride C-H Chang andD M Goldenberg ldquoRecombinant Bispecific Monoclonal Anti-bodies Prepared by theDock-and-Lock Strategy for PretargetedRadioimmunotherapyrdquo Seminars in Nuclear Medicine vol 40no 3 pp 190ndash203 2010
[236] R M Sharkey E A Rossi C-H Chang and D M Golden-berg ldquoImproved cancer therapy and molecular imaging withmultivalent multispecific antibodiesrdquo Cancer Biotherapy andRadiopharmaceuticals vol 25 no 1 pp 1ndash12 2010
[237] D M Goldenberg R M Sharkey G Paganelli J Barbet andJ Chatal ldquoAntibody pretargeting advances cancer radioim-munodetection and radioimmunotherapyrdquo Journal of ClinicalOncology vol 24 no 5 pp 823ndash834 2006
[238] O C Boerman F G van Schaijk W J G Oyen and FH M Corstens ldquoPretargeted radioimmunotherapy of cancerprogress step by steprdquo Journal of Nuclear Medicine vol 44 no3 pp 400ndash411 2003
[239] J Schuhmacher S Kaul G Klivenyi et al ldquoImmunoscintigra-phy with positron emission tomography Gallium-68 chelateimaging of breast cancer pretargeted with bispecific anti-MUC1anti-Ga chelate antibodiesrdquo Cancer Research vol 61 no9 pp 3712ndash3717 2001
[240] J Schuhmacher G Klivenyi S Kaul et al ldquoPretargeting ofhuman mammary carcinoma xenografts with bispecific anti-MUC1anti-Ga chelate antibodies and immunoscintigraphywith PETrdquo Nuclear Medicine and Biology vol 28 no 7 pp 821ndash828 2001
[241] C Somasundaram S Matzku J Schuhmacher and M ZollerldquoDevelopment of a bispecific monoclonal antibody against agallium-67 chelate and the human melanoma-associated anti-gen p97 for potential use in pretargeted immunoscintigraphyrdquoCancer Immunology Immunotherapy vol 36 no 5 pp 337ndash3451993
[242] E A Rossi D L Rossi R Stein D M Goldenberg and C-H Chang ldquoA bispecific antibody-IFN1205722b immunocytokine tar-geting CD20 and HLA-DR is highly toxic to human lymphomaandmultiplemyeloma cellsrdquoCancer Research vol 70 no 19 pp7600ndash7609 2010
[243] R M Sharkey H Karacay S Litwin et al ldquoImproved ther-apeutic results by pretargeted radioimmunotherapy of non-Hodgkinrsquos lymphoma with a new recombinant trivalent anti-CD20 bispecific antibodyrdquo Cancer Research vol 68 no 13 pp5282ndash5290 2008
[244] G L Griffiths C-H Chang W J McBride et al ldquoReagentsandmethods for PETusing bispecific antibody pretargeting and68Ga-radiolabeled bivalent hapten-peptide-chelate conjugatesrdquoJournal of Nuclear Medicine vol 45 no 1 pp 30ndash39 2004
[245] J Watine M Miedouge and B Friedberg ldquoCarcinoembryonicantigen as an independent prognostic factor of recurrence andsurvival in patients resected for colorectal liver metastases Asystematic reviewrdquo Diseases of the Colon amp Rectum vol 44 no12 pp 1791ndash1799 2001
[246] M J Goldstein and E P Mitchell ldquoCarcinoembryonic antigenin the staging and follow-up of patients with colorectal cancerrdquoCancer Investigation vol 23 no 4 pp 338ndash351 2005
[247] D V Gold D M Goldenberg H Karacay et al ldquoA novelbispecific trivalent antibody construct for targeting pancreaticcarcinomardquo Cancer Research vol 68 no 12 pp 4819ndash48262008
[248] J Schuhmacher G Klivenyi R Matys et al ldquoMultistep tumortargeting in nudemice using bispecific antibodies and a galliumchelate suitable for immunoscintigraphy with positron emis-sion tomographyrdquo Cancer Research vol 55 no 1 pp 115ndash1231995
[249] G Klivenyi J Schuhmacher E Patzelt et al ldquoGallium-68chelate imaging of human colon carcinoma xenografts pre-targeted with bispecific anti-CD44(V6)anti-gallium chelateantibodiesrdquo Journal ofNuclearMedicine vol 39 no 10 pp 1769ndash1776 1998
[250] M Zoller J Schuhmacher J Reed W Maier-Borst and SMatzku ldquoEstablishment and characterization of monoclonal
24 Contrast Media amp Molecular Imaging
antibodies against an octahedral gallium chelate suitable forimmunoscintigraphy with PETrdquo Journal of Nuclear Medicinevol 33 no 7 pp 1366ndash1372 1992
[251] R M Sharkey T M Cardillo E A Rossi et al ldquoSignal ampli-fication in molecular imaging by pretargeting a multivalentbispecific antibodyrdquo Nature Medicine vol 11 no 11 pp 1250ndash1255 2005
[252] D M Goldenberg and R M Sharkey ldquoNovel radiolabeledantibody conjugatesrdquo Oncogene vol 26 no 25 pp 3734ndash37442007
[253] D M Goldenberg E A Rossi R M Sharkey W J McBrideand C-H Chang ldquoMultifunctional antibodies by the dock-and-lock method for improved cancer imaging and therapy bypretargetingrdquo Journal of NuclearMedicine vol 49 no 1 pp 158ndash163 2008
[254] R Schoffelen R M Sharkey D M Goldenberg et al ldquoPre-targeted immuno-positron emission tomography imaging ofcarcinoembryonic antigen-expressing tumors with a bispecificantibody and a68Ga- And18F-labeled hapten peptide in micewith human tumor xenograftsrdquoMolecular Cancer Therapeuticsvol 9 no 4 pp 1019ndash1027 2010
[255] E S Bos W H Kuijpers M Meesters-Winters et al ldquoIn vitroevaluation of DNA-DNA hybridization as a two-step approachin radioimmunotherapy of cancerrdquoCancer Research vol 54 no13 pp 3479ndash3486 1994
[256] G Paganelli M Bartolomei M Ferrari et al ldquoPre-TargetedLocoregional Radioimmunotherapy withrdquo Cancer biotherapyand radiopharmaceuticals vol 16 no 3 pp 227ndash235 2001
[257] A Forero P L Weiden J M Vose et al ldquoPhase 1 trial of a novelanti-CD20 fusion protein in pretargeted radioimmunotherapyfor B-cell non-Hodgkin lymphomardquo Blood vol 104 no 1 pp227ndash236 2004
[258] DM Goldenberg C-H Chang E A RossiW J McBride andR M Sharkey ldquoPretargeted molecular imaging and radioim-munotherapyrdquoTheranostics vol 2 no 5 pp 523ndash540 2012
[259] H Karacay R M Sharkey W J McBride E A Rossi C-HChang and D M Goldenberg ldquoOptimization of hapten-peptide labeling for pretargeted immunoPET of bispecificantibody using generator-produced 68Gardquo Journal of NuclearMedicine vol 52 no 4 pp 555ndash559 2011
[260] J R Oh and B C Ahn ldquoFalse-positive uptake on radioiodinewhole-body scintigraphy physiologic and pathologic variantsunrelated to thyroid cancerrdquo American Journal of NuclearMedicine and Molecular Imaging vol 2 no 2 pp 141ndash150 2012
[261] E Frampas C Rousseau C Bodet-Milin J Barbet J-F Chataland F Kraeber-Bodere ldquoImprovement of radioimmunotherapyusing pretargetingrdquo Frontiers in Oncology vol 3 Article ID00159 2013
[262] C S McKay and M G Finn ldquoClick chemistry in complexmixtures Bioorthogonal bioconjugationrdquo Chemistry amp Biologyvol 21 no 9 pp 1075ndash1101 2014
[263] B L Oliveira Z Guo and G J Bernardes ldquoInverse electrondemand DielsndashAlder reactions in chemical biologyrdquo ChemicalSociety Reviews vol 46 no 16 pp 4895ndash4950 2017
[264] B Nichols Z Qin J Yang D R Vera and N K Devaraj ldquo68Gachelating bioorthogonal tetrazine polymers for the multisteplabeling of cancer biomarkersrdquo Chemical Communications vol50 no 40 pp 5215ndash5217 2014
[265] R Rossin P R Verkerk S M van den Bosch et al ldquoInvivo chemistry for pretargeted tumor imaging in live micerdquoAngewandte Chemie International Edition vol 49 no 19 pp3375ndash3378 2010
[266] B M Zeglis K K Sevak T Reiner et al ldquoA pretargetedPET imaging strategy based on bioorthogonal diels-alder clickchemistryrdquo Journal of Nuclear Medicine vol 54 no 8 pp 1389ndash1396 2013
[267] J L Houghton R Membreno D Abdel-Atti et al ldquoEstablish-ment of the invivo efficacy of pretargeted radioimmunotherapyutilizing inverse electron demand diels-alder click chemistryrdquoMolecular Cancer Therapeutics vol 16 no 1 pp 124ndash133 2017
[268] J Funkhouser ldquoReinventing pharma the theranostic revolu-tionrdquo Current Drug Discovery pp 17ndash19 2002
[269] J Sorensen I Velikyan A Wennborg et al ldquoMeasuring HER2-expression in metastatic breast cancer using 68Ga-ABY025PETCTrdquo European Journal of Nuclear Medicine and MolecularImaging vol 41 pp S226ndashS226 2014
[270] I Velikyan A Wennborg J Feldwisch et al ldquoGMP compliantpreparation of a 68Gallium-labeled Affibody analogue forbreast cancer patient examination first-in-manrdquoEur JNuclMedMol Imaging vol 41 pp S228ndashS229 2014
[271] K Oberg ldquoMolecular imaging radiotherapy Theranostics forpersonalized patient management of neuroendocrine tumors(NETs)rdquoTheranostics vol 2 no 5 pp 448ndash458 2012
[272] I Velikyan AWennborg J FeldwischH Lindman J Carlssonand J Sorensen ldquoGood manufacturing practice production of [(68) Ga]Ga-ABY-025 for HER2 specific breast cancer imagingrdquoAmerican Journal of Nuclear Medicine and Molecular Imagingvol 6 no 2 pp 135ndash153 2016
[273] M Sandstrom K Lindskog I Velikyan et al ldquoBiodistributionand radiation dosimetry of the anti-HER2 Affibody molecule68Ga-ABY-025 in breast cancer patientsrdquo Journal of NuclearMedicine vol 57 no 6 pp 867ndash871 2016
[274] D Sandberg V Tolmachev I Velikyan et al ldquoIntra-imagereferencing for simplified assessment of HER2-expression inbreast cancer metastases using the Affibody molecule ABY-025with PET and SPECTrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 44 no 8 pp 1337ndash1346 2017
[275] H ZhangM AMoroz I Serganova et al ldquoImaging expressionof the human somatostatin receptor subtype-2 reporter genewith 68Ga-DOTATOCrdquo Journal ofNuclearMedicine vol 52 no1 pp 123ndash131 2011
[276] M Naji and A Al-Nahhas ldquo68Ga-labelled peptides in themanagement of neuroectodermal tumoursrdquo European Journalof Nuclear Medicine and Molecular Imaging vol 39 no 1 ppS61ndashS67 2012
[277] I Velikyan ldquoThe diversity of 68Ga-Based imaging agentsrdquoRecent Results in Cancer Research vol 194 pp 101ndash131 2013
[278] K Ferreira H-Y Hu V Fetz et al ldquoMultivalent siderophore-dotam conjugates as theranostics for imaging and treatment ofbacterial infectionsrdquo Angewandte Chemie International Editionvol 56 no 28 pp 8272ndash8276 2017
Computational and Mathematical Methods in Medicine
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Submit your manuscripts atwwwhindawicom
18 Contrast Media amp Molecular Imaging
[72] T Ebenhan J R Zeevaart and J D Venter ldquoPreclinicalevaluation of 68Ga-labeled 1 4 7-triazacyclononane-1 4 7-triacetic acid-ubiquicidin as a radioligand for PET infectionimagingrdquo Journal of Nuclear Medicine vol 55 no 2 pp 308ndash314 2014
[73] B B Mokaleng T Ebenhan S Ramesh et al ldquoSynthesis 68Ga-radiolabeling and preliminary in vivo assessment of adepsipeptide-derived compound as a potential PETCTinfection imaging agentrdquo BioMed Research International vol2015 Article ID 284354 2015
[74] T Ebenhan B Mokaleng J Venter H Kruger J Zeevaart andM Sathekge ldquoPreclinical Assessment of a 68Ga-DOTA-Functionalized Depsipeptide as a Radiodiagnostic InfectionImaging AgentrdquoMolecules vol 22 no 9 p 1403 2017
[75] S Chopra B Singh A Koul A Mishra and H Wester ldquoSyn-thesis of DOTA conjugated GF-17 and RAWVAWR-NH2 andradiolabeling with 68Ga as a potential PET tracer for infectionimagingrdquo J Nucl Med vol 57 Supplement 2 p 1115 2016
[76] M Petrik HHaas P Laverman et al ldquo 68Ga-triacetylfusarinineC and 68Ga-ferrioxamine e for aspergillus infection imaginguptake specificity in various microorganismsrdquoMolecular Imag-ing and Biology vol 16 no 1 pp 102ndash108 2014
[77] V Kumar and D K Boddeti ldquo 68Ga-radiopharmaceuticals forPET imaging of infection and inflammationrdquo Recent Results inCancer Research vol 194 pp 189ndash219 2013
[78] M Vorster A Maes A Jacobs et al ldquoEvaluating the possiblerole of 68Ga-citrate PETCT in the characterization of indeter-minate lung lesionsrdquo Annals of Nuclear Medicine vol 28 no 6pp 523ndash530 2014
[79] M Vorster B Mokaleng M M Sathekge and T Ebenhan ldquoAmodified technique for efficient radiolabeling of 68Ga-citratefrom a SnO2-based 68Ge68Ga generator for better infectionimagingrdquoHellenic Journal of Nuclear Medicine vol 16 no 3 pp193ndash198 2013
[80] S Salomaeki J Kemppainen U Hohenthal et al ldquoHead-to-head comparison of 68Ga-Citrate and 18F-FDG PETCT fordetection of infectious foci in patients with staphylococcusaureus bacteraemiardquo Contrast Media amp Molecular Imaging vol2017 p 8 2017
[81] L Fass ldquoImaging and cancer a reviewrdquoMolecular Oncology vol2 no 2 pp 115ndash152 2008
[82] A Chopra L Shan W C Eckelman et al ldquoMolecular imagingand contrast agent database (MICAD) Evolution and progressrdquoMolecular Imaging and Biology vol 14 no 1 pp 4ndash13 2012
[83] A Sanchez-Crespo P Andreo and S A Larsson ldquoPositronflight in human tissues and its influence on PET image spatialresolutionrdquo European Journal of Nuclear Medicine and Molecu-lar Imaging vol 31 no 1 pp 44ndash51 2004
[84] H W A M De Jong L Perk G W M Visser R Boellaard GAM S Van Dongen and A A Lammertsma ldquoHigh resolutionPET imaging characteristics of68Ga 124i and89Zr comparedto18Frdquo in Proceedings of the Nuclear Science Symposium Con-ference Record 2005 IEEE pp 1624ndash1627 Puerto Rico October2005
[85] I Velikyan A Sundin B Eriksson et al ldquoIn vivo bindingof [68Ga]-DOTATOC to somatostatin receptors in neuroen-docrine tumours - impact of peptide massrdquo Nuclear Medicineand Biology vol 37 no 3 pp 265ndash275 2010
[86] U Eberlein and M Lassmann ldquoDosimetry of [68Ga]-labeledcompoundsrdquo Applied Radiation and Isotopes vol 76 pp 70ndash742013
[87] C PettinatoA SarnelliMDiDonna et al ldquo68Ga-DOTANOCBiodistribution and dosimetry in patients affected by neuroen-docrine tumorsrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 35 no 1 pp 72ndash79 2008
[88] B P Burke G S Clemente and S J Archibald ldquoRecentadvances in chelator design and labelling methodology for68Ga radiopharmaceuticalsrdquo Journal of Labelled Compoundsand Radiopharmaceuticals vol 57 no 4 pp 239ndash243 2014
[89] I Velikyan U Rosenstrom S Estrada et al ldquoSynthesis andpreclinical evaluation of 68Ga-labeled collagelin analogs forimaging and quantification of fibrosisrdquo Nuclear Medicine andBiology vol 41 no 9 pp 728ndash736 2014
[90] M F Ferreira G Pereira J P Andre and etal C ldquoGa[NO2A-N-(120572-amino)propionate] chelates Synthesis and evaluation aspotential tracers for 68Ga PETrdquoDalton Transactions vol 43 no21 pp 8037ndash8047 2014
[91] J Notni J Simecek and H-J Wester ldquoPhosphinic acid func-tionalized polyazacycloalkane chelators for radiodiagnosticsand radiotherapeutics Unique characteristics and applicationsrdquoChemMedChem vol 9 no 6 pp 1107ndash1115 2014
[92] J Simecek O Zemek P Hermann J Notni and H J WesterldquoTailored gallium( III) chelator NOPO synthesis characteriza-tion bioconjugation and application in preclinical Ga-68-PETimagingrdquoMolecular Pharmaceutics 2013
[93] D Parker B P Waldron and D S Yufit ldquoCrystallographicand solution NMR structural analyses of four hexacoordinatedgallium(iii) complexes based on ligands derived from 6-amino-perhydro-14-diazepinerdquo Dalton Transactions vol 42 no 22pp 8001ndash8008 2013
[94] B P Waldron D Parker C Burchardt D S Yufit M ZimnyandF Roesch ldquoStructure and stability of hexadentate complexesof ligands based on AAZTA for efficient PET labelling withgallium-68rdquo Chemical Communications vol 49 no 6 pp 579ndash581 2013
[95] D Parker and B PWaldron ldquoConformational analysis and syn-thetic approaches to polydentate perhydro-diazepine ligandsfor the complexation of gallium(iii)rdquo Organic amp BiomolecularChemistry vol 11 no 17 pp 2827ndash2838 2013
[96] I Velikyan H Maecke and B Langstrom ldquoConvenient prepa-ration of 68Ga-based PET-radiopharmaceuticals at room tem-peraturerdquo Bioconjugate Chemistry vol 19 no 2 pp 569ndash5732008
[97] J Erchegyi R Cescato B Waser J E Rivier and J C ReubildquoN-Imidazolebenzyl-histidine substitution in somatostatin andin its octapeptide analogue modulates receptor selectivity andfunctionrdquo Journal of Medicinal Chemistry vol 54 no 17 pp5981ndash5987 2011
[98] R Saha N Saha R S Donofrio and L L Bestervelt ldquoMicrobialsiderophores Amini reviewrdquo Journal of Basic Microbiology vol53 no 4 pp 303ndash317 2013
[99] V Nikolova S Angelova N Markova and T Dudev ldquoGalliumas a Therapeutic Agent A Thermodynamic Evaluation of theCompetition between Ga3+ and Fe3+ Ions in MetalloproteinsrdquoThe Journal of Physical Chemistry B vol 120 no 9 pp 2241ndash2248 2016
[100] C R Chitambar ldquoGallium and its competing roles with ironin biological systemsrdquo Biochimica et Biophysica Acta (BBA) -Molecular Cell Research vol 1863 no 8 pp 2044ndash2053 2016
[101] J A Lessa M A Soares and R G dos Santos ldquoGallium(III)complexes with 2-acetylpyridine-derived thiosemicarbazonesantimicrobial and cytotoxic effects and investigation on theinteractions with tubulinrdquo BioMetals vol 26 pp 151ndash165 2013
Contrast Media amp Molecular Imaging 19
[102] M van Oosten M Hahn L M A Crane et al ldquoTargetedimaging of bacterial infections Advances hurdles and hopesrdquoFEMS Microbiology Reviews vol 39 no 6 pp 892ndash916 2015
[103] M Vorster AMaes C V DWiele andM Sathekge ldquoGallium-68 PET A Powerful Generator-based Alternative to Infectionand Inflammation Imagingrdquo Seminars in Nuclear Medicine vol46 no 5 pp 436ndash447 2016
[104] M Kircher and C Lapa ldquoNovel Noninvasive Nuclear MedicineImaging Techniques for Cardiac Inflammationrdquo Current Car-diovascular Imaging Reports vol 10 no 2 article no 6 2017
[105] D AHammoud ldquoMolecular imaging of inflammation Currentstatusrdquo Journal of Nuclear Medicine vol 57 no 8 pp 1161ndash11652016
[106] D R Brenner D Scherer K Muir et al ldquoA review of the appli-cation of inflammatory biomarkers in epidemiologic cancerresearchrdquo Cancer Epidemiology Biomarkers amp Prevention vol23 no 9 pp 1729ndash1751 2014
[107] M D Turner B Nedjai T Hurst and D J PenningtonldquoCytokines and chemokines at the crossroads of cell signallingand inflammatory diseaserdquo Biochimica et Biophysica Acta (BBA)- Molecular Cell Research vol 1843 no 11 pp 2563ndash2582 2014
[108] L Werner H Guzner-Gur and I Dotan ldquoInvolvement ofCXCR4CXCR7CXCL12 interactions in inflammatory boweldiseaserdquoTheranostics vol 3 no 1 pp 40ndash46 2013
[109] S Jalkanen and M Salmi ldquoVAP-1 and CD73 endothelial cellsurface enzymes in leukocyte extravasationrdquo ArteriosclerosisThrombosis and Vascular Biology vol 28 no 1 pp 18ndash26 2008
[110] G Malviya F Galli I Sonni and A Signore ldquoImaging T-lymphocytes in inflammatory diseases A nuclear medicineapproachrdquo The Quarterly Journal of Nuclear Medicine andMolecular Imaging vol 58 no 3 pp 237ndash257 2014
[111] S Gratz H J RennenO C BoermanW J Oyen and P Burmaldquo(99m)Tc-interleukin-8 for imaging acute osteomyelitisrdquo Jour-nal of Nuclear Medicine vol 42 no 8 pp 1257ndash1264 2001
[112] S Gratz H J Rennen O C Boerman W J Oyen andF H Corstens ldquoRapid imaging of experimental colitis with(99m)Tc-interleukin-8 in rabbitsrdquo Journal of Nuclear Medicnevol 42 no 6 pp 917ndash923 2001
[113] C Alkim H Alkim A R Koksal S Boga and I SenldquoAngiogenesis in inflammatory bowel diseaserdquo InternationalJournal of Inflammation vol 2015 Article ID 970890 2015
[114] I S Alam T H Witney G Tomasi et al ldquoRadiolabeled RGDtracer kinetics annotates differential 120572v1205733 integrin expressionlinked to cell intrinsic and vessel expressionrdquoMolecular Imagingand Biology vol 16 no 4 pp 558ndash566 2014
[115] J Notni K Pohle and H-J Wester ldquoBe spoilt for choice withradiolabelled RGD peptides Preclinical evaluation of 68Ga-TRAP(RGD)3rdquoNuclear Medicine and Biology vol 40 no 1 pp33ndash41 2013
[116] J Oxboel M Brandt-Larsen C Schjoeth-Eskesen et al ldquoCom-parison of two new angiogenesis PET tracers 68Ga-NODAGA-E[c(RGDyK)]2 and 64Cu-NODAGA-E[c(RGDyK)]2 in vivoimaging studies in human xenograft tumorsrdquo Nuclear Medicineand Biology vol 41 no 3 pp 259ndash267 2014
[117] J Simecek J Notni T G Kapp H Kessler and H-J WesterldquoBenefits of NOPO as chelator in gallium-68 peptides exempli-fied by preclinical characterization of 68Ga-NOPO-c(RGDfK)rdquoMolecular Pharmaceutics vol 11 no 5 pp 1687ndash1695 2014
[118] M Trajkovic-Arsic P Mohajerani A Sarantopoulos et alldquoMultimodal molecular imaging of integrin avb3 for in vivodetection of pancreatic cancerrdquo Journal of NuclearMedicine vol55 no 3 pp 446ndash451 2014
[119] H Cai and P S Conti ldquoRGD-based PET tracers for imagingreceptor integrin 120572 v1205733 expressionrdquo Journal of Labelled Com-pounds and Radiopharmaceuticals vol 56 no 5 pp 264ndash2792013
[120] I Dijkgraaf S Y A Terry W J Mcbride et al ldquoImagingintegrin alpha-v-beta-3 expression in tumors with an 18F-labeled dimeric RGD peptiderdquo Contrast Media amp MolecularImaging vol 8 no 3 pp 238ndash245 2013
[121] P A Knetsch M Petrik C Rangger et al ldquo[68Ga]NS3-RGD and [68Ga] Oxo-DO3A-RGD for imaging 120572v1205733 integrinexpression Synthesis evaluation and comparisonrdquo NuclearMedicine and Biology vol 40 no 1 pp 65ndash72 2013
[122] Z Liu and F Wang ldquoDevelopment of RGD-based radiotracersfor tumor imaging and therapy Translating from bench tobedsiderdquo Current Molecular Medicine vol 13 no 10 pp 1487ndash1505 2013
[123] H Choi J H Phi J C Paeng et al ldquoImaging of integrin 120572v1205733expression using 68Ga-RGD positron emission tomography inpediatric cerebral infarctrdquoMolecular Imaging vol 12 no 4 pp213ndash217 2013
[124] H-J Yoon K W Kang I K Chun et al ldquoCorrelation of breastcancer subtypes based on estrogen receptor progesteronereceptor and HER2 with functional imaging parameters from68Ga-RGD PETCT and 18F-FDG PETCTrdquo European Journalof Nuclear Medicine and Molecular Imaging vol 41 no 8 pp1534ndash1543 2014
[125] R P Baum H R Kulkarni D Muller et al ldquoFirst-in-human study demonstrating tumor-angiogenesis by PETCTimaging with 68Ga-NODAGA-THERANOST a high-affinitypeptidomimetic for 120572v1205733 integrin receptor targetingrdquo CancerBiotherapy andRadiopharmaceuticals vol 30 no 4 pp 152ndash1592015
[126] R Haubner A Finkenstedt A Stegmayr et alldquo[68Ga]NODAGA-RGD ndash Metabolic stability biodistributionand dosimetry data from patients with hepatocellularcarcinoma and liver cirrhosisrdquo European Journal of NuclearMedicine and Molecular Imaging vol 43 no 11 pp 2005ndash20132016
[127] V Lopez-Rodrıguez C Galindo-Sarco F O Garcıa-Perez GFerro-Flores O Arrieta and M A Avila-Rodrıguez ldquoPET-based human dosimetry of the dimeric 120572v1205733 integrin ligand68Ga-DOTA-E-[c(RGDfK)]2 a potential tracer for imagingtumor angiogenesisrdquo Journal of Nuclear Medicine vol 57 no 3pp 404ndash409 2016
[128] M V Backer Z Levashova V Patel et al ldquoMolecular imagingof VEGF receptors in angiogenic vasculature with single-chainVEGF-based probesrdquo Nature Medicine vol 13 no 4 pp 504ndash509 2007
[129] MV Backer Z Levashova R Levenson F G Blankenberg andJ M Backer ldquoCysteine-containing fusion tag for site-specificconjugation of therapeutic and imaging agents to targetingproteinsrdquoMethods in Molecular Biology (Clifton NJ) vol 494pp 275ndash294 2008
[130] M Eder A V Krivoshein M Backer J M Backer UHaberkorn and M Eisenhut ldquoScVEGF-PEG-HBED-CC andscVEGF-PEG-NOTA conjugates comparison of easy-to-labelrecombinant proteins for [68Ga]PET imaging of VEGF recep-tors in angiogenic vasculaturerdquo Nuclear Medicine and Biologyvol 37 no 4 pp 405ndash412 2010
[131] E Blom I Velikyan A Monazzam P Razifar et al ldquoSynthe-sis and characterization of scVEGF-PEG-[ 68Ga]NOTA andscVEGF-PEG-[ 68Ga]DOTA PET tracersrdquo Journal of Labelled
20 Contrast Media amp Molecular Imaging
Compounds and Radiopharmaceuticals vol 54 no 11 pp 685ndash692 2011
[132] S Gratz M Behe and O C Boerman ldquo 99119898Tc-E-selectinbinding peptide for imaging acute osteomyelitis in a novel ratmodelrdquo Nuclear Medicine Communications vol 22 no 9 pp1003ndash1013 2001
[133] S B Jensen M Kakela L Joslashdal et al ldquoExploring the radiosyn-thesis and in vitro characteristics of [68Ga]Ga-DOTA-Siglec-9rdquoJournal of Labelled Compounds and Radiopharmaceuticals vol60 no 9 pp 439ndash449 2017
[134] B A Teicher and S P Fricker ldquoCXCL12 (SDF-1)CXCR4pathway in cancerrdquo Clinical Cancer Research vol 16 no 11 pp2927ndash2931 2010
[135] O Jacobson I D Weiss D O Kiesewetter J M Farber andX Chen ldquoPET of tumor CXCR4 expression with 4-18F-T140rdquoJournal of Nuclear Medicine vol 51 no 11 pp 1796ndash1804 2010
[136] A Aghanejad A R Jalilian Y Fazaeli et al ldquoSynthesis andevaluation of [67Ga]-AMD3100 A novel imaging agent fortargeting the chemokine receptorCXCR4rdquo Scientia Pharmaceu-tica vol 82 no 1 pp 29ndash42 2014
[137] O Jacobson I D Weiss L P Szajek et al ldquoPET imaging ofCXCR4 using copper-64 labeled peptide antagonistrdquoTheranos-tics vol 1 pp 251ndash262 2011
[138] O Jacobson I D Weiss L P Szajek et al ldquoImprovement ofCXCR4 tracer specificity for PET imagingrdquo Journal of Con-trolled Release vol 157 no 2 pp 216ndash223 2012
[139] H J Wester U Keller M Schottelius et al ldquoDisclosing theCXCR4 expression in lymphoproliferative diseases by targetedmolecular imagingrdquo Theranostics vol 5 no 6 pp 618ndash6302015
[140] E Gourni O Demmer M Schottelius et al ldquoPET of CXCR4expression by a 68Ga-labeled highly specific targeted contrastagentrdquo Journal of NuclearMedicine vol 52 no 11 pp 1803ndash18102011
[141] O Demmer I Dijkgraaf U Schumacher et al ldquoDesignsynthesis and functionalization of dimeric peptides targetingchemokine receptor CXCR4rdquo Journal of Medicinal Chemistryvol 54 no 21 pp 7648ndash7662 2011
[142] O Demmer E Gourni U Schumacher H Kessler and H-JWester ldquoPET Imaging of CXCR4 Receptors in Cancer by a NewOptimized Ligandrdquo ChemMedChem vol 6 no 10 pp 1789ndash1791 2011
[143] U Hennrich L Seyler M Schafer et al ldquoSynthesis and invitro evaluation of 68Ga-DOTA-4-FBn-TN14003 a novel tracerfor the imaging of CXCR4 expressionrdquo Bioorganic amp MedicinalChemistry vol 20 no 4 pp 1502ndash1510 2012
[144] G P C George E Stevens O Aberg et al ldquoPreclinical evalua-tion of a CXCR4-specific 68Ga-labelled TN14003 derivative forcancer PET imagingrdquo Bioorganic amp Medicinal Chemistry vol22 no 2 pp 796ndash803 2014
[145] S Poty E Gourni P Desogere et al ldquoAMD3100 A VersatilePlatform for CXCR4 Targeting 68Ga-Based Radiopharmaceu-ticalsrdquo Bioconjugate Chemistry vol 27 no 3 pp 752ndash761 2016
[146] K Philipp-Abbrederis K Herrmann S Knop et al ldquoIn vivomolecular imaging of chemokine receptor CXCR4 expressionin patients with advancedmultiple myelomardquo EMBOMolecularMedicine vol 7 no 4 pp 477ndash487 2015
[147] Z Wang M Zhang L Wang et al ldquoProspective study of 68Ga-NOTA-NFB Radiation dosimetry in healthy volunteers andfirst application in glioma patientsrdquo Theranostics vol 5 no 8pp 882ndash889 2015
[148] I M Jackson P J Scott and S Thompson ldquoClinical Applica-tions of Radiolabeled Peptides for PETrdquo Seminars in NuclearMedicine vol 47 no 5 pp 493ndash523 2017
[149] C Lapa T Reiter R A Werner et al ldquo[68Ga]Pentixafor-PETCT for Imaging of Chemokine Receptor 4 Expression afterMyocardial Infarctionrdquo JACC Cardiovascular Imaging vol 8no 12 pp 1466ndash1468 2015
[150] C Rischpler S G Nekolla H Kossmann et al ldquoUpregu-lated myocardial CXCR4-expression after myocardial infarc-tion assessed by simultaneous GA-68 pentixafor PETMRIrdquoJournal of Nuclear Cardiology vol 23 no 1 pp 131ndash133 2016
[151] F Hyafil J Pelisek I Laitinen et al ldquoImaging the CytokineReceptorCXCR4 in atherosclerotic plaqueswith the radiotracer68Ga-Pentixafor for PETrdquo Journal of Nuclear Medicine vol 58no 3 pp 499ndash506 2017
[152] Y Yi ldquoFolate receptor-targeted diagnostics and therapeutics forinflammatory diseasesrdquo ImmuneNetwork vol 16 no 6 pp 337ndash343 2016
[153] C M Paulos M J Turk G J Breur and P S Low ldquoFolatereceptor-mediated targeting of therapeutic and imaging agentsto activated macrophages in rheumatoid arthritisrdquo AdvancedDrug Delivery Reviews vol 56 no 8 pp 1205ndash1217 2004
[154] W Han R Zaynagetdinov F E Yull et al ldquoMolecular imagingof folate receptor 120573-positive macrophages during acute lunginflammationrdquo American Journal of Respiratory Cell and Molec-ular Biology vol 53 no 1 pp 50ndash59 2015
[155] B Kuhle C Muller and T L Ross ldquoA Novel 68Ga-Labeledpteroic acid-based PET tracer for tumor imaging via the folatereceptorrdquo Recent Results in Cancer Research vol 194 pp 257ndash267 2013
[156] C Brand V A Longo M Groaning W A Weber and TReiner ldquoDevelopment of a New Folate-Derived Ga-68-BasedPET Imaging AgentrdquoMolecular Imaging and Biology vol 19 no5 pp 754ndash761 2017
[157] M Fani XWang G Nicolas et al ldquoDevelopment of new folate-based PET radiotracers Preclinical evaluation of 68Ga-DOTA-folate conjugatesrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 38 no 1 pp 108ndash119 2011
[158] C J Mathias M R Lewis D E Reichert et al ldquoPreparationof 66Ga- and 68Ga-labeled Ga(III)-deferoxamine-folate aspotential folate-receptor-targeted PET radiopharmaceuticalsrdquoNuclear Medicine and Biology vol 30 no 7 pp 725ndash731 2003
[159] S-M Kim N Choi S Hwang et al ldquoFolate receptor-specific positron emission tomography imaging with folic acid-conjugated tissue inhibitor of metalloproteinase-2rdquo Bulletin ofthe Korean Chemical Society vol 34 no 11 pp 3243ndash3248 2013
[160] M Fani M-L Tamma G P Nicolas et al ldquoIn vivo imagingof folate receptor positive tumor xenografts using novel 68Ga-NODAGA-folate conjugatesrdquo Molecular Pharmaceutics vol 9no 5 pp 1136ndash1145 2012
[161] C Muller and R Schibli ldquoProspects in folate receptor-targetedradionuclide therapyrdquo Frontiers in Oncology vol 3 Article IDArticle 249 2013
[162] A Jain A Mathur U Pandey et al ldquoSynthesis and evaluationof a 68Ga labeled folic acid derivative for targeting folatereceptorsrdquo Applied Radiation and Isotopes vol 116 pp 77ndash842016
[163] W Xia A R Hilgenbrink E L Matteson M B Lockwood J-X Cheng and P S Low ldquoA functional folate receptor is inducedduring macrophage activation and can be used to target drugsto activated macrophagesrdquo Blood vol 113 no 2 pp 438ndash4462009
Contrast Media amp Molecular Imaging 21
[164] E P Krenning W A P Breeman P P M Kooij et alldquoLocalisation of endocrine-related tumours with radioiodi-nated analogue of somatostatinrdquoThe Lancet vol 1 no 8632 pp242ndash244 1989
[165] E P Krenning D J KwekkeboomWH Bakker et al ldquoSomato-statin receptor scintigraphy with [111In-DTPA-d-Phe1]- and[123I-Tyr3]-octreotide the Rotterdam experience with morethan 1000 patientsrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 20 no 8 pp 716ndash731 1993
[166] A Stahl G Meisetschlager M Schottelius et al ldquo[123I]Mtr-TOCA a radioiodinated and carbohydrated analogue ofoctreotide Scintigraphic comparison with [111In]octreotiderdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 33 no 1 pp 45ndash52 2006
[167] R Lebtahi J le Cloirec C Houzard et al ldquoDetection of neu-roendocrine tumors 99mTc-P829 scintigraphy compared with111In-pentetreotide scintigraphyrdquo Journal of Nuclear Medicinevol 43 no 7 pp 889ndash895 2002
[168] C Decristoforo T Maina B Nock M Gabriel P Cordopatisand R Moncayo ldquo99mTc-demotate 1 First data in tumourpatients - Results of a pilotphase I studyrdquo European Journal ofNuclearMedicine andMolecular Imaging vol 30 no 9 pp 1211ndash1219 2003
[169] C Decristoforo S J Mather W Cholewinski E DonnemillerG Riccabona and R Moncayo ldquo(99m)Tc-EDDAHYNIC-TOC A new (99m)Tc-labelled radiopharmaceutical forimaging somatostatin receptor-positive tumours First clinicalresults and intra-patient comparison with 111In-labelledoctreotide derivativesrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 27 no 9 pp 1318ndash1325 2000
[170] A Hubalewska-Dydejczyk K Fross-Baron R Mikołajczak etal ldquo99mTc-EDDAHYNIC-octreotate scintigraphy an efficientmethod for the detection and staging of carcinoid tumoursResults of 3 yearsrsquo experiencerdquo European Journal of NuclearMedicine and Molecular Imaging vol 33 no 10 pp 1123ndash11332006
[171] M Bangard M Behe S Guhlke et al ldquoDetection of somato-statin receptor-positive tumours using the new 99mC-tricine-HYNIC-D-Phe1-Tyr3-octreotide First results in patients andcomparison with 111In-DTPA-D-Phe1-octreotiderdquo EuropeanJournal of Nuclear Medicine and Molecular Imaging vol 27 no6 pp 628ndash637 2000
[172] A Helisch G J Forster H Reber et al ldquoPre-therapeuticdosimetry and biodistribution of 86Y-DOTA- Phe1-Tyr3-octreotide versus 111In-pentetreotide in patients with advancedneuroendocrine tumoursrdquo European Journal of NuclearMedicine and Molecular Imaging vol 31 no 10 pp 1386ndash13922004
[173] M Henze J Schuhmacher P Hipp et al ldquoPET imaging ofsomatostatin receptors using [68GA]DOTA-D-Phe1-Tyr3-Octreotide First results in patients with meningiomasrdquo Journalof Nuclear Medicine vol 42 no 7 pp 1053ndash1056 2001
[174] I Kayani J B Bomanji A Groves et al ldquoFunctional imaging ofneuroendocrine tumors with combined PETCT using 68Ga-DOTATATE (Dota-DPhe1 Tyr3-octreotate) and 18F-FDGrdquoCancer vol 112 no 11 pp 2447ndash2455 2008
[175] A Al-Nahhas ldquoNuclear medicine imaging of neuroendocrinetumoursrdquo Clinical Medicine vol 12 no 4 pp 377ndash380 2012
[176] V Ambrosini S Nicolini P Caroli et al ldquoPETCT imaging indifferent types of lung cancer an overviewrdquo European Journal ofRadiology vol 81 no 5 pp 988ndash1001 2012
[177] V Ambrosini D Campana P Tomassetti and S Fanti ldquo68Ga-labelled peptides for diagnosis of gastroenteropancreatic NETrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 39 no 1 pp S52ndashS60 2012
[178] K E Oberg J-C Reubi D J Kwekkeboom and E P KrenningldquoRole of somatostatins in gastroenteropancreatic neuroen-docrine tumor development and therapyrdquoGastroenterology vol139 no 3 pp 753-753 2010
[179] K Oberg ldquoGallium-68 somatostatin receptor PETCT Is ittime to replace 111Indium DTPA octreotide for patients withneuroendocrine tumorsrdquo Endocrine Journal vol 42 no 1 pp3-4 2012
[180] R Srirajaskanthan I Kayani A M Quigley J Soh M ECaplin and J Bomanji ldquoThe role of 68Ga-DOTATATE PET inpatients with neuroendocrine tumors and negative or equivocalfindings on 111In-DTPA-octreotide scintigraphyrdquo Journal ofNuclear Medicine vol 51 no 6 pp 875ndash882 2010
[181] A Kroiss D Putzer and C Uprimny ldquoFunctional imag-ing in phaeochromocytoma and neuroblastoma with 68Ga-DOTA-Tyr3-octreotide positron emission tomography and123I-metaiodobenzylguanidinerdquo European Journal of NuclearMedicine and Molecular Imaging vol 38 no 5 pp 865ndash8732011
[182] M Naji C Zhao S J Welsh et al ldquo68Ga-DOTA-TATE PETvs 123I-MIBG in identifying malignant neural crest tumoursrdquoMolecular Imaging and Biology vol 13 no 4 pp 769ndash775 2011
[183] V Ambrosini P Tomassetti P Castellucci et al ldquoComparisonbetween 68Ga-DOTA-NOC and 18F-DOPA PET for the detec-tion of gastro-entero-pancreatic and lung neuro-endocrinetumoursrdquo European Journal of Nuclear Medicine and MolecularImaging vol 35 no 8 pp 1431ndash1438 2008
[184] D Putzer M Gabriel B Henninger et al ldquoBone metastasesin patients with neuroendocrine tumor 68Ga- DOTA-Tyr3-octreotide PET in comparison to CT and bone scintigraphyrdquoJournal of Nuclear Medicine vol 50 no 8 pp 1214ndash1221 2009
[185] L K Anzola-Fuentes M Chianelli F Galli et al ldquoSomatostatinreceptor scintigraphy in patients with rheumatoid arthritis andsecondary Sjogrenrsquos syndrome treated with Infliximab a pilotstudyrdquo EJNMMI Research vol 6 no 1 article no 49 2016
[186] T Nobashi Y Nakamoto T Kubo et al ldquoThe utility of PETCTwith 68Ga-DOTATOC in sarcoidosis comparison with 67Ga-scintigraphyrdquoAnnals ofNuclearMedicine vol 30 no 8 pp 544ndash552 2016
[187] C Boy T A Heusner T D Poeppel et al ldquo68Ga-DOTATOCPETCT and somatostatin receptor (sst1-sst5) expression innormal human tissue Correlation of sst2mRNAand SUVmaxrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 38 no 7 pp 1224ndash1236 2011
[188] P Rinne S Hellberg M Kiugel et al ldquoComparison of Somato-statin Receptor 2-Targeting PET Tracers in the Detection ofMouse Atherosclerotic Plaquesrdquo Molecular Imaging and Biol-ogy vol 18 no 1 pp 99ndash108 2016
[189] M Asti E Ferrari S Croci et al ldquoSynthesis and characteri-zation of 68Ga-labeled curcumin and curcuminoid complexesas potential radiotracers for imaging of cancer and alzheimersdiseaserdquo Inorganic Chemistry vol 53 no 10 pp 4922ndash49332014
[190] A Signore I Santino and A W J M Glaudemans ldquoIn vivoimaging of microorganismsrdquo Clinical and Translational Imag-ing vol 4 no 3 pp 161-162 2016
[191] S Auletta F Galli C Lauri D Martinelli I Santino andA Signore ldquoImaging bacteria with radiolabelled quinolones
22 Contrast Media amp Molecular Imaging
cephalosporins and siderophores for imaging infection a sys-tematic reviewrdquo Clinical and Translational Imaging vol 4 no 4pp 229ndash252 2016
[192] X Ning S Lee Z Wang et al ldquoMaltodextrin-based imagingprobes detect bacteria in vivo with high sensitivity and speci-ficityrdquo Nature Materials vol 10 no 8 pp 602ndash607 2011
[193] J Ady andY Fong ldquoImaging for infection Fromvisualization ofinflammation to visualization of microbesrdquo Surgical Infectionsvol 15 no 6 pp 700ndash707 2014
[194] J M Sierra D Rodriguez-Puig A Soriano J Mensa C Pieraand J Vila ldquoAccumulation of 99mTc-ciprofloxacin in Staphy-lococcus aureus and Pseudomonas aeruginosardquo AntimicrobialAgents and Chemotherapy vol 52 no 7 pp 2691-2692 2008
[195] D I Andersson and D Hughes ldquoMicrobiological effects ofsublethal levels of antibioticsrdquoNature ReviewsMicrobiology vol12 no 7 pp 465ndash478 2014
[196] N Dumarey D Blocklet T Appelboom L Tant and ASchoutens ldquoInfecton is not specific for bacterial osteo-articularinfective pathologyrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 29 no 4 pp 530ndash535 2002
[197] K E Britton D W Wareham S S Das et al ldquoImaging bacte-rial infection with 99mTc-ciprofloxacin (Infecton)rdquo Journal ofClinical Pathology vol 55 no 11 pp 817ndash823 2002
[198] G Ferro-Flores M A Avila-Rodrıguez and F O Garcıa-PerezldquoImaging of bacteria with radiolabeled ubiquicidin by SPECTand PET techniquesrdquo Clinical and Translational Imaging vol 4no 3 pp 175ndash182 2016
[199] P S Hiemstra M T van den Barselaar M Roest P H Nibber-ing and R van Furth ldquoUbiquicidin a novel murine microbi-cidal protein present in the cytosolic fraction of macrophagesrdquoJournal of Leukocyte Biology vol 66 no 3 pp 423ndash428 1999
[200] M S Akhtar A Qaisar J Irfanullah et al ldquoAntimicrobialpeptide 99mTc-ubiquicidin 29ndash41 as human infection-imagingagent clinical trialrdquo Journal of Nuclear Medicne vol 46 no 4pp 567ndash573 2005
[201] M Assadi K Vahdat I Nabipour et al ldquoDiagnostic value of99mTc-ubiquicidin scintigraphy for osteomyelitis and compar-isons with 99mTc-methylene diphosphonate scintigraphy andmagnetic resonance imagingrdquo Nuclear Medicine Communica-tions vol 32 no 8 pp 716ndash723 2011
[202] T Emery ldquoExchange of Iron by Gallium in SiderophoresrdquoBiochemistry vol 25 no 16 pp 4629ndash4633 1986
[203] M Petrik C Zhai H Haas and C Decristoforo ldquoSiderophoresfor molecular imaging applicationsrdquo Clinical and TranslationalImaging vol 5 no 1 pp 15ndash27 2017
[204] H J Flint E A BayerM T Rincon R Lamed and B AWhiteldquoPolysaccharide utilization by gut bacteria potential for newinsights from genomic analysisrdquo Nature Reviews Microbiologyvol 6 no 2 pp 121ndash131 2008
[205] GGowrishankarMNamavari E B Jouannot et al ldquoInvestiga-tion of 6-[18F]-fluoromaltose as a novel PET tracer for imagingbacterial infectionrdquo PLoS ONE vol 9 no 9 Article ID e1079512014
[206] N Gholipour M Akhlaghi A M Kheirabadi et al ldquoChelator-free radiolabeling of dextran with 68Ga for PET studiesrdquoJournal of Radioanalytical and Nuclear Chemistry vol 311 no3 pp 1811ndash1817 2017
[207] C Bettegowda C A Foss I Cheong et al ldquoImaging bac-terial infections with radiolabeled 1-(21015840-deoxy-21015840- fluoro-120573-D-arabinofuranosyl)-5-iodouracilrdquo Proceedings of the NationalAcadamy of Sciences of the United States of America vol 102 no4 pp 1145ndash1150 2005
[208] S A Soghomonyan M Doubrovin J Pike et al ldquoPositronemission tomography (PET) imaging of tumor-localizedSalmonella expressing HSV1-TKrdquo Cancer GeneTherapy vol 12no 1 pp 101ndash108 2005
[209] C Palestro K Nichols S Sheikh-Fayyaz S Dewey P Singhaland K Bhargava ldquoCan Gallium-68 PET differentiate acuteinterstitial nephritis from acute tubular necrosisrdquo Journal ofNuclear Medicne vol 57 Supplement 2 p 551 2016
[210] A J Morguet D L Munz V Ivancevic et al ldquoImmunoscintig-raphy using technetium-99m-labeled anti-NCA-95 antigranu-locyte antibodies as an adjunct to echocardiography in subacuteinfective endocarditisrdquo Journal of the American College ofCardiology vol 23 no 5 pp 1171ndash1178 1994
[211] C van der Laken O Boerman W Oyen et al ldquoIn Vivo Expres-sion of Interleukin-1 Receptors during Various ExperimentallyInduced Inflammatory Conditionsrdquo The Journal of InfectiousDiseases vol 177 no 5 pp 1398ndash1401 1998
[212] C J Van Der Laken O C Boerman W J G Oyen M T PVan De Ven J W M Van Der Meer and F H M CorstensldquoScintigraphic detection of infection and inflammation Newdevelopments with special emphasis on receptor interactionrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 25 no 5 pp 535ndash546 1998
[213] C J van der LakenOC BoermanW J GOyenM T P van deVen J W M van der Meer and F H M Corstens ldquoImaging ofinfection in rabbits with radioiodinated interleukin-1 (120572 and 120573)its receptor antagonist and a chemotactic peptide a comparativestudyrdquo European Journal of Nuclear Medicine and MolecularImaging vol 25 no 4 pp 347ndash352 1998
[214] C J Van Der Laken O C BoermanW J G Oyen M T P VanDe Ven F H M Corstens and J W M Ven Der Meer ldquoThekinetics of radiolabelled interleukin-8 in infection and sterileinflammationrdquo Nuclear Medicine Communications vol 19 no3 pp 271ndash282 1998
[215] E Lazzeri P Erba M Perri et al ldquoScintigraphic imaging ofvertebral osteomyelitis with 111in-biotinrdquoThe Spine Journal vol33 no 7 pp E198ndashE204 2008
[216] E Blom B Langstrom and I Velikyan ldquo68Ga-labeling of biotinanalogues and their characterizationrdquo Bioconjugate Chemistryvol 20 no 6 pp 1146ndash1151 2009
[217] O Eriksson F Carlsson E Blom et al ldquoPreclinical evaluationof a 68Ga-labeled biotin analogue for applications in islettransplantationrdquo Nuclear Medicine and Biology vol 39 no 3pp 415ndash421 2012
[218] E A Weinstein A A Ordonez V P DeMarco et alldquoImaging Enterobacteriaceae infection in vivo with 18F-fluoro-deoxysorbitol positron emission tomographyrdquo Science Transla-tional Medicine vol 6 no 259 p 259ra146 2014
[219] K M Nielsen M H Kyneb A K O Alstrup et alldquo68Ga-labeled phage-display selected peptides as tracers forpositron emission tomography imaging of Staphylococcusaureus biofilm-associated infections Selection radiolabellingand preliminary biological evaluationrdquo Nuclear Medicine andBiology vol 43 no 10 pp 593ndash605 2016
[220] T J Makinen P Lankinen T Poyhonen J Jalava H T Aroand A Roivainen ldquoComparison of 18F-FDG and 68Ga PETimaging in the assessment of experimental osteomyelitis due toStaphylococcus aureusrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 32 no 11 pp 1259ndash1268 2005
[221] JMU Silvola I LaitinenH J Sipila et al ldquoUptake of 68galliumin atherosclerotic plaques in LDLRminusminusApoB100100micerdquo EJN-MMI Research vol 1 no 1 pp 1ndash8 2011
Contrast Media amp Molecular Imaging 23
[222] T A Wynn ldquoCellular and molecular mechanisms of fibrosisrdquoThe Journal of Pathology vol 214 no 2 pp 199ndash210 2008
[223] T Derlin D Jonigk J Bauersachs and FM Bengel ldquoMolecularImaging of Chemokine Receptor CXCR4 in NonndashSmall CellLung Cancer Using 68Ga-Pentixafor PETCT ComparisonWith 18F-FDGrdquo Clinical Nuclear Medicine 2016
[224] I Velikyan U Rosenstrom T N Bulenga O Eriksson andG Antoni ldquoFeasibility of multiple examinations using68ga-labelled collagelin analogues Organ distribution in rat forextrapolation to human organ and whole-body radiationdosimetryrdquo Pharmaceuticals vol 9 no 2 article no 31 2016
[225] S Jadhav M Kakela J Makila et al ldquoSynthesis and in VivoPET Imaging of Hyaluronan Conjugates of OligonucleotidesrdquoBioconjugate Chemistry vol 27 no 2 pp 391ndash403 2016
[226] A Autio A Saraste N Kudomi et al ldquoAssessment of bloodflow with (68) Ga-DOTA PET in experimental inflammation avalidation study using (15) O-waterrdquo American Journal ofNuclear Medicine and Molecular Imaging vol 4 no 6 pp 571ndash579 2014
[227] G Davies A Rolle A Maurer et al ldquoTowards translationalimmunoPETMR imaging of invasive pulmonary aspergillosisthe Humanised Monoclonal Antibody JF5 detects in vivordquoTheranostics vol 7 no 14 pp 3398ndash3414 2017
[228] DGoodwin CMeares GDavid et al ldquoMonoclonal antibodiesas reversible equilibrium carriers of radiopharmaceuticalsrdquoInternational Journal of Radiation Applications and Instrumen-tation Part B Nuclear Medicine and Biology vol 13 no 4 pp383ndash391 1986
[229] D A Goodwin C F Mears M McTigue and G S DavidldquoMonoclonal antibody hapten radiopharmaceutical deliveryrdquoNuclear Medicine Communications vol 7 no 8 pp 569ndash5801986
[230] S E Halpern and R O Dillman ldquoProblems associated withradioimmunodetection and possibilities for future solutionsrdquo JBiol Response Mod vol 6 no 3 pp 235ndash262 1987
[231] H Hong J Sun and W Cai ldquoRadionuclide-based cancerimaging targeting the carcinoembryonic antigenrdquo BiomarkerInsights vol 3 pp 435ndash451 2008
[232] G J Forster E B Santos P M Smith-Jones P Zanzonico andS M Larson ldquoPretargeted radioimmunotherapy with a single-chain antibodystreptavidin construct and radiolabeledDOTA-biotin Strategies for reduction of the renal doserdquo Journal ofNuclear Medicine vol 47 no 1 pp 140ndash149 2006
[233] Z Yao M Zhang H Kobayashi et al ldquoImproved targeting ofradiolabeled streptavidin in tumors pretargeted with biotiny-lated monoclonal antibodies through an avidin chaserdquo Journalof Nuclear Medicine vol 36 no 5 pp 837ndash841 1995
[234] C-H Chang R M Sharkey E A Rossi et al ldquoMolecularAdvances in Pretargeting Radioimunotherapy with BispecificAntibodies 1 Supported in part by USPHS Grant R01-CA-84379from the NIH and Department of Energy Grant DE-FG01-00NE22941 (both to R M S)1rdquo Mol Cancer Ther vol 1 no 7pp 553ndash563 2002
[235] R M Sharkey E A Rossi W J McBride C-H Chang andD M Goldenberg ldquoRecombinant Bispecific Monoclonal Anti-bodies Prepared by theDock-and-Lock Strategy for PretargetedRadioimmunotherapyrdquo Seminars in Nuclear Medicine vol 40no 3 pp 190ndash203 2010
[236] R M Sharkey E A Rossi C-H Chang and D M Golden-berg ldquoImproved cancer therapy and molecular imaging withmultivalent multispecific antibodiesrdquo Cancer Biotherapy andRadiopharmaceuticals vol 25 no 1 pp 1ndash12 2010
[237] D M Goldenberg R M Sharkey G Paganelli J Barbet andJ Chatal ldquoAntibody pretargeting advances cancer radioim-munodetection and radioimmunotherapyrdquo Journal of ClinicalOncology vol 24 no 5 pp 823ndash834 2006
[238] O C Boerman F G van Schaijk W J G Oyen and FH M Corstens ldquoPretargeted radioimmunotherapy of cancerprogress step by steprdquo Journal of Nuclear Medicine vol 44 no3 pp 400ndash411 2003
[239] J Schuhmacher S Kaul G Klivenyi et al ldquoImmunoscintigra-phy with positron emission tomography Gallium-68 chelateimaging of breast cancer pretargeted with bispecific anti-MUC1anti-Ga chelate antibodiesrdquo Cancer Research vol 61 no9 pp 3712ndash3717 2001
[240] J Schuhmacher G Klivenyi S Kaul et al ldquoPretargeting ofhuman mammary carcinoma xenografts with bispecific anti-MUC1anti-Ga chelate antibodies and immunoscintigraphywith PETrdquo Nuclear Medicine and Biology vol 28 no 7 pp 821ndash828 2001
[241] C Somasundaram S Matzku J Schuhmacher and M ZollerldquoDevelopment of a bispecific monoclonal antibody against agallium-67 chelate and the human melanoma-associated anti-gen p97 for potential use in pretargeted immunoscintigraphyrdquoCancer Immunology Immunotherapy vol 36 no 5 pp 337ndash3451993
[242] E A Rossi D L Rossi R Stein D M Goldenberg and C-H Chang ldquoA bispecific antibody-IFN1205722b immunocytokine tar-geting CD20 and HLA-DR is highly toxic to human lymphomaandmultiplemyeloma cellsrdquoCancer Research vol 70 no 19 pp7600ndash7609 2010
[243] R M Sharkey H Karacay S Litwin et al ldquoImproved ther-apeutic results by pretargeted radioimmunotherapy of non-Hodgkinrsquos lymphoma with a new recombinant trivalent anti-CD20 bispecific antibodyrdquo Cancer Research vol 68 no 13 pp5282ndash5290 2008
[244] G L Griffiths C-H Chang W J McBride et al ldquoReagentsandmethods for PETusing bispecific antibody pretargeting and68Ga-radiolabeled bivalent hapten-peptide-chelate conjugatesrdquoJournal of Nuclear Medicine vol 45 no 1 pp 30ndash39 2004
[245] J Watine M Miedouge and B Friedberg ldquoCarcinoembryonicantigen as an independent prognostic factor of recurrence andsurvival in patients resected for colorectal liver metastases Asystematic reviewrdquo Diseases of the Colon amp Rectum vol 44 no12 pp 1791ndash1799 2001
[246] M J Goldstein and E P Mitchell ldquoCarcinoembryonic antigenin the staging and follow-up of patients with colorectal cancerrdquoCancer Investigation vol 23 no 4 pp 338ndash351 2005
[247] D V Gold D M Goldenberg H Karacay et al ldquoA novelbispecific trivalent antibody construct for targeting pancreaticcarcinomardquo Cancer Research vol 68 no 12 pp 4819ndash48262008
[248] J Schuhmacher G Klivenyi R Matys et al ldquoMultistep tumortargeting in nudemice using bispecific antibodies and a galliumchelate suitable for immunoscintigraphy with positron emis-sion tomographyrdquo Cancer Research vol 55 no 1 pp 115ndash1231995
[249] G Klivenyi J Schuhmacher E Patzelt et al ldquoGallium-68chelate imaging of human colon carcinoma xenografts pre-targeted with bispecific anti-CD44(V6)anti-gallium chelateantibodiesrdquo Journal ofNuclearMedicine vol 39 no 10 pp 1769ndash1776 1998
[250] M Zoller J Schuhmacher J Reed W Maier-Borst and SMatzku ldquoEstablishment and characterization of monoclonal
24 Contrast Media amp Molecular Imaging
antibodies against an octahedral gallium chelate suitable forimmunoscintigraphy with PETrdquo Journal of Nuclear Medicinevol 33 no 7 pp 1366ndash1372 1992
[251] R M Sharkey T M Cardillo E A Rossi et al ldquoSignal ampli-fication in molecular imaging by pretargeting a multivalentbispecific antibodyrdquo Nature Medicine vol 11 no 11 pp 1250ndash1255 2005
[252] D M Goldenberg and R M Sharkey ldquoNovel radiolabeledantibody conjugatesrdquo Oncogene vol 26 no 25 pp 3734ndash37442007
[253] D M Goldenberg E A Rossi R M Sharkey W J McBrideand C-H Chang ldquoMultifunctional antibodies by the dock-and-lock method for improved cancer imaging and therapy bypretargetingrdquo Journal of NuclearMedicine vol 49 no 1 pp 158ndash163 2008
[254] R Schoffelen R M Sharkey D M Goldenberg et al ldquoPre-targeted immuno-positron emission tomography imaging ofcarcinoembryonic antigen-expressing tumors with a bispecificantibody and a68Ga- And18F-labeled hapten peptide in micewith human tumor xenograftsrdquoMolecular Cancer Therapeuticsvol 9 no 4 pp 1019ndash1027 2010
[255] E S Bos W H Kuijpers M Meesters-Winters et al ldquoIn vitroevaluation of DNA-DNA hybridization as a two-step approachin radioimmunotherapy of cancerrdquoCancer Research vol 54 no13 pp 3479ndash3486 1994
[256] G Paganelli M Bartolomei M Ferrari et al ldquoPre-TargetedLocoregional Radioimmunotherapy withrdquo Cancer biotherapyand radiopharmaceuticals vol 16 no 3 pp 227ndash235 2001
[257] A Forero P L Weiden J M Vose et al ldquoPhase 1 trial of a novelanti-CD20 fusion protein in pretargeted radioimmunotherapyfor B-cell non-Hodgkin lymphomardquo Blood vol 104 no 1 pp227ndash236 2004
[258] DM Goldenberg C-H Chang E A RossiW J McBride andR M Sharkey ldquoPretargeted molecular imaging and radioim-munotherapyrdquoTheranostics vol 2 no 5 pp 523ndash540 2012
[259] H Karacay R M Sharkey W J McBride E A Rossi C-HChang and D M Goldenberg ldquoOptimization of hapten-peptide labeling for pretargeted immunoPET of bispecificantibody using generator-produced 68Gardquo Journal of NuclearMedicine vol 52 no 4 pp 555ndash559 2011
[260] J R Oh and B C Ahn ldquoFalse-positive uptake on radioiodinewhole-body scintigraphy physiologic and pathologic variantsunrelated to thyroid cancerrdquo American Journal of NuclearMedicine and Molecular Imaging vol 2 no 2 pp 141ndash150 2012
[261] E Frampas C Rousseau C Bodet-Milin J Barbet J-F Chataland F Kraeber-Bodere ldquoImprovement of radioimmunotherapyusing pretargetingrdquo Frontiers in Oncology vol 3 Article ID00159 2013
[262] C S McKay and M G Finn ldquoClick chemistry in complexmixtures Bioorthogonal bioconjugationrdquo Chemistry amp Biologyvol 21 no 9 pp 1075ndash1101 2014
[263] B L Oliveira Z Guo and G J Bernardes ldquoInverse electrondemand DielsndashAlder reactions in chemical biologyrdquo ChemicalSociety Reviews vol 46 no 16 pp 4895ndash4950 2017
[264] B Nichols Z Qin J Yang D R Vera and N K Devaraj ldquo68Gachelating bioorthogonal tetrazine polymers for the multisteplabeling of cancer biomarkersrdquo Chemical Communications vol50 no 40 pp 5215ndash5217 2014
[265] R Rossin P R Verkerk S M van den Bosch et al ldquoInvivo chemistry for pretargeted tumor imaging in live micerdquoAngewandte Chemie International Edition vol 49 no 19 pp3375ndash3378 2010
[266] B M Zeglis K K Sevak T Reiner et al ldquoA pretargetedPET imaging strategy based on bioorthogonal diels-alder clickchemistryrdquo Journal of Nuclear Medicine vol 54 no 8 pp 1389ndash1396 2013
[267] J L Houghton R Membreno D Abdel-Atti et al ldquoEstablish-ment of the invivo efficacy of pretargeted radioimmunotherapyutilizing inverse electron demand diels-alder click chemistryrdquoMolecular Cancer Therapeutics vol 16 no 1 pp 124ndash133 2017
[268] J Funkhouser ldquoReinventing pharma the theranostic revolu-tionrdquo Current Drug Discovery pp 17ndash19 2002
[269] J Sorensen I Velikyan A Wennborg et al ldquoMeasuring HER2-expression in metastatic breast cancer using 68Ga-ABY025PETCTrdquo European Journal of Nuclear Medicine and MolecularImaging vol 41 pp S226ndashS226 2014
[270] I Velikyan A Wennborg J Feldwisch et al ldquoGMP compliantpreparation of a 68Gallium-labeled Affibody analogue forbreast cancer patient examination first-in-manrdquoEur JNuclMedMol Imaging vol 41 pp S228ndashS229 2014
[271] K Oberg ldquoMolecular imaging radiotherapy Theranostics forpersonalized patient management of neuroendocrine tumors(NETs)rdquoTheranostics vol 2 no 5 pp 448ndash458 2012
[272] I Velikyan AWennborg J FeldwischH Lindman J Carlssonand J Sorensen ldquoGood manufacturing practice production of [(68) Ga]Ga-ABY-025 for HER2 specific breast cancer imagingrdquoAmerican Journal of Nuclear Medicine and Molecular Imagingvol 6 no 2 pp 135ndash153 2016
[273] M Sandstrom K Lindskog I Velikyan et al ldquoBiodistributionand radiation dosimetry of the anti-HER2 Affibody molecule68Ga-ABY-025 in breast cancer patientsrdquo Journal of NuclearMedicine vol 57 no 6 pp 867ndash871 2016
[274] D Sandberg V Tolmachev I Velikyan et al ldquoIntra-imagereferencing for simplified assessment of HER2-expression inbreast cancer metastases using the Affibody molecule ABY-025with PET and SPECTrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 44 no 8 pp 1337ndash1346 2017
[275] H ZhangM AMoroz I Serganova et al ldquoImaging expressionof the human somatostatin receptor subtype-2 reporter genewith 68Ga-DOTATOCrdquo Journal ofNuclearMedicine vol 52 no1 pp 123ndash131 2011
[276] M Naji and A Al-Nahhas ldquo68Ga-labelled peptides in themanagement of neuroectodermal tumoursrdquo European Journalof Nuclear Medicine and Molecular Imaging vol 39 no 1 ppS61ndashS67 2012
[277] I Velikyan ldquoThe diversity of 68Ga-Based imaging agentsrdquoRecent Results in Cancer Research vol 194 pp 101ndash131 2013
[278] K Ferreira H-Y Hu V Fetz et al ldquoMultivalent siderophore-dotam conjugates as theranostics for imaging and treatment ofbacterial infectionsrdquo Angewandte Chemie International Editionvol 56 no 28 pp 8272ndash8276 2017
Computational and Mathematical Methods in Medicine
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Research and TreatmentAIDS
Hindawiwwwhindawicom Volume 2018
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Parkinsonrsquos Disease
Evidence-Based Complementary andAlternative Medicine
Volume 2018Hindawiwwwhindawicom
Submit your manuscripts atwwwhindawicom
Contrast Media amp Molecular Imaging 19
[102] M van Oosten M Hahn L M A Crane et al ldquoTargetedimaging of bacterial infections Advances hurdles and hopesrdquoFEMS Microbiology Reviews vol 39 no 6 pp 892ndash916 2015
[103] M Vorster AMaes C V DWiele andM Sathekge ldquoGallium-68 PET A Powerful Generator-based Alternative to Infectionand Inflammation Imagingrdquo Seminars in Nuclear Medicine vol46 no 5 pp 436ndash447 2016
[104] M Kircher and C Lapa ldquoNovel Noninvasive Nuclear MedicineImaging Techniques for Cardiac Inflammationrdquo Current Car-diovascular Imaging Reports vol 10 no 2 article no 6 2017
[105] D AHammoud ldquoMolecular imaging of inflammation Currentstatusrdquo Journal of Nuclear Medicine vol 57 no 8 pp 1161ndash11652016
[106] D R Brenner D Scherer K Muir et al ldquoA review of the appli-cation of inflammatory biomarkers in epidemiologic cancerresearchrdquo Cancer Epidemiology Biomarkers amp Prevention vol23 no 9 pp 1729ndash1751 2014
[107] M D Turner B Nedjai T Hurst and D J PenningtonldquoCytokines and chemokines at the crossroads of cell signallingand inflammatory diseaserdquo Biochimica et Biophysica Acta (BBA)- Molecular Cell Research vol 1843 no 11 pp 2563ndash2582 2014
[108] L Werner H Guzner-Gur and I Dotan ldquoInvolvement ofCXCR4CXCR7CXCL12 interactions in inflammatory boweldiseaserdquoTheranostics vol 3 no 1 pp 40ndash46 2013
[109] S Jalkanen and M Salmi ldquoVAP-1 and CD73 endothelial cellsurface enzymes in leukocyte extravasationrdquo ArteriosclerosisThrombosis and Vascular Biology vol 28 no 1 pp 18ndash26 2008
[110] G Malviya F Galli I Sonni and A Signore ldquoImaging T-lymphocytes in inflammatory diseases A nuclear medicineapproachrdquo The Quarterly Journal of Nuclear Medicine andMolecular Imaging vol 58 no 3 pp 237ndash257 2014
[111] S Gratz H J RennenO C BoermanW J Oyen and P Burmaldquo(99m)Tc-interleukin-8 for imaging acute osteomyelitisrdquo Jour-nal of Nuclear Medicine vol 42 no 8 pp 1257ndash1264 2001
[112] S Gratz H J Rennen O C Boerman W J Oyen andF H Corstens ldquoRapid imaging of experimental colitis with(99m)Tc-interleukin-8 in rabbitsrdquo Journal of Nuclear Medicnevol 42 no 6 pp 917ndash923 2001
[113] C Alkim H Alkim A R Koksal S Boga and I SenldquoAngiogenesis in inflammatory bowel diseaserdquo InternationalJournal of Inflammation vol 2015 Article ID 970890 2015
[114] I S Alam T H Witney G Tomasi et al ldquoRadiolabeled RGDtracer kinetics annotates differential 120572v1205733 integrin expressionlinked to cell intrinsic and vessel expressionrdquoMolecular Imagingand Biology vol 16 no 4 pp 558ndash566 2014
[115] J Notni K Pohle and H-J Wester ldquoBe spoilt for choice withradiolabelled RGD peptides Preclinical evaluation of 68Ga-TRAP(RGD)3rdquoNuclear Medicine and Biology vol 40 no 1 pp33ndash41 2013
[116] J Oxboel M Brandt-Larsen C Schjoeth-Eskesen et al ldquoCom-parison of two new angiogenesis PET tracers 68Ga-NODAGA-E[c(RGDyK)]2 and 64Cu-NODAGA-E[c(RGDyK)]2 in vivoimaging studies in human xenograft tumorsrdquo Nuclear Medicineand Biology vol 41 no 3 pp 259ndash267 2014
[117] J Simecek J Notni T G Kapp H Kessler and H-J WesterldquoBenefits of NOPO as chelator in gallium-68 peptides exempli-fied by preclinical characterization of 68Ga-NOPO-c(RGDfK)rdquoMolecular Pharmaceutics vol 11 no 5 pp 1687ndash1695 2014
[118] M Trajkovic-Arsic P Mohajerani A Sarantopoulos et alldquoMultimodal molecular imaging of integrin avb3 for in vivodetection of pancreatic cancerrdquo Journal of NuclearMedicine vol55 no 3 pp 446ndash451 2014
[119] H Cai and P S Conti ldquoRGD-based PET tracers for imagingreceptor integrin 120572 v1205733 expressionrdquo Journal of Labelled Com-pounds and Radiopharmaceuticals vol 56 no 5 pp 264ndash2792013
[120] I Dijkgraaf S Y A Terry W J Mcbride et al ldquoImagingintegrin alpha-v-beta-3 expression in tumors with an 18F-labeled dimeric RGD peptiderdquo Contrast Media amp MolecularImaging vol 8 no 3 pp 238ndash245 2013
[121] P A Knetsch M Petrik C Rangger et al ldquo[68Ga]NS3-RGD and [68Ga] Oxo-DO3A-RGD for imaging 120572v1205733 integrinexpression Synthesis evaluation and comparisonrdquo NuclearMedicine and Biology vol 40 no 1 pp 65ndash72 2013
[122] Z Liu and F Wang ldquoDevelopment of RGD-based radiotracersfor tumor imaging and therapy Translating from bench tobedsiderdquo Current Molecular Medicine vol 13 no 10 pp 1487ndash1505 2013
[123] H Choi J H Phi J C Paeng et al ldquoImaging of integrin 120572v1205733expression using 68Ga-RGD positron emission tomography inpediatric cerebral infarctrdquoMolecular Imaging vol 12 no 4 pp213ndash217 2013
[124] H-J Yoon K W Kang I K Chun et al ldquoCorrelation of breastcancer subtypes based on estrogen receptor progesteronereceptor and HER2 with functional imaging parameters from68Ga-RGD PETCT and 18F-FDG PETCTrdquo European Journalof Nuclear Medicine and Molecular Imaging vol 41 no 8 pp1534ndash1543 2014
[125] R P Baum H R Kulkarni D Muller et al ldquoFirst-in-human study demonstrating tumor-angiogenesis by PETCTimaging with 68Ga-NODAGA-THERANOST a high-affinitypeptidomimetic for 120572v1205733 integrin receptor targetingrdquo CancerBiotherapy andRadiopharmaceuticals vol 30 no 4 pp 152ndash1592015
[126] R Haubner A Finkenstedt A Stegmayr et alldquo[68Ga]NODAGA-RGD ndash Metabolic stability biodistributionand dosimetry data from patients with hepatocellularcarcinoma and liver cirrhosisrdquo European Journal of NuclearMedicine and Molecular Imaging vol 43 no 11 pp 2005ndash20132016
[127] V Lopez-Rodrıguez C Galindo-Sarco F O Garcıa-Perez GFerro-Flores O Arrieta and M A Avila-Rodrıguez ldquoPET-based human dosimetry of the dimeric 120572v1205733 integrin ligand68Ga-DOTA-E-[c(RGDfK)]2 a potential tracer for imagingtumor angiogenesisrdquo Journal of Nuclear Medicine vol 57 no 3pp 404ndash409 2016
[128] M V Backer Z Levashova V Patel et al ldquoMolecular imagingof VEGF receptors in angiogenic vasculature with single-chainVEGF-based probesrdquo Nature Medicine vol 13 no 4 pp 504ndash509 2007
[129] MV Backer Z Levashova R Levenson F G Blankenberg andJ M Backer ldquoCysteine-containing fusion tag for site-specificconjugation of therapeutic and imaging agents to targetingproteinsrdquoMethods in Molecular Biology (Clifton NJ) vol 494pp 275ndash294 2008
[130] M Eder A V Krivoshein M Backer J M Backer UHaberkorn and M Eisenhut ldquoScVEGF-PEG-HBED-CC andscVEGF-PEG-NOTA conjugates comparison of easy-to-labelrecombinant proteins for [68Ga]PET imaging of VEGF recep-tors in angiogenic vasculaturerdquo Nuclear Medicine and Biologyvol 37 no 4 pp 405ndash412 2010
[131] E Blom I Velikyan A Monazzam P Razifar et al ldquoSynthe-sis and characterization of scVEGF-PEG-[ 68Ga]NOTA andscVEGF-PEG-[ 68Ga]DOTA PET tracersrdquo Journal of Labelled
20 Contrast Media amp Molecular Imaging
Compounds and Radiopharmaceuticals vol 54 no 11 pp 685ndash692 2011
[132] S Gratz M Behe and O C Boerman ldquo 99119898Tc-E-selectinbinding peptide for imaging acute osteomyelitis in a novel ratmodelrdquo Nuclear Medicine Communications vol 22 no 9 pp1003ndash1013 2001
[133] S B Jensen M Kakela L Joslashdal et al ldquoExploring the radiosyn-thesis and in vitro characteristics of [68Ga]Ga-DOTA-Siglec-9rdquoJournal of Labelled Compounds and Radiopharmaceuticals vol60 no 9 pp 439ndash449 2017
[134] B A Teicher and S P Fricker ldquoCXCL12 (SDF-1)CXCR4pathway in cancerrdquo Clinical Cancer Research vol 16 no 11 pp2927ndash2931 2010
[135] O Jacobson I D Weiss D O Kiesewetter J M Farber andX Chen ldquoPET of tumor CXCR4 expression with 4-18F-T140rdquoJournal of Nuclear Medicine vol 51 no 11 pp 1796ndash1804 2010
[136] A Aghanejad A R Jalilian Y Fazaeli et al ldquoSynthesis andevaluation of [67Ga]-AMD3100 A novel imaging agent fortargeting the chemokine receptorCXCR4rdquo Scientia Pharmaceu-tica vol 82 no 1 pp 29ndash42 2014
[137] O Jacobson I D Weiss L P Szajek et al ldquoPET imaging ofCXCR4 using copper-64 labeled peptide antagonistrdquoTheranos-tics vol 1 pp 251ndash262 2011
[138] O Jacobson I D Weiss L P Szajek et al ldquoImprovement ofCXCR4 tracer specificity for PET imagingrdquo Journal of Con-trolled Release vol 157 no 2 pp 216ndash223 2012
[139] H J Wester U Keller M Schottelius et al ldquoDisclosing theCXCR4 expression in lymphoproliferative diseases by targetedmolecular imagingrdquo Theranostics vol 5 no 6 pp 618ndash6302015
[140] E Gourni O Demmer M Schottelius et al ldquoPET of CXCR4expression by a 68Ga-labeled highly specific targeted contrastagentrdquo Journal of NuclearMedicine vol 52 no 11 pp 1803ndash18102011
[141] O Demmer I Dijkgraaf U Schumacher et al ldquoDesignsynthesis and functionalization of dimeric peptides targetingchemokine receptor CXCR4rdquo Journal of Medicinal Chemistryvol 54 no 21 pp 7648ndash7662 2011
[142] O Demmer E Gourni U Schumacher H Kessler and H-JWester ldquoPET Imaging of CXCR4 Receptors in Cancer by a NewOptimized Ligandrdquo ChemMedChem vol 6 no 10 pp 1789ndash1791 2011
[143] U Hennrich L Seyler M Schafer et al ldquoSynthesis and invitro evaluation of 68Ga-DOTA-4-FBn-TN14003 a novel tracerfor the imaging of CXCR4 expressionrdquo Bioorganic amp MedicinalChemistry vol 20 no 4 pp 1502ndash1510 2012
[144] G P C George E Stevens O Aberg et al ldquoPreclinical evalua-tion of a CXCR4-specific 68Ga-labelled TN14003 derivative forcancer PET imagingrdquo Bioorganic amp Medicinal Chemistry vol22 no 2 pp 796ndash803 2014
[145] S Poty E Gourni P Desogere et al ldquoAMD3100 A VersatilePlatform for CXCR4 Targeting 68Ga-Based Radiopharmaceu-ticalsrdquo Bioconjugate Chemistry vol 27 no 3 pp 752ndash761 2016
[146] K Philipp-Abbrederis K Herrmann S Knop et al ldquoIn vivomolecular imaging of chemokine receptor CXCR4 expressionin patients with advancedmultiple myelomardquo EMBOMolecularMedicine vol 7 no 4 pp 477ndash487 2015
[147] Z Wang M Zhang L Wang et al ldquoProspective study of 68Ga-NOTA-NFB Radiation dosimetry in healthy volunteers andfirst application in glioma patientsrdquo Theranostics vol 5 no 8pp 882ndash889 2015
[148] I M Jackson P J Scott and S Thompson ldquoClinical Applica-tions of Radiolabeled Peptides for PETrdquo Seminars in NuclearMedicine vol 47 no 5 pp 493ndash523 2017
[149] C Lapa T Reiter R A Werner et al ldquo[68Ga]Pentixafor-PETCT for Imaging of Chemokine Receptor 4 Expression afterMyocardial Infarctionrdquo JACC Cardiovascular Imaging vol 8no 12 pp 1466ndash1468 2015
[150] C Rischpler S G Nekolla H Kossmann et al ldquoUpregu-lated myocardial CXCR4-expression after myocardial infarc-tion assessed by simultaneous GA-68 pentixafor PETMRIrdquoJournal of Nuclear Cardiology vol 23 no 1 pp 131ndash133 2016
[151] F Hyafil J Pelisek I Laitinen et al ldquoImaging the CytokineReceptorCXCR4 in atherosclerotic plaqueswith the radiotracer68Ga-Pentixafor for PETrdquo Journal of Nuclear Medicine vol 58no 3 pp 499ndash506 2017
[152] Y Yi ldquoFolate receptor-targeted diagnostics and therapeutics forinflammatory diseasesrdquo ImmuneNetwork vol 16 no 6 pp 337ndash343 2016
[153] C M Paulos M J Turk G J Breur and P S Low ldquoFolatereceptor-mediated targeting of therapeutic and imaging agentsto activated macrophages in rheumatoid arthritisrdquo AdvancedDrug Delivery Reviews vol 56 no 8 pp 1205ndash1217 2004
[154] W Han R Zaynagetdinov F E Yull et al ldquoMolecular imagingof folate receptor 120573-positive macrophages during acute lunginflammationrdquo American Journal of Respiratory Cell and Molec-ular Biology vol 53 no 1 pp 50ndash59 2015
[155] B Kuhle C Muller and T L Ross ldquoA Novel 68Ga-Labeledpteroic acid-based PET tracer for tumor imaging via the folatereceptorrdquo Recent Results in Cancer Research vol 194 pp 257ndash267 2013
[156] C Brand V A Longo M Groaning W A Weber and TReiner ldquoDevelopment of a New Folate-Derived Ga-68-BasedPET Imaging AgentrdquoMolecular Imaging and Biology vol 19 no5 pp 754ndash761 2017
[157] M Fani XWang G Nicolas et al ldquoDevelopment of new folate-based PET radiotracers Preclinical evaluation of 68Ga-DOTA-folate conjugatesrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 38 no 1 pp 108ndash119 2011
[158] C J Mathias M R Lewis D E Reichert et al ldquoPreparationof 66Ga- and 68Ga-labeled Ga(III)-deferoxamine-folate aspotential folate-receptor-targeted PET radiopharmaceuticalsrdquoNuclear Medicine and Biology vol 30 no 7 pp 725ndash731 2003
[159] S-M Kim N Choi S Hwang et al ldquoFolate receptor-specific positron emission tomography imaging with folic acid-conjugated tissue inhibitor of metalloproteinase-2rdquo Bulletin ofthe Korean Chemical Society vol 34 no 11 pp 3243ndash3248 2013
[160] M Fani M-L Tamma G P Nicolas et al ldquoIn vivo imagingof folate receptor positive tumor xenografts using novel 68Ga-NODAGA-folate conjugatesrdquo Molecular Pharmaceutics vol 9no 5 pp 1136ndash1145 2012
[161] C Muller and R Schibli ldquoProspects in folate receptor-targetedradionuclide therapyrdquo Frontiers in Oncology vol 3 Article IDArticle 249 2013
[162] A Jain A Mathur U Pandey et al ldquoSynthesis and evaluationof a 68Ga labeled folic acid derivative for targeting folatereceptorsrdquo Applied Radiation and Isotopes vol 116 pp 77ndash842016
[163] W Xia A R Hilgenbrink E L Matteson M B Lockwood J-X Cheng and P S Low ldquoA functional folate receptor is inducedduring macrophage activation and can be used to target drugsto activated macrophagesrdquo Blood vol 113 no 2 pp 438ndash4462009
Contrast Media amp Molecular Imaging 21
[164] E P Krenning W A P Breeman P P M Kooij et alldquoLocalisation of endocrine-related tumours with radioiodi-nated analogue of somatostatinrdquoThe Lancet vol 1 no 8632 pp242ndash244 1989
[165] E P Krenning D J KwekkeboomWH Bakker et al ldquoSomato-statin receptor scintigraphy with [111In-DTPA-d-Phe1]- and[123I-Tyr3]-octreotide the Rotterdam experience with morethan 1000 patientsrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 20 no 8 pp 716ndash731 1993
[166] A Stahl G Meisetschlager M Schottelius et al ldquo[123I]Mtr-TOCA a radioiodinated and carbohydrated analogue ofoctreotide Scintigraphic comparison with [111In]octreotiderdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 33 no 1 pp 45ndash52 2006
[167] R Lebtahi J le Cloirec C Houzard et al ldquoDetection of neu-roendocrine tumors 99mTc-P829 scintigraphy compared with111In-pentetreotide scintigraphyrdquo Journal of Nuclear Medicinevol 43 no 7 pp 889ndash895 2002
[168] C Decristoforo T Maina B Nock M Gabriel P Cordopatisand R Moncayo ldquo99mTc-demotate 1 First data in tumourpatients - Results of a pilotphase I studyrdquo European Journal ofNuclearMedicine andMolecular Imaging vol 30 no 9 pp 1211ndash1219 2003
[169] C Decristoforo S J Mather W Cholewinski E DonnemillerG Riccabona and R Moncayo ldquo(99m)Tc-EDDAHYNIC-TOC A new (99m)Tc-labelled radiopharmaceutical forimaging somatostatin receptor-positive tumours First clinicalresults and intra-patient comparison with 111In-labelledoctreotide derivativesrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 27 no 9 pp 1318ndash1325 2000
[170] A Hubalewska-Dydejczyk K Fross-Baron R Mikołajczak etal ldquo99mTc-EDDAHYNIC-octreotate scintigraphy an efficientmethod for the detection and staging of carcinoid tumoursResults of 3 yearsrsquo experiencerdquo European Journal of NuclearMedicine and Molecular Imaging vol 33 no 10 pp 1123ndash11332006
[171] M Bangard M Behe S Guhlke et al ldquoDetection of somato-statin receptor-positive tumours using the new 99mC-tricine-HYNIC-D-Phe1-Tyr3-octreotide First results in patients andcomparison with 111In-DTPA-D-Phe1-octreotiderdquo EuropeanJournal of Nuclear Medicine and Molecular Imaging vol 27 no6 pp 628ndash637 2000
[172] A Helisch G J Forster H Reber et al ldquoPre-therapeuticdosimetry and biodistribution of 86Y-DOTA- Phe1-Tyr3-octreotide versus 111In-pentetreotide in patients with advancedneuroendocrine tumoursrdquo European Journal of NuclearMedicine and Molecular Imaging vol 31 no 10 pp 1386ndash13922004
[173] M Henze J Schuhmacher P Hipp et al ldquoPET imaging ofsomatostatin receptors using [68GA]DOTA-D-Phe1-Tyr3-Octreotide First results in patients with meningiomasrdquo Journalof Nuclear Medicine vol 42 no 7 pp 1053ndash1056 2001
[174] I Kayani J B Bomanji A Groves et al ldquoFunctional imaging ofneuroendocrine tumors with combined PETCT using 68Ga-DOTATATE (Dota-DPhe1 Tyr3-octreotate) and 18F-FDGrdquoCancer vol 112 no 11 pp 2447ndash2455 2008
[175] A Al-Nahhas ldquoNuclear medicine imaging of neuroendocrinetumoursrdquo Clinical Medicine vol 12 no 4 pp 377ndash380 2012
[176] V Ambrosini S Nicolini P Caroli et al ldquoPETCT imaging indifferent types of lung cancer an overviewrdquo European Journal ofRadiology vol 81 no 5 pp 988ndash1001 2012
[177] V Ambrosini D Campana P Tomassetti and S Fanti ldquo68Ga-labelled peptides for diagnosis of gastroenteropancreatic NETrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 39 no 1 pp S52ndashS60 2012
[178] K E Oberg J-C Reubi D J Kwekkeboom and E P KrenningldquoRole of somatostatins in gastroenteropancreatic neuroen-docrine tumor development and therapyrdquoGastroenterology vol139 no 3 pp 753-753 2010
[179] K Oberg ldquoGallium-68 somatostatin receptor PETCT Is ittime to replace 111Indium DTPA octreotide for patients withneuroendocrine tumorsrdquo Endocrine Journal vol 42 no 1 pp3-4 2012
[180] R Srirajaskanthan I Kayani A M Quigley J Soh M ECaplin and J Bomanji ldquoThe role of 68Ga-DOTATATE PET inpatients with neuroendocrine tumors and negative or equivocalfindings on 111In-DTPA-octreotide scintigraphyrdquo Journal ofNuclear Medicine vol 51 no 6 pp 875ndash882 2010
[181] A Kroiss D Putzer and C Uprimny ldquoFunctional imag-ing in phaeochromocytoma and neuroblastoma with 68Ga-DOTA-Tyr3-octreotide positron emission tomography and123I-metaiodobenzylguanidinerdquo European Journal of NuclearMedicine and Molecular Imaging vol 38 no 5 pp 865ndash8732011
[182] M Naji C Zhao S J Welsh et al ldquo68Ga-DOTA-TATE PETvs 123I-MIBG in identifying malignant neural crest tumoursrdquoMolecular Imaging and Biology vol 13 no 4 pp 769ndash775 2011
[183] V Ambrosini P Tomassetti P Castellucci et al ldquoComparisonbetween 68Ga-DOTA-NOC and 18F-DOPA PET for the detec-tion of gastro-entero-pancreatic and lung neuro-endocrinetumoursrdquo European Journal of Nuclear Medicine and MolecularImaging vol 35 no 8 pp 1431ndash1438 2008
[184] D Putzer M Gabriel B Henninger et al ldquoBone metastasesin patients with neuroendocrine tumor 68Ga- DOTA-Tyr3-octreotide PET in comparison to CT and bone scintigraphyrdquoJournal of Nuclear Medicine vol 50 no 8 pp 1214ndash1221 2009
[185] L K Anzola-Fuentes M Chianelli F Galli et al ldquoSomatostatinreceptor scintigraphy in patients with rheumatoid arthritis andsecondary Sjogrenrsquos syndrome treated with Infliximab a pilotstudyrdquo EJNMMI Research vol 6 no 1 article no 49 2016
[186] T Nobashi Y Nakamoto T Kubo et al ldquoThe utility of PETCTwith 68Ga-DOTATOC in sarcoidosis comparison with 67Ga-scintigraphyrdquoAnnals ofNuclearMedicine vol 30 no 8 pp 544ndash552 2016
[187] C Boy T A Heusner T D Poeppel et al ldquo68Ga-DOTATOCPETCT and somatostatin receptor (sst1-sst5) expression innormal human tissue Correlation of sst2mRNAand SUVmaxrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 38 no 7 pp 1224ndash1236 2011
[188] P Rinne S Hellberg M Kiugel et al ldquoComparison of Somato-statin Receptor 2-Targeting PET Tracers in the Detection ofMouse Atherosclerotic Plaquesrdquo Molecular Imaging and Biol-ogy vol 18 no 1 pp 99ndash108 2016
[189] M Asti E Ferrari S Croci et al ldquoSynthesis and characteri-zation of 68Ga-labeled curcumin and curcuminoid complexesas potential radiotracers for imaging of cancer and alzheimersdiseaserdquo Inorganic Chemistry vol 53 no 10 pp 4922ndash49332014
[190] A Signore I Santino and A W J M Glaudemans ldquoIn vivoimaging of microorganismsrdquo Clinical and Translational Imag-ing vol 4 no 3 pp 161-162 2016
[191] S Auletta F Galli C Lauri D Martinelli I Santino andA Signore ldquoImaging bacteria with radiolabelled quinolones
22 Contrast Media amp Molecular Imaging
cephalosporins and siderophores for imaging infection a sys-tematic reviewrdquo Clinical and Translational Imaging vol 4 no 4pp 229ndash252 2016
[192] X Ning S Lee Z Wang et al ldquoMaltodextrin-based imagingprobes detect bacteria in vivo with high sensitivity and speci-ficityrdquo Nature Materials vol 10 no 8 pp 602ndash607 2011
[193] J Ady andY Fong ldquoImaging for infection Fromvisualization ofinflammation to visualization of microbesrdquo Surgical Infectionsvol 15 no 6 pp 700ndash707 2014
[194] J M Sierra D Rodriguez-Puig A Soriano J Mensa C Pieraand J Vila ldquoAccumulation of 99mTc-ciprofloxacin in Staphy-lococcus aureus and Pseudomonas aeruginosardquo AntimicrobialAgents and Chemotherapy vol 52 no 7 pp 2691-2692 2008
[195] D I Andersson and D Hughes ldquoMicrobiological effects ofsublethal levels of antibioticsrdquoNature ReviewsMicrobiology vol12 no 7 pp 465ndash478 2014
[196] N Dumarey D Blocklet T Appelboom L Tant and ASchoutens ldquoInfecton is not specific for bacterial osteo-articularinfective pathologyrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 29 no 4 pp 530ndash535 2002
[197] K E Britton D W Wareham S S Das et al ldquoImaging bacte-rial infection with 99mTc-ciprofloxacin (Infecton)rdquo Journal ofClinical Pathology vol 55 no 11 pp 817ndash823 2002
[198] G Ferro-Flores M A Avila-Rodrıguez and F O Garcıa-PerezldquoImaging of bacteria with radiolabeled ubiquicidin by SPECTand PET techniquesrdquo Clinical and Translational Imaging vol 4no 3 pp 175ndash182 2016
[199] P S Hiemstra M T van den Barselaar M Roest P H Nibber-ing and R van Furth ldquoUbiquicidin a novel murine microbi-cidal protein present in the cytosolic fraction of macrophagesrdquoJournal of Leukocyte Biology vol 66 no 3 pp 423ndash428 1999
[200] M S Akhtar A Qaisar J Irfanullah et al ldquoAntimicrobialpeptide 99mTc-ubiquicidin 29ndash41 as human infection-imagingagent clinical trialrdquo Journal of Nuclear Medicne vol 46 no 4pp 567ndash573 2005
[201] M Assadi K Vahdat I Nabipour et al ldquoDiagnostic value of99mTc-ubiquicidin scintigraphy for osteomyelitis and compar-isons with 99mTc-methylene diphosphonate scintigraphy andmagnetic resonance imagingrdquo Nuclear Medicine Communica-tions vol 32 no 8 pp 716ndash723 2011
[202] T Emery ldquoExchange of Iron by Gallium in SiderophoresrdquoBiochemistry vol 25 no 16 pp 4629ndash4633 1986
[203] M Petrik C Zhai H Haas and C Decristoforo ldquoSiderophoresfor molecular imaging applicationsrdquo Clinical and TranslationalImaging vol 5 no 1 pp 15ndash27 2017
[204] H J Flint E A BayerM T Rincon R Lamed and B AWhiteldquoPolysaccharide utilization by gut bacteria potential for newinsights from genomic analysisrdquo Nature Reviews Microbiologyvol 6 no 2 pp 121ndash131 2008
[205] GGowrishankarMNamavari E B Jouannot et al ldquoInvestiga-tion of 6-[18F]-fluoromaltose as a novel PET tracer for imagingbacterial infectionrdquo PLoS ONE vol 9 no 9 Article ID e1079512014
[206] N Gholipour M Akhlaghi A M Kheirabadi et al ldquoChelator-free radiolabeling of dextran with 68Ga for PET studiesrdquoJournal of Radioanalytical and Nuclear Chemistry vol 311 no3 pp 1811ndash1817 2017
[207] C Bettegowda C A Foss I Cheong et al ldquoImaging bac-terial infections with radiolabeled 1-(21015840-deoxy-21015840- fluoro-120573-D-arabinofuranosyl)-5-iodouracilrdquo Proceedings of the NationalAcadamy of Sciences of the United States of America vol 102 no4 pp 1145ndash1150 2005
[208] S A Soghomonyan M Doubrovin J Pike et al ldquoPositronemission tomography (PET) imaging of tumor-localizedSalmonella expressing HSV1-TKrdquo Cancer GeneTherapy vol 12no 1 pp 101ndash108 2005
[209] C Palestro K Nichols S Sheikh-Fayyaz S Dewey P Singhaland K Bhargava ldquoCan Gallium-68 PET differentiate acuteinterstitial nephritis from acute tubular necrosisrdquo Journal ofNuclear Medicne vol 57 Supplement 2 p 551 2016
[210] A J Morguet D L Munz V Ivancevic et al ldquoImmunoscintig-raphy using technetium-99m-labeled anti-NCA-95 antigranu-locyte antibodies as an adjunct to echocardiography in subacuteinfective endocarditisrdquo Journal of the American College ofCardiology vol 23 no 5 pp 1171ndash1178 1994
[211] C van der Laken O Boerman W Oyen et al ldquoIn Vivo Expres-sion of Interleukin-1 Receptors during Various ExperimentallyInduced Inflammatory Conditionsrdquo The Journal of InfectiousDiseases vol 177 no 5 pp 1398ndash1401 1998
[212] C J Van Der Laken O C Boerman W J G Oyen M T PVan De Ven J W M Van Der Meer and F H M CorstensldquoScintigraphic detection of infection and inflammation Newdevelopments with special emphasis on receptor interactionrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 25 no 5 pp 535ndash546 1998
[213] C J van der LakenOC BoermanW J GOyenM T P van deVen J W M van der Meer and F H M Corstens ldquoImaging ofinfection in rabbits with radioiodinated interleukin-1 (120572 and 120573)its receptor antagonist and a chemotactic peptide a comparativestudyrdquo European Journal of Nuclear Medicine and MolecularImaging vol 25 no 4 pp 347ndash352 1998
[214] C J Van Der Laken O C BoermanW J G Oyen M T P VanDe Ven F H M Corstens and J W M Ven Der Meer ldquoThekinetics of radiolabelled interleukin-8 in infection and sterileinflammationrdquo Nuclear Medicine Communications vol 19 no3 pp 271ndash282 1998
[215] E Lazzeri P Erba M Perri et al ldquoScintigraphic imaging ofvertebral osteomyelitis with 111in-biotinrdquoThe Spine Journal vol33 no 7 pp E198ndashE204 2008
[216] E Blom B Langstrom and I Velikyan ldquo68Ga-labeling of biotinanalogues and their characterizationrdquo Bioconjugate Chemistryvol 20 no 6 pp 1146ndash1151 2009
[217] O Eriksson F Carlsson E Blom et al ldquoPreclinical evaluationof a 68Ga-labeled biotin analogue for applications in islettransplantationrdquo Nuclear Medicine and Biology vol 39 no 3pp 415ndash421 2012
[218] E A Weinstein A A Ordonez V P DeMarco et alldquoImaging Enterobacteriaceae infection in vivo with 18F-fluoro-deoxysorbitol positron emission tomographyrdquo Science Transla-tional Medicine vol 6 no 259 p 259ra146 2014
[219] K M Nielsen M H Kyneb A K O Alstrup et alldquo68Ga-labeled phage-display selected peptides as tracers forpositron emission tomography imaging of Staphylococcusaureus biofilm-associated infections Selection radiolabellingand preliminary biological evaluationrdquo Nuclear Medicine andBiology vol 43 no 10 pp 593ndash605 2016
[220] T J Makinen P Lankinen T Poyhonen J Jalava H T Aroand A Roivainen ldquoComparison of 18F-FDG and 68Ga PETimaging in the assessment of experimental osteomyelitis due toStaphylococcus aureusrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 32 no 11 pp 1259ndash1268 2005
[221] JMU Silvola I LaitinenH J Sipila et al ldquoUptake of 68galliumin atherosclerotic plaques in LDLRminusminusApoB100100micerdquo EJN-MMI Research vol 1 no 1 pp 1ndash8 2011
Contrast Media amp Molecular Imaging 23
[222] T A Wynn ldquoCellular and molecular mechanisms of fibrosisrdquoThe Journal of Pathology vol 214 no 2 pp 199ndash210 2008
[223] T Derlin D Jonigk J Bauersachs and FM Bengel ldquoMolecularImaging of Chemokine Receptor CXCR4 in NonndashSmall CellLung Cancer Using 68Ga-Pentixafor PETCT ComparisonWith 18F-FDGrdquo Clinical Nuclear Medicine 2016
[224] I Velikyan U Rosenstrom T N Bulenga O Eriksson andG Antoni ldquoFeasibility of multiple examinations using68ga-labelled collagelin analogues Organ distribution in rat forextrapolation to human organ and whole-body radiationdosimetryrdquo Pharmaceuticals vol 9 no 2 article no 31 2016
[225] S Jadhav M Kakela J Makila et al ldquoSynthesis and in VivoPET Imaging of Hyaluronan Conjugates of OligonucleotidesrdquoBioconjugate Chemistry vol 27 no 2 pp 391ndash403 2016
[226] A Autio A Saraste N Kudomi et al ldquoAssessment of bloodflow with (68) Ga-DOTA PET in experimental inflammation avalidation study using (15) O-waterrdquo American Journal ofNuclear Medicine and Molecular Imaging vol 4 no 6 pp 571ndash579 2014
[227] G Davies A Rolle A Maurer et al ldquoTowards translationalimmunoPETMR imaging of invasive pulmonary aspergillosisthe Humanised Monoclonal Antibody JF5 detects in vivordquoTheranostics vol 7 no 14 pp 3398ndash3414 2017
[228] DGoodwin CMeares GDavid et al ldquoMonoclonal antibodiesas reversible equilibrium carriers of radiopharmaceuticalsrdquoInternational Journal of Radiation Applications and Instrumen-tation Part B Nuclear Medicine and Biology vol 13 no 4 pp383ndash391 1986
[229] D A Goodwin C F Mears M McTigue and G S DavidldquoMonoclonal antibody hapten radiopharmaceutical deliveryrdquoNuclear Medicine Communications vol 7 no 8 pp 569ndash5801986
[230] S E Halpern and R O Dillman ldquoProblems associated withradioimmunodetection and possibilities for future solutionsrdquo JBiol Response Mod vol 6 no 3 pp 235ndash262 1987
[231] H Hong J Sun and W Cai ldquoRadionuclide-based cancerimaging targeting the carcinoembryonic antigenrdquo BiomarkerInsights vol 3 pp 435ndash451 2008
[232] G J Forster E B Santos P M Smith-Jones P Zanzonico andS M Larson ldquoPretargeted radioimmunotherapy with a single-chain antibodystreptavidin construct and radiolabeledDOTA-biotin Strategies for reduction of the renal doserdquo Journal ofNuclear Medicine vol 47 no 1 pp 140ndash149 2006
[233] Z Yao M Zhang H Kobayashi et al ldquoImproved targeting ofradiolabeled streptavidin in tumors pretargeted with biotiny-lated monoclonal antibodies through an avidin chaserdquo Journalof Nuclear Medicine vol 36 no 5 pp 837ndash841 1995
[234] C-H Chang R M Sharkey E A Rossi et al ldquoMolecularAdvances in Pretargeting Radioimunotherapy with BispecificAntibodies 1 Supported in part by USPHS Grant R01-CA-84379from the NIH and Department of Energy Grant DE-FG01-00NE22941 (both to R M S)1rdquo Mol Cancer Ther vol 1 no 7pp 553ndash563 2002
[235] R M Sharkey E A Rossi W J McBride C-H Chang andD M Goldenberg ldquoRecombinant Bispecific Monoclonal Anti-bodies Prepared by theDock-and-Lock Strategy for PretargetedRadioimmunotherapyrdquo Seminars in Nuclear Medicine vol 40no 3 pp 190ndash203 2010
[236] R M Sharkey E A Rossi C-H Chang and D M Golden-berg ldquoImproved cancer therapy and molecular imaging withmultivalent multispecific antibodiesrdquo Cancer Biotherapy andRadiopharmaceuticals vol 25 no 1 pp 1ndash12 2010
[237] D M Goldenberg R M Sharkey G Paganelli J Barbet andJ Chatal ldquoAntibody pretargeting advances cancer radioim-munodetection and radioimmunotherapyrdquo Journal of ClinicalOncology vol 24 no 5 pp 823ndash834 2006
[238] O C Boerman F G van Schaijk W J G Oyen and FH M Corstens ldquoPretargeted radioimmunotherapy of cancerprogress step by steprdquo Journal of Nuclear Medicine vol 44 no3 pp 400ndash411 2003
[239] J Schuhmacher S Kaul G Klivenyi et al ldquoImmunoscintigra-phy with positron emission tomography Gallium-68 chelateimaging of breast cancer pretargeted with bispecific anti-MUC1anti-Ga chelate antibodiesrdquo Cancer Research vol 61 no9 pp 3712ndash3717 2001
[240] J Schuhmacher G Klivenyi S Kaul et al ldquoPretargeting ofhuman mammary carcinoma xenografts with bispecific anti-MUC1anti-Ga chelate antibodies and immunoscintigraphywith PETrdquo Nuclear Medicine and Biology vol 28 no 7 pp 821ndash828 2001
[241] C Somasundaram S Matzku J Schuhmacher and M ZollerldquoDevelopment of a bispecific monoclonal antibody against agallium-67 chelate and the human melanoma-associated anti-gen p97 for potential use in pretargeted immunoscintigraphyrdquoCancer Immunology Immunotherapy vol 36 no 5 pp 337ndash3451993
[242] E A Rossi D L Rossi R Stein D M Goldenberg and C-H Chang ldquoA bispecific antibody-IFN1205722b immunocytokine tar-geting CD20 and HLA-DR is highly toxic to human lymphomaandmultiplemyeloma cellsrdquoCancer Research vol 70 no 19 pp7600ndash7609 2010
[243] R M Sharkey H Karacay S Litwin et al ldquoImproved ther-apeutic results by pretargeted radioimmunotherapy of non-Hodgkinrsquos lymphoma with a new recombinant trivalent anti-CD20 bispecific antibodyrdquo Cancer Research vol 68 no 13 pp5282ndash5290 2008
[244] G L Griffiths C-H Chang W J McBride et al ldquoReagentsandmethods for PETusing bispecific antibody pretargeting and68Ga-radiolabeled bivalent hapten-peptide-chelate conjugatesrdquoJournal of Nuclear Medicine vol 45 no 1 pp 30ndash39 2004
[245] J Watine M Miedouge and B Friedberg ldquoCarcinoembryonicantigen as an independent prognostic factor of recurrence andsurvival in patients resected for colorectal liver metastases Asystematic reviewrdquo Diseases of the Colon amp Rectum vol 44 no12 pp 1791ndash1799 2001
[246] M J Goldstein and E P Mitchell ldquoCarcinoembryonic antigenin the staging and follow-up of patients with colorectal cancerrdquoCancer Investigation vol 23 no 4 pp 338ndash351 2005
[247] D V Gold D M Goldenberg H Karacay et al ldquoA novelbispecific trivalent antibody construct for targeting pancreaticcarcinomardquo Cancer Research vol 68 no 12 pp 4819ndash48262008
[248] J Schuhmacher G Klivenyi R Matys et al ldquoMultistep tumortargeting in nudemice using bispecific antibodies and a galliumchelate suitable for immunoscintigraphy with positron emis-sion tomographyrdquo Cancer Research vol 55 no 1 pp 115ndash1231995
[249] G Klivenyi J Schuhmacher E Patzelt et al ldquoGallium-68chelate imaging of human colon carcinoma xenografts pre-targeted with bispecific anti-CD44(V6)anti-gallium chelateantibodiesrdquo Journal ofNuclearMedicine vol 39 no 10 pp 1769ndash1776 1998
[250] M Zoller J Schuhmacher J Reed W Maier-Borst and SMatzku ldquoEstablishment and characterization of monoclonal
24 Contrast Media amp Molecular Imaging
antibodies against an octahedral gallium chelate suitable forimmunoscintigraphy with PETrdquo Journal of Nuclear Medicinevol 33 no 7 pp 1366ndash1372 1992
[251] R M Sharkey T M Cardillo E A Rossi et al ldquoSignal ampli-fication in molecular imaging by pretargeting a multivalentbispecific antibodyrdquo Nature Medicine vol 11 no 11 pp 1250ndash1255 2005
[252] D M Goldenberg and R M Sharkey ldquoNovel radiolabeledantibody conjugatesrdquo Oncogene vol 26 no 25 pp 3734ndash37442007
[253] D M Goldenberg E A Rossi R M Sharkey W J McBrideand C-H Chang ldquoMultifunctional antibodies by the dock-and-lock method for improved cancer imaging and therapy bypretargetingrdquo Journal of NuclearMedicine vol 49 no 1 pp 158ndash163 2008
[254] R Schoffelen R M Sharkey D M Goldenberg et al ldquoPre-targeted immuno-positron emission tomography imaging ofcarcinoembryonic antigen-expressing tumors with a bispecificantibody and a68Ga- And18F-labeled hapten peptide in micewith human tumor xenograftsrdquoMolecular Cancer Therapeuticsvol 9 no 4 pp 1019ndash1027 2010
[255] E S Bos W H Kuijpers M Meesters-Winters et al ldquoIn vitroevaluation of DNA-DNA hybridization as a two-step approachin radioimmunotherapy of cancerrdquoCancer Research vol 54 no13 pp 3479ndash3486 1994
[256] G Paganelli M Bartolomei M Ferrari et al ldquoPre-TargetedLocoregional Radioimmunotherapy withrdquo Cancer biotherapyand radiopharmaceuticals vol 16 no 3 pp 227ndash235 2001
[257] A Forero P L Weiden J M Vose et al ldquoPhase 1 trial of a novelanti-CD20 fusion protein in pretargeted radioimmunotherapyfor B-cell non-Hodgkin lymphomardquo Blood vol 104 no 1 pp227ndash236 2004
[258] DM Goldenberg C-H Chang E A RossiW J McBride andR M Sharkey ldquoPretargeted molecular imaging and radioim-munotherapyrdquoTheranostics vol 2 no 5 pp 523ndash540 2012
[259] H Karacay R M Sharkey W J McBride E A Rossi C-HChang and D M Goldenberg ldquoOptimization of hapten-peptide labeling for pretargeted immunoPET of bispecificantibody using generator-produced 68Gardquo Journal of NuclearMedicine vol 52 no 4 pp 555ndash559 2011
[260] J R Oh and B C Ahn ldquoFalse-positive uptake on radioiodinewhole-body scintigraphy physiologic and pathologic variantsunrelated to thyroid cancerrdquo American Journal of NuclearMedicine and Molecular Imaging vol 2 no 2 pp 141ndash150 2012
[261] E Frampas C Rousseau C Bodet-Milin J Barbet J-F Chataland F Kraeber-Bodere ldquoImprovement of radioimmunotherapyusing pretargetingrdquo Frontiers in Oncology vol 3 Article ID00159 2013
[262] C S McKay and M G Finn ldquoClick chemistry in complexmixtures Bioorthogonal bioconjugationrdquo Chemistry amp Biologyvol 21 no 9 pp 1075ndash1101 2014
[263] B L Oliveira Z Guo and G J Bernardes ldquoInverse electrondemand DielsndashAlder reactions in chemical biologyrdquo ChemicalSociety Reviews vol 46 no 16 pp 4895ndash4950 2017
[264] B Nichols Z Qin J Yang D R Vera and N K Devaraj ldquo68Gachelating bioorthogonal tetrazine polymers for the multisteplabeling of cancer biomarkersrdquo Chemical Communications vol50 no 40 pp 5215ndash5217 2014
[265] R Rossin P R Verkerk S M van den Bosch et al ldquoInvivo chemistry for pretargeted tumor imaging in live micerdquoAngewandte Chemie International Edition vol 49 no 19 pp3375ndash3378 2010
[266] B M Zeglis K K Sevak T Reiner et al ldquoA pretargetedPET imaging strategy based on bioorthogonal diels-alder clickchemistryrdquo Journal of Nuclear Medicine vol 54 no 8 pp 1389ndash1396 2013
[267] J L Houghton R Membreno D Abdel-Atti et al ldquoEstablish-ment of the invivo efficacy of pretargeted radioimmunotherapyutilizing inverse electron demand diels-alder click chemistryrdquoMolecular Cancer Therapeutics vol 16 no 1 pp 124ndash133 2017
[268] J Funkhouser ldquoReinventing pharma the theranostic revolu-tionrdquo Current Drug Discovery pp 17ndash19 2002
[269] J Sorensen I Velikyan A Wennborg et al ldquoMeasuring HER2-expression in metastatic breast cancer using 68Ga-ABY025PETCTrdquo European Journal of Nuclear Medicine and MolecularImaging vol 41 pp S226ndashS226 2014
[270] I Velikyan A Wennborg J Feldwisch et al ldquoGMP compliantpreparation of a 68Gallium-labeled Affibody analogue forbreast cancer patient examination first-in-manrdquoEur JNuclMedMol Imaging vol 41 pp S228ndashS229 2014
[271] K Oberg ldquoMolecular imaging radiotherapy Theranostics forpersonalized patient management of neuroendocrine tumors(NETs)rdquoTheranostics vol 2 no 5 pp 448ndash458 2012
[272] I Velikyan AWennborg J FeldwischH Lindman J Carlssonand J Sorensen ldquoGood manufacturing practice production of [(68) Ga]Ga-ABY-025 for HER2 specific breast cancer imagingrdquoAmerican Journal of Nuclear Medicine and Molecular Imagingvol 6 no 2 pp 135ndash153 2016
[273] M Sandstrom K Lindskog I Velikyan et al ldquoBiodistributionand radiation dosimetry of the anti-HER2 Affibody molecule68Ga-ABY-025 in breast cancer patientsrdquo Journal of NuclearMedicine vol 57 no 6 pp 867ndash871 2016
[274] D Sandberg V Tolmachev I Velikyan et al ldquoIntra-imagereferencing for simplified assessment of HER2-expression inbreast cancer metastases using the Affibody molecule ABY-025with PET and SPECTrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 44 no 8 pp 1337ndash1346 2017
[275] H ZhangM AMoroz I Serganova et al ldquoImaging expressionof the human somatostatin receptor subtype-2 reporter genewith 68Ga-DOTATOCrdquo Journal ofNuclearMedicine vol 52 no1 pp 123ndash131 2011
[276] M Naji and A Al-Nahhas ldquo68Ga-labelled peptides in themanagement of neuroectodermal tumoursrdquo European Journalof Nuclear Medicine and Molecular Imaging vol 39 no 1 ppS61ndashS67 2012
[277] I Velikyan ldquoThe diversity of 68Ga-Based imaging agentsrdquoRecent Results in Cancer Research vol 194 pp 101ndash131 2013
[278] K Ferreira H-Y Hu V Fetz et al ldquoMultivalent siderophore-dotam conjugates as theranostics for imaging and treatment ofbacterial infectionsrdquo Angewandte Chemie International Editionvol 56 no 28 pp 8272ndash8276 2017
Computational and Mathematical Methods in Medicine
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Diabetes ResearchJournal of
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Research and TreatmentAIDS
Hindawiwwwhindawicom Volume 2018
Gastroenterology Research and Practice
Hindawiwwwhindawicom Volume 2018
Parkinsonrsquos Disease
Evidence-Based Complementary andAlternative Medicine
Volume 2018Hindawiwwwhindawicom
Submit your manuscripts atwwwhindawicom
20 Contrast Media amp Molecular Imaging
Compounds and Radiopharmaceuticals vol 54 no 11 pp 685ndash692 2011
[132] S Gratz M Behe and O C Boerman ldquo 99119898Tc-E-selectinbinding peptide for imaging acute osteomyelitis in a novel ratmodelrdquo Nuclear Medicine Communications vol 22 no 9 pp1003ndash1013 2001
[133] S B Jensen M Kakela L Joslashdal et al ldquoExploring the radiosyn-thesis and in vitro characteristics of [68Ga]Ga-DOTA-Siglec-9rdquoJournal of Labelled Compounds and Radiopharmaceuticals vol60 no 9 pp 439ndash449 2017
[134] B A Teicher and S P Fricker ldquoCXCL12 (SDF-1)CXCR4pathway in cancerrdquo Clinical Cancer Research vol 16 no 11 pp2927ndash2931 2010
[135] O Jacobson I D Weiss D O Kiesewetter J M Farber andX Chen ldquoPET of tumor CXCR4 expression with 4-18F-T140rdquoJournal of Nuclear Medicine vol 51 no 11 pp 1796ndash1804 2010
[136] A Aghanejad A R Jalilian Y Fazaeli et al ldquoSynthesis andevaluation of [67Ga]-AMD3100 A novel imaging agent fortargeting the chemokine receptorCXCR4rdquo Scientia Pharmaceu-tica vol 82 no 1 pp 29ndash42 2014
[137] O Jacobson I D Weiss L P Szajek et al ldquoPET imaging ofCXCR4 using copper-64 labeled peptide antagonistrdquoTheranos-tics vol 1 pp 251ndash262 2011
[138] O Jacobson I D Weiss L P Szajek et al ldquoImprovement ofCXCR4 tracer specificity for PET imagingrdquo Journal of Con-trolled Release vol 157 no 2 pp 216ndash223 2012
[139] H J Wester U Keller M Schottelius et al ldquoDisclosing theCXCR4 expression in lymphoproliferative diseases by targetedmolecular imagingrdquo Theranostics vol 5 no 6 pp 618ndash6302015
[140] E Gourni O Demmer M Schottelius et al ldquoPET of CXCR4expression by a 68Ga-labeled highly specific targeted contrastagentrdquo Journal of NuclearMedicine vol 52 no 11 pp 1803ndash18102011
[141] O Demmer I Dijkgraaf U Schumacher et al ldquoDesignsynthesis and functionalization of dimeric peptides targetingchemokine receptor CXCR4rdquo Journal of Medicinal Chemistryvol 54 no 21 pp 7648ndash7662 2011
[142] O Demmer E Gourni U Schumacher H Kessler and H-JWester ldquoPET Imaging of CXCR4 Receptors in Cancer by a NewOptimized Ligandrdquo ChemMedChem vol 6 no 10 pp 1789ndash1791 2011
[143] U Hennrich L Seyler M Schafer et al ldquoSynthesis and invitro evaluation of 68Ga-DOTA-4-FBn-TN14003 a novel tracerfor the imaging of CXCR4 expressionrdquo Bioorganic amp MedicinalChemistry vol 20 no 4 pp 1502ndash1510 2012
[144] G P C George E Stevens O Aberg et al ldquoPreclinical evalua-tion of a CXCR4-specific 68Ga-labelled TN14003 derivative forcancer PET imagingrdquo Bioorganic amp Medicinal Chemistry vol22 no 2 pp 796ndash803 2014
[145] S Poty E Gourni P Desogere et al ldquoAMD3100 A VersatilePlatform for CXCR4 Targeting 68Ga-Based Radiopharmaceu-ticalsrdquo Bioconjugate Chemistry vol 27 no 3 pp 752ndash761 2016
[146] K Philipp-Abbrederis K Herrmann S Knop et al ldquoIn vivomolecular imaging of chemokine receptor CXCR4 expressionin patients with advancedmultiple myelomardquo EMBOMolecularMedicine vol 7 no 4 pp 477ndash487 2015
[147] Z Wang M Zhang L Wang et al ldquoProspective study of 68Ga-NOTA-NFB Radiation dosimetry in healthy volunteers andfirst application in glioma patientsrdquo Theranostics vol 5 no 8pp 882ndash889 2015
[148] I M Jackson P J Scott and S Thompson ldquoClinical Applica-tions of Radiolabeled Peptides for PETrdquo Seminars in NuclearMedicine vol 47 no 5 pp 493ndash523 2017
[149] C Lapa T Reiter R A Werner et al ldquo[68Ga]Pentixafor-PETCT for Imaging of Chemokine Receptor 4 Expression afterMyocardial Infarctionrdquo JACC Cardiovascular Imaging vol 8no 12 pp 1466ndash1468 2015
[150] C Rischpler S G Nekolla H Kossmann et al ldquoUpregu-lated myocardial CXCR4-expression after myocardial infarc-tion assessed by simultaneous GA-68 pentixafor PETMRIrdquoJournal of Nuclear Cardiology vol 23 no 1 pp 131ndash133 2016
[151] F Hyafil J Pelisek I Laitinen et al ldquoImaging the CytokineReceptorCXCR4 in atherosclerotic plaqueswith the radiotracer68Ga-Pentixafor for PETrdquo Journal of Nuclear Medicine vol 58no 3 pp 499ndash506 2017
[152] Y Yi ldquoFolate receptor-targeted diagnostics and therapeutics forinflammatory diseasesrdquo ImmuneNetwork vol 16 no 6 pp 337ndash343 2016
[153] C M Paulos M J Turk G J Breur and P S Low ldquoFolatereceptor-mediated targeting of therapeutic and imaging agentsto activated macrophages in rheumatoid arthritisrdquo AdvancedDrug Delivery Reviews vol 56 no 8 pp 1205ndash1217 2004
[154] W Han R Zaynagetdinov F E Yull et al ldquoMolecular imagingof folate receptor 120573-positive macrophages during acute lunginflammationrdquo American Journal of Respiratory Cell and Molec-ular Biology vol 53 no 1 pp 50ndash59 2015
[155] B Kuhle C Muller and T L Ross ldquoA Novel 68Ga-Labeledpteroic acid-based PET tracer for tumor imaging via the folatereceptorrdquo Recent Results in Cancer Research vol 194 pp 257ndash267 2013
[156] C Brand V A Longo M Groaning W A Weber and TReiner ldquoDevelopment of a New Folate-Derived Ga-68-BasedPET Imaging AgentrdquoMolecular Imaging and Biology vol 19 no5 pp 754ndash761 2017
[157] M Fani XWang G Nicolas et al ldquoDevelopment of new folate-based PET radiotracers Preclinical evaluation of 68Ga-DOTA-folate conjugatesrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 38 no 1 pp 108ndash119 2011
[158] C J Mathias M R Lewis D E Reichert et al ldquoPreparationof 66Ga- and 68Ga-labeled Ga(III)-deferoxamine-folate aspotential folate-receptor-targeted PET radiopharmaceuticalsrdquoNuclear Medicine and Biology vol 30 no 7 pp 725ndash731 2003
[159] S-M Kim N Choi S Hwang et al ldquoFolate receptor-specific positron emission tomography imaging with folic acid-conjugated tissue inhibitor of metalloproteinase-2rdquo Bulletin ofthe Korean Chemical Society vol 34 no 11 pp 3243ndash3248 2013
[160] M Fani M-L Tamma G P Nicolas et al ldquoIn vivo imagingof folate receptor positive tumor xenografts using novel 68Ga-NODAGA-folate conjugatesrdquo Molecular Pharmaceutics vol 9no 5 pp 1136ndash1145 2012
[161] C Muller and R Schibli ldquoProspects in folate receptor-targetedradionuclide therapyrdquo Frontiers in Oncology vol 3 Article IDArticle 249 2013
[162] A Jain A Mathur U Pandey et al ldquoSynthesis and evaluationof a 68Ga labeled folic acid derivative for targeting folatereceptorsrdquo Applied Radiation and Isotopes vol 116 pp 77ndash842016
[163] W Xia A R Hilgenbrink E L Matteson M B Lockwood J-X Cheng and P S Low ldquoA functional folate receptor is inducedduring macrophage activation and can be used to target drugsto activated macrophagesrdquo Blood vol 113 no 2 pp 438ndash4462009
Contrast Media amp Molecular Imaging 21
[164] E P Krenning W A P Breeman P P M Kooij et alldquoLocalisation of endocrine-related tumours with radioiodi-nated analogue of somatostatinrdquoThe Lancet vol 1 no 8632 pp242ndash244 1989
[165] E P Krenning D J KwekkeboomWH Bakker et al ldquoSomato-statin receptor scintigraphy with [111In-DTPA-d-Phe1]- and[123I-Tyr3]-octreotide the Rotterdam experience with morethan 1000 patientsrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 20 no 8 pp 716ndash731 1993
[166] A Stahl G Meisetschlager M Schottelius et al ldquo[123I]Mtr-TOCA a radioiodinated and carbohydrated analogue ofoctreotide Scintigraphic comparison with [111In]octreotiderdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 33 no 1 pp 45ndash52 2006
[167] R Lebtahi J le Cloirec C Houzard et al ldquoDetection of neu-roendocrine tumors 99mTc-P829 scintigraphy compared with111In-pentetreotide scintigraphyrdquo Journal of Nuclear Medicinevol 43 no 7 pp 889ndash895 2002
[168] C Decristoforo T Maina B Nock M Gabriel P Cordopatisand R Moncayo ldquo99mTc-demotate 1 First data in tumourpatients - Results of a pilotphase I studyrdquo European Journal ofNuclearMedicine andMolecular Imaging vol 30 no 9 pp 1211ndash1219 2003
[169] C Decristoforo S J Mather W Cholewinski E DonnemillerG Riccabona and R Moncayo ldquo(99m)Tc-EDDAHYNIC-TOC A new (99m)Tc-labelled radiopharmaceutical forimaging somatostatin receptor-positive tumours First clinicalresults and intra-patient comparison with 111In-labelledoctreotide derivativesrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 27 no 9 pp 1318ndash1325 2000
[170] A Hubalewska-Dydejczyk K Fross-Baron R Mikołajczak etal ldquo99mTc-EDDAHYNIC-octreotate scintigraphy an efficientmethod for the detection and staging of carcinoid tumoursResults of 3 yearsrsquo experiencerdquo European Journal of NuclearMedicine and Molecular Imaging vol 33 no 10 pp 1123ndash11332006
[171] M Bangard M Behe S Guhlke et al ldquoDetection of somato-statin receptor-positive tumours using the new 99mC-tricine-HYNIC-D-Phe1-Tyr3-octreotide First results in patients andcomparison with 111In-DTPA-D-Phe1-octreotiderdquo EuropeanJournal of Nuclear Medicine and Molecular Imaging vol 27 no6 pp 628ndash637 2000
[172] A Helisch G J Forster H Reber et al ldquoPre-therapeuticdosimetry and biodistribution of 86Y-DOTA- Phe1-Tyr3-octreotide versus 111In-pentetreotide in patients with advancedneuroendocrine tumoursrdquo European Journal of NuclearMedicine and Molecular Imaging vol 31 no 10 pp 1386ndash13922004
[173] M Henze J Schuhmacher P Hipp et al ldquoPET imaging ofsomatostatin receptors using [68GA]DOTA-D-Phe1-Tyr3-Octreotide First results in patients with meningiomasrdquo Journalof Nuclear Medicine vol 42 no 7 pp 1053ndash1056 2001
[174] I Kayani J B Bomanji A Groves et al ldquoFunctional imaging ofneuroendocrine tumors with combined PETCT using 68Ga-DOTATATE (Dota-DPhe1 Tyr3-octreotate) and 18F-FDGrdquoCancer vol 112 no 11 pp 2447ndash2455 2008
[175] A Al-Nahhas ldquoNuclear medicine imaging of neuroendocrinetumoursrdquo Clinical Medicine vol 12 no 4 pp 377ndash380 2012
[176] V Ambrosini S Nicolini P Caroli et al ldquoPETCT imaging indifferent types of lung cancer an overviewrdquo European Journal ofRadiology vol 81 no 5 pp 988ndash1001 2012
[177] V Ambrosini D Campana P Tomassetti and S Fanti ldquo68Ga-labelled peptides for diagnosis of gastroenteropancreatic NETrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 39 no 1 pp S52ndashS60 2012
[178] K E Oberg J-C Reubi D J Kwekkeboom and E P KrenningldquoRole of somatostatins in gastroenteropancreatic neuroen-docrine tumor development and therapyrdquoGastroenterology vol139 no 3 pp 753-753 2010
[179] K Oberg ldquoGallium-68 somatostatin receptor PETCT Is ittime to replace 111Indium DTPA octreotide for patients withneuroendocrine tumorsrdquo Endocrine Journal vol 42 no 1 pp3-4 2012
[180] R Srirajaskanthan I Kayani A M Quigley J Soh M ECaplin and J Bomanji ldquoThe role of 68Ga-DOTATATE PET inpatients with neuroendocrine tumors and negative or equivocalfindings on 111In-DTPA-octreotide scintigraphyrdquo Journal ofNuclear Medicine vol 51 no 6 pp 875ndash882 2010
[181] A Kroiss D Putzer and C Uprimny ldquoFunctional imag-ing in phaeochromocytoma and neuroblastoma with 68Ga-DOTA-Tyr3-octreotide positron emission tomography and123I-metaiodobenzylguanidinerdquo European Journal of NuclearMedicine and Molecular Imaging vol 38 no 5 pp 865ndash8732011
[182] M Naji C Zhao S J Welsh et al ldquo68Ga-DOTA-TATE PETvs 123I-MIBG in identifying malignant neural crest tumoursrdquoMolecular Imaging and Biology vol 13 no 4 pp 769ndash775 2011
[183] V Ambrosini P Tomassetti P Castellucci et al ldquoComparisonbetween 68Ga-DOTA-NOC and 18F-DOPA PET for the detec-tion of gastro-entero-pancreatic and lung neuro-endocrinetumoursrdquo European Journal of Nuclear Medicine and MolecularImaging vol 35 no 8 pp 1431ndash1438 2008
[184] D Putzer M Gabriel B Henninger et al ldquoBone metastasesin patients with neuroendocrine tumor 68Ga- DOTA-Tyr3-octreotide PET in comparison to CT and bone scintigraphyrdquoJournal of Nuclear Medicine vol 50 no 8 pp 1214ndash1221 2009
[185] L K Anzola-Fuentes M Chianelli F Galli et al ldquoSomatostatinreceptor scintigraphy in patients with rheumatoid arthritis andsecondary Sjogrenrsquos syndrome treated with Infliximab a pilotstudyrdquo EJNMMI Research vol 6 no 1 article no 49 2016
[186] T Nobashi Y Nakamoto T Kubo et al ldquoThe utility of PETCTwith 68Ga-DOTATOC in sarcoidosis comparison with 67Ga-scintigraphyrdquoAnnals ofNuclearMedicine vol 30 no 8 pp 544ndash552 2016
[187] C Boy T A Heusner T D Poeppel et al ldquo68Ga-DOTATOCPETCT and somatostatin receptor (sst1-sst5) expression innormal human tissue Correlation of sst2mRNAand SUVmaxrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 38 no 7 pp 1224ndash1236 2011
[188] P Rinne S Hellberg M Kiugel et al ldquoComparison of Somato-statin Receptor 2-Targeting PET Tracers in the Detection ofMouse Atherosclerotic Plaquesrdquo Molecular Imaging and Biol-ogy vol 18 no 1 pp 99ndash108 2016
[189] M Asti E Ferrari S Croci et al ldquoSynthesis and characteri-zation of 68Ga-labeled curcumin and curcuminoid complexesas potential radiotracers for imaging of cancer and alzheimersdiseaserdquo Inorganic Chemistry vol 53 no 10 pp 4922ndash49332014
[190] A Signore I Santino and A W J M Glaudemans ldquoIn vivoimaging of microorganismsrdquo Clinical and Translational Imag-ing vol 4 no 3 pp 161-162 2016
[191] S Auletta F Galli C Lauri D Martinelli I Santino andA Signore ldquoImaging bacteria with radiolabelled quinolones
22 Contrast Media amp Molecular Imaging
cephalosporins and siderophores for imaging infection a sys-tematic reviewrdquo Clinical and Translational Imaging vol 4 no 4pp 229ndash252 2016
[192] X Ning S Lee Z Wang et al ldquoMaltodextrin-based imagingprobes detect bacteria in vivo with high sensitivity and speci-ficityrdquo Nature Materials vol 10 no 8 pp 602ndash607 2011
[193] J Ady andY Fong ldquoImaging for infection Fromvisualization ofinflammation to visualization of microbesrdquo Surgical Infectionsvol 15 no 6 pp 700ndash707 2014
[194] J M Sierra D Rodriguez-Puig A Soriano J Mensa C Pieraand J Vila ldquoAccumulation of 99mTc-ciprofloxacin in Staphy-lococcus aureus and Pseudomonas aeruginosardquo AntimicrobialAgents and Chemotherapy vol 52 no 7 pp 2691-2692 2008
[195] D I Andersson and D Hughes ldquoMicrobiological effects ofsublethal levels of antibioticsrdquoNature ReviewsMicrobiology vol12 no 7 pp 465ndash478 2014
[196] N Dumarey D Blocklet T Appelboom L Tant and ASchoutens ldquoInfecton is not specific for bacterial osteo-articularinfective pathologyrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 29 no 4 pp 530ndash535 2002
[197] K E Britton D W Wareham S S Das et al ldquoImaging bacte-rial infection with 99mTc-ciprofloxacin (Infecton)rdquo Journal ofClinical Pathology vol 55 no 11 pp 817ndash823 2002
[198] G Ferro-Flores M A Avila-Rodrıguez and F O Garcıa-PerezldquoImaging of bacteria with radiolabeled ubiquicidin by SPECTand PET techniquesrdquo Clinical and Translational Imaging vol 4no 3 pp 175ndash182 2016
[199] P S Hiemstra M T van den Barselaar M Roest P H Nibber-ing and R van Furth ldquoUbiquicidin a novel murine microbi-cidal protein present in the cytosolic fraction of macrophagesrdquoJournal of Leukocyte Biology vol 66 no 3 pp 423ndash428 1999
[200] M S Akhtar A Qaisar J Irfanullah et al ldquoAntimicrobialpeptide 99mTc-ubiquicidin 29ndash41 as human infection-imagingagent clinical trialrdquo Journal of Nuclear Medicne vol 46 no 4pp 567ndash573 2005
[201] M Assadi K Vahdat I Nabipour et al ldquoDiagnostic value of99mTc-ubiquicidin scintigraphy for osteomyelitis and compar-isons with 99mTc-methylene diphosphonate scintigraphy andmagnetic resonance imagingrdquo Nuclear Medicine Communica-tions vol 32 no 8 pp 716ndash723 2011
[202] T Emery ldquoExchange of Iron by Gallium in SiderophoresrdquoBiochemistry vol 25 no 16 pp 4629ndash4633 1986
[203] M Petrik C Zhai H Haas and C Decristoforo ldquoSiderophoresfor molecular imaging applicationsrdquo Clinical and TranslationalImaging vol 5 no 1 pp 15ndash27 2017
[204] H J Flint E A BayerM T Rincon R Lamed and B AWhiteldquoPolysaccharide utilization by gut bacteria potential for newinsights from genomic analysisrdquo Nature Reviews Microbiologyvol 6 no 2 pp 121ndash131 2008
[205] GGowrishankarMNamavari E B Jouannot et al ldquoInvestiga-tion of 6-[18F]-fluoromaltose as a novel PET tracer for imagingbacterial infectionrdquo PLoS ONE vol 9 no 9 Article ID e1079512014
[206] N Gholipour M Akhlaghi A M Kheirabadi et al ldquoChelator-free radiolabeling of dextran with 68Ga for PET studiesrdquoJournal of Radioanalytical and Nuclear Chemistry vol 311 no3 pp 1811ndash1817 2017
[207] C Bettegowda C A Foss I Cheong et al ldquoImaging bac-terial infections with radiolabeled 1-(21015840-deoxy-21015840- fluoro-120573-D-arabinofuranosyl)-5-iodouracilrdquo Proceedings of the NationalAcadamy of Sciences of the United States of America vol 102 no4 pp 1145ndash1150 2005
[208] S A Soghomonyan M Doubrovin J Pike et al ldquoPositronemission tomography (PET) imaging of tumor-localizedSalmonella expressing HSV1-TKrdquo Cancer GeneTherapy vol 12no 1 pp 101ndash108 2005
[209] C Palestro K Nichols S Sheikh-Fayyaz S Dewey P Singhaland K Bhargava ldquoCan Gallium-68 PET differentiate acuteinterstitial nephritis from acute tubular necrosisrdquo Journal ofNuclear Medicne vol 57 Supplement 2 p 551 2016
[210] A J Morguet D L Munz V Ivancevic et al ldquoImmunoscintig-raphy using technetium-99m-labeled anti-NCA-95 antigranu-locyte antibodies as an adjunct to echocardiography in subacuteinfective endocarditisrdquo Journal of the American College ofCardiology vol 23 no 5 pp 1171ndash1178 1994
[211] C van der Laken O Boerman W Oyen et al ldquoIn Vivo Expres-sion of Interleukin-1 Receptors during Various ExperimentallyInduced Inflammatory Conditionsrdquo The Journal of InfectiousDiseases vol 177 no 5 pp 1398ndash1401 1998
[212] C J Van Der Laken O C Boerman W J G Oyen M T PVan De Ven J W M Van Der Meer and F H M CorstensldquoScintigraphic detection of infection and inflammation Newdevelopments with special emphasis on receptor interactionrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 25 no 5 pp 535ndash546 1998
[213] C J van der LakenOC BoermanW J GOyenM T P van deVen J W M van der Meer and F H M Corstens ldquoImaging ofinfection in rabbits with radioiodinated interleukin-1 (120572 and 120573)its receptor antagonist and a chemotactic peptide a comparativestudyrdquo European Journal of Nuclear Medicine and MolecularImaging vol 25 no 4 pp 347ndash352 1998
[214] C J Van Der Laken O C BoermanW J G Oyen M T P VanDe Ven F H M Corstens and J W M Ven Der Meer ldquoThekinetics of radiolabelled interleukin-8 in infection and sterileinflammationrdquo Nuclear Medicine Communications vol 19 no3 pp 271ndash282 1998
[215] E Lazzeri P Erba M Perri et al ldquoScintigraphic imaging ofvertebral osteomyelitis with 111in-biotinrdquoThe Spine Journal vol33 no 7 pp E198ndashE204 2008
[216] E Blom B Langstrom and I Velikyan ldquo68Ga-labeling of biotinanalogues and their characterizationrdquo Bioconjugate Chemistryvol 20 no 6 pp 1146ndash1151 2009
[217] O Eriksson F Carlsson E Blom et al ldquoPreclinical evaluationof a 68Ga-labeled biotin analogue for applications in islettransplantationrdquo Nuclear Medicine and Biology vol 39 no 3pp 415ndash421 2012
[218] E A Weinstein A A Ordonez V P DeMarco et alldquoImaging Enterobacteriaceae infection in vivo with 18F-fluoro-deoxysorbitol positron emission tomographyrdquo Science Transla-tional Medicine vol 6 no 259 p 259ra146 2014
[219] K M Nielsen M H Kyneb A K O Alstrup et alldquo68Ga-labeled phage-display selected peptides as tracers forpositron emission tomography imaging of Staphylococcusaureus biofilm-associated infections Selection radiolabellingand preliminary biological evaluationrdquo Nuclear Medicine andBiology vol 43 no 10 pp 593ndash605 2016
[220] T J Makinen P Lankinen T Poyhonen J Jalava H T Aroand A Roivainen ldquoComparison of 18F-FDG and 68Ga PETimaging in the assessment of experimental osteomyelitis due toStaphylococcus aureusrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 32 no 11 pp 1259ndash1268 2005
[221] JMU Silvola I LaitinenH J Sipila et al ldquoUptake of 68galliumin atherosclerotic plaques in LDLRminusminusApoB100100micerdquo EJN-MMI Research vol 1 no 1 pp 1ndash8 2011
Contrast Media amp Molecular Imaging 23
[222] T A Wynn ldquoCellular and molecular mechanisms of fibrosisrdquoThe Journal of Pathology vol 214 no 2 pp 199ndash210 2008
[223] T Derlin D Jonigk J Bauersachs and FM Bengel ldquoMolecularImaging of Chemokine Receptor CXCR4 in NonndashSmall CellLung Cancer Using 68Ga-Pentixafor PETCT ComparisonWith 18F-FDGrdquo Clinical Nuclear Medicine 2016
[224] I Velikyan U Rosenstrom T N Bulenga O Eriksson andG Antoni ldquoFeasibility of multiple examinations using68ga-labelled collagelin analogues Organ distribution in rat forextrapolation to human organ and whole-body radiationdosimetryrdquo Pharmaceuticals vol 9 no 2 article no 31 2016
[225] S Jadhav M Kakela J Makila et al ldquoSynthesis and in VivoPET Imaging of Hyaluronan Conjugates of OligonucleotidesrdquoBioconjugate Chemistry vol 27 no 2 pp 391ndash403 2016
[226] A Autio A Saraste N Kudomi et al ldquoAssessment of bloodflow with (68) Ga-DOTA PET in experimental inflammation avalidation study using (15) O-waterrdquo American Journal ofNuclear Medicine and Molecular Imaging vol 4 no 6 pp 571ndash579 2014
[227] G Davies A Rolle A Maurer et al ldquoTowards translationalimmunoPETMR imaging of invasive pulmonary aspergillosisthe Humanised Monoclonal Antibody JF5 detects in vivordquoTheranostics vol 7 no 14 pp 3398ndash3414 2017
[228] DGoodwin CMeares GDavid et al ldquoMonoclonal antibodiesas reversible equilibrium carriers of radiopharmaceuticalsrdquoInternational Journal of Radiation Applications and Instrumen-tation Part B Nuclear Medicine and Biology vol 13 no 4 pp383ndash391 1986
[229] D A Goodwin C F Mears M McTigue and G S DavidldquoMonoclonal antibody hapten radiopharmaceutical deliveryrdquoNuclear Medicine Communications vol 7 no 8 pp 569ndash5801986
[230] S E Halpern and R O Dillman ldquoProblems associated withradioimmunodetection and possibilities for future solutionsrdquo JBiol Response Mod vol 6 no 3 pp 235ndash262 1987
[231] H Hong J Sun and W Cai ldquoRadionuclide-based cancerimaging targeting the carcinoembryonic antigenrdquo BiomarkerInsights vol 3 pp 435ndash451 2008
[232] G J Forster E B Santos P M Smith-Jones P Zanzonico andS M Larson ldquoPretargeted radioimmunotherapy with a single-chain antibodystreptavidin construct and radiolabeledDOTA-biotin Strategies for reduction of the renal doserdquo Journal ofNuclear Medicine vol 47 no 1 pp 140ndash149 2006
[233] Z Yao M Zhang H Kobayashi et al ldquoImproved targeting ofradiolabeled streptavidin in tumors pretargeted with biotiny-lated monoclonal antibodies through an avidin chaserdquo Journalof Nuclear Medicine vol 36 no 5 pp 837ndash841 1995
[234] C-H Chang R M Sharkey E A Rossi et al ldquoMolecularAdvances in Pretargeting Radioimunotherapy with BispecificAntibodies 1 Supported in part by USPHS Grant R01-CA-84379from the NIH and Department of Energy Grant DE-FG01-00NE22941 (both to R M S)1rdquo Mol Cancer Ther vol 1 no 7pp 553ndash563 2002
[235] R M Sharkey E A Rossi W J McBride C-H Chang andD M Goldenberg ldquoRecombinant Bispecific Monoclonal Anti-bodies Prepared by theDock-and-Lock Strategy for PretargetedRadioimmunotherapyrdquo Seminars in Nuclear Medicine vol 40no 3 pp 190ndash203 2010
[236] R M Sharkey E A Rossi C-H Chang and D M Golden-berg ldquoImproved cancer therapy and molecular imaging withmultivalent multispecific antibodiesrdquo Cancer Biotherapy andRadiopharmaceuticals vol 25 no 1 pp 1ndash12 2010
[237] D M Goldenberg R M Sharkey G Paganelli J Barbet andJ Chatal ldquoAntibody pretargeting advances cancer radioim-munodetection and radioimmunotherapyrdquo Journal of ClinicalOncology vol 24 no 5 pp 823ndash834 2006
[238] O C Boerman F G van Schaijk W J G Oyen and FH M Corstens ldquoPretargeted radioimmunotherapy of cancerprogress step by steprdquo Journal of Nuclear Medicine vol 44 no3 pp 400ndash411 2003
[239] J Schuhmacher S Kaul G Klivenyi et al ldquoImmunoscintigra-phy with positron emission tomography Gallium-68 chelateimaging of breast cancer pretargeted with bispecific anti-MUC1anti-Ga chelate antibodiesrdquo Cancer Research vol 61 no9 pp 3712ndash3717 2001
[240] J Schuhmacher G Klivenyi S Kaul et al ldquoPretargeting ofhuman mammary carcinoma xenografts with bispecific anti-MUC1anti-Ga chelate antibodies and immunoscintigraphywith PETrdquo Nuclear Medicine and Biology vol 28 no 7 pp 821ndash828 2001
[241] C Somasundaram S Matzku J Schuhmacher and M ZollerldquoDevelopment of a bispecific monoclonal antibody against agallium-67 chelate and the human melanoma-associated anti-gen p97 for potential use in pretargeted immunoscintigraphyrdquoCancer Immunology Immunotherapy vol 36 no 5 pp 337ndash3451993
[242] E A Rossi D L Rossi R Stein D M Goldenberg and C-H Chang ldquoA bispecific antibody-IFN1205722b immunocytokine tar-geting CD20 and HLA-DR is highly toxic to human lymphomaandmultiplemyeloma cellsrdquoCancer Research vol 70 no 19 pp7600ndash7609 2010
[243] R M Sharkey H Karacay S Litwin et al ldquoImproved ther-apeutic results by pretargeted radioimmunotherapy of non-Hodgkinrsquos lymphoma with a new recombinant trivalent anti-CD20 bispecific antibodyrdquo Cancer Research vol 68 no 13 pp5282ndash5290 2008
[244] G L Griffiths C-H Chang W J McBride et al ldquoReagentsandmethods for PETusing bispecific antibody pretargeting and68Ga-radiolabeled bivalent hapten-peptide-chelate conjugatesrdquoJournal of Nuclear Medicine vol 45 no 1 pp 30ndash39 2004
[245] J Watine M Miedouge and B Friedberg ldquoCarcinoembryonicantigen as an independent prognostic factor of recurrence andsurvival in patients resected for colorectal liver metastases Asystematic reviewrdquo Diseases of the Colon amp Rectum vol 44 no12 pp 1791ndash1799 2001
[246] M J Goldstein and E P Mitchell ldquoCarcinoembryonic antigenin the staging and follow-up of patients with colorectal cancerrdquoCancer Investigation vol 23 no 4 pp 338ndash351 2005
[247] D V Gold D M Goldenberg H Karacay et al ldquoA novelbispecific trivalent antibody construct for targeting pancreaticcarcinomardquo Cancer Research vol 68 no 12 pp 4819ndash48262008
[248] J Schuhmacher G Klivenyi R Matys et al ldquoMultistep tumortargeting in nudemice using bispecific antibodies and a galliumchelate suitable for immunoscintigraphy with positron emis-sion tomographyrdquo Cancer Research vol 55 no 1 pp 115ndash1231995
[249] G Klivenyi J Schuhmacher E Patzelt et al ldquoGallium-68chelate imaging of human colon carcinoma xenografts pre-targeted with bispecific anti-CD44(V6)anti-gallium chelateantibodiesrdquo Journal ofNuclearMedicine vol 39 no 10 pp 1769ndash1776 1998
[250] M Zoller J Schuhmacher J Reed W Maier-Borst and SMatzku ldquoEstablishment and characterization of monoclonal
24 Contrast Media amp Molecular Imaging
antibodies against an octahedral gallium chelate suitable forimmunoscintigraphy with PETrdquo Journal of Nuclear Medicinevol 33 no 7 pp 1366ndash1372 1992
[251] R M Sharkey T M Cardillo E A Rossi et al ldquoSignal ampli-fication in molecular imaging by pretargeting a multivalentbispecific antibodyrdquo Nature Medicine vol 11 no 11 pp 1250ndash1255 2005
[252] D M Goldenberg and R M Sharkey ldquoNovel radiolabeledantibody conjugatesrdquo Oncogene vol 26 no 25 pp 3734ndash37442007
[253] D M Goldenberg E A Rossi R M Sharkey W J McBrideand C-H Chang ldquoMultifunctional antibodies by the dock-and-lock method for improved cancer imaging and therapy bypretargetingrdquo Journal of NuclearMedicine vol 49 no 1 pp 158ndash163 2008
[254] R Schoffelen R M Sharkey D M Goldenberg et al ldquoPre-targeted immuno-positron emission tomography imaging ofcarcinoembryonic antigen-expressing tumors with a bispecificantibody and a68Ga- And18F-labeled hapten peptide in micewith human tumor xenograftsrdquoMolecular Cancer Therapeuticsvol 9 no 4 pp 1019ndash1027 2010
[255] E S Bos W H Kuijpers M Meesters-Winters et al ldquoIn vitroevaluation of DNA-DNA hybridization as a two-step approachin radioimmunotherapy of cancerrdquoCancer Research vol 54 no13 pp 3479ndash3486 1994
[256] G Paganelli M Bartolomei M Ferrari et al ldquoPre-TargetedLocoregional Radioimmunotherapy withrdquo Cancer biotherapyand radiopharmaceuticals vol 16 no 3 pp 227ndash235 2001
[257] A Forero P L Weiden J M Vose et al ldquoPhase 1 trial of a novelanti-CD20 fusion protein in pretargeted radioimmunotherapyfor B-cell non-Hodgkin lymphomardquo Blood vol 104 no 1 pp227ndash236 2004
[258] DM Goldenberg C-H Chang E A RossiW J McBride andR M Sharkey ldquoPretargeted molecular imaging and radioim-munotherapyrdquoTheranostics vol 2 no 5 pp 523ndash540 2012
[259] H Karacay R M Sharkey W J McBride E A Rossi C-HChang and D M Goldenberg ldquoOptimization of hapten-peptide labeling for pretargeted immunoPET of bispecificantibody using generator-produced 68Gardquo Journal of NuclearMedicine vol 52 no 4 pp 555ndash559 2011
[260] J R Oh and B C Ahn ldquoFalse-positive uptake on radioiodinewhole-body scintigraphy physiologic and pathologic variantsunrelated to thyroid cancerrdquo American Journal of NuclearMedicine and Molecular Imaging vol 2 no 2 pp 141ndash150 2012
[261] E Frampas C Rousseau C Bodet-Milin J Barbet J-F Chataland F Kraeber-Bodere ldquoImprovement of radioimmunotherapyusing pretargetingrdquo Frontiers in Oncology vol 3 Article ID00159 2013
[262] C S McKay and M G Finn ldquoClick chemistry in complexmixtures Bioorthogonal bioconjugationrdquo Chemistry amp Biologyvol 21 no 9 pp 1075ndash1101 2014
[263] B L Oliveira Z Guo and G J Bernardes ldquoInverse electrondemand DielsndashAlder reactions in chemical biologyrdquo ChemicalSociety Reviews vol 46 no 16 pp 4895ndash4950 2017
[264] B Nichols Z Qin J Yang D R Vera and N K Devaraj ldquo68Gachelating bioorthogonal tetrazine polymers for the multisteplabeling of cancer biomarkersrdquo Chemical Communications vol50 no 40 pp 5215ndash5217 2014
[265] R Rossin P R Verkerk S M van den Bosch et al ldquoInvivo chemistry for pretargeted tumor imaging in live micerdquoAngewandte Chemie International Edition vol 49 no 19 pp3375ndash3378 2010
[266] B M Zeglis K K Sevak T Reiner et al ldquoA pretargetedPET imaging strategy based on bioorthogonal diels-alder clickchemistryrdquo Journal of Nuclear Medicine vol 54 no 8 pp 1389ndash1396 2013
[267] J L Houghton R Membreno D Abdel-Atti et al ldquoEstablish-ment of the invivo efficacy of pretargeted radioimmunotherapyutilizing inverse electron demand diels-alder click chemistryrdquoMolecular Cancer Therapeutics vol 16 no 1 pp 124ndash133 2017
[268] J Funkhouser ldquoReinventing pharma the theranostic revolu-tionrdquo Current Drug Discovery pp 17ndash19 2002
[269] J Sorensen I Velikyan A Wennborg et al ldquoMeasuring HER2-expression in metastatic breast cancer using 68Ga-ABY025PETCTrdquo European Journal of Nuclear Medicine and MolecularImaging vol 41 pp S226ndashS226 2014
[270] I Velikyan A Wennborg J Feldwisch et al ldquoGMP compliantpreparation of a 68Gallium-labeled Affibody analogue forbreast cancer patient examination first-in-manrdquoEur JNuclMedMol Imaging vol 41 pp S228ndashS229 2014
[271] K Oberg ldquoMolecular imaging radiotherapy Theranostics forpersonalized patient management of neuroendocrine tumors(NETs)rdquoTheranostics vol 2 no 5 pp 448ndash458 2012
[272] I Velikyan AWennborg J FeldwischH Lindman J Carlssonand J Sorensen ldquoGood manufacturing practice production of [(68) Ga]Ga-ABY-025 for HER2 specific breast cancer imagingrdquoAmerican Journal of Nuclear Medicine and Molecular Imagingvol 6 no 2 pp 135ndash153 2016
[273] M Sandstrom K Lindskog I Velikyan et al ldquoBiodistributionand radiation dosimetry of the anti-HER2 Affibody molecule68Ga-ABY-025 in breast cancer patientsrdquo Journal of NuclearMedicine vol 57 no 6 pp 867ndash871 2016
[274] D Sandberg V Tolmachev I Velikyan et al ldquoIntra-imagereferencing for simplified assessment of HER2-expression inbreast cancer metastases using the Affibody molecule ABY-025with PET and SPECTrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 44 no 8 pp 1337ndash1346 2017
[275] H ZhangM AMoroz I Serganova et al ldquoImaging expressionof the human somatostatin receptor subtype-2 reporter genewith 68Ga-DOTATOCrdquo Journal ofNuclearMedicine vol 52 no1 pp 123ndash131 2011
[276] M Naji and A Al-Nahhas ldquo68Ga-labelled peptides in themanagement of neuroectodermal tumoursrdquo European Journalof Nuclear Medicine and Molecular Imaging vol 39 no 1 ppS61ndashS67 2012
[277] I Velikyan ldquoThe diversity of 68Ga-Based imaging agentsrdquoRecent Results in Cancer Research vol 194 pp 101ndash131 2013
[278] K Ferreira H-Y Hu V Fetz et al ldquoMultivalent siderophore-dotam conjugates as theranostics for imaging and treatment ofbacterial infectionsrdquo Angewandte Chemie International Editionvol 56 no 28 pp 8272ndash8276 2017
Computational and Mathematical Methods in Medicine
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Research and TreatmentAIDS
Hindawiwwwhindawicom Volume 2018
Gastroenterology Research and Practice
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Parkinsonrsquos Disease
Evidence-Based Complementary andAlternative Medicine
Volume 2018Hindawiwwwhindawicom
Submit your manuscripts atwwwhindawicom
Contrast Media amp Molecular Imaging 21
[164] E P Krenning W A P Breeman P P M Kooij et alldquoLocalisation of endocrine-related tumours with radioiodi-nated analogue of somatostatinrdquoThe Lancet vol 1 no 8632 pp242ndash244 1989
[165] E P Krenning D J KwekkeboomWH Bakker et al ldquoSomato-statin receptor scintigraphy with [111In-DTPA-d-Phe1]- and[123I-Tyr3]-octreotide the Rotterdam experience with morethan 1000 patientsrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 20 no 8 pp 716ndash731 1993
[166] A Stahl G Meisetschlager M Schottelius et al ldquo[123I]Mtr-TOCA a radioiodinated and carbohydrated analogue ofoctreotide Scintigraphic comparison with [111In]octreotiderdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 33 no 1 pp 45ndash52 2006
[167] R Lebtahi J le Cloirec C Houzard et al ldquoDetection of neu-roendocrine tumors 99mTc-P829 scintigraphy compared with111In-pentetreotide scintigraphyrdquo Journal of Nuclear Medicinevol 43 no 7 pp 889ndash895 2002
[168] C Decristoforo T Maina B Nock M Gabriel P Cordopatisand R Moncayo ldquo99mTc-demotate 1 First data in tumourpatients - Results of a pilotphase I studyrdquo European Journal ofNuclearMedicine andMolecular Imaging vol 30 no 9 pp 1211ndash1219 2003
[169] C Decristoforo S J Mather W Cholewinski E DonnemillerG Riccabona and R Moncayo ldquo(99m)Tc-EDDAHYNIC-TOC A new (99m)Tc-labelled radiopharmaceutical forimaging somatostatin receptor-positive tumours First clinicalresults and intra-patient comparison with 111In-labelledoctreotide derivativesrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 27 no 9 pp 1318ndash1325 2000
[170] A Hubalewska-Dydejczyk K Fross-Baron R Mikołajczak etal ldquo99mTc-EDDAHYNIC-octreotate scintigraphy an efficientmethod for the detection and staging of carcinoid tumoursResults of 3 yearsrsquo experiencerdquo European Journal of NuclearMedicine and Molecular Imaging vol 33 no 10 pp 1123ndash11332006
[171] M Bangard M Behe S Guhlke et al ldquoDetection of somato-statin receptor-positive tumours using the new 99mC-tricine-HYNIC-D-Phe1-Tyr3-octreotide First results in patients andcomparison with 111In-DTPA-D-Phe1-octreotiderdquo EuropeanJournal of Nuclear Medicine and Molecular Imaging vol 27 no6 pp 628ndash637 2000
[172] A Helisch G J Forster H Reber et al ldquoPre-therapeuticdosimetry and biodistribution of 86Y-DOTA- Phe1-Tyr3-octreotide versus 111In-pentetreotide in patients with advancedneuroendocrine tumoursrdquo European Journal of NuclearMedicine and Molecular Imaging vol 31 no 10 pp 1386ndash13922004
[173] M Henze J Schuhmacher P Hipp et al ldquoPET imaging ofsomatostatin receptors using [68GA]DOTA-D-Phe1-Tyr3-Octreotide First results in patients with meningiomasrdquo Journalof Nuclear Medicine vol 42 no 7 pp 1053ndash1056 2001
[174] I Kayani J B Bomanji A Groves et al ldquoFunctional imaging ofneuroendocrine tumors with combined PETCT using 68Ga-DOTATATE (Dota-DPhe1 Tyr3-octreotate) and 18F-FDGrdquoCancer vol 112 no 11 pp 2447ndash2455 2008
[175] A Al-Nahhas ldquoNuclear medicine imaging of neuroendocrinetumoursrdquo Clinical Medicine vol 12 no 4 pp 377ndash380 2012
[176] V Ambrosini S Nicolini P Caroli et al ldquoPETCT imaging indifferent types of lung cancer an overviewrdquo European Journal ofRadiology vol 81 no 5 pp 988ndash1001 2012
[177] V Ambrosini D Campana P Tomassetti and S Fanti ldquo68Ga-labelled peptides for diagnosis of gastroenteropancreatic NETrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 39 no 1 pp S52ndashS60 2012
[178] K E Oberg J-C Reubi D J Kwekkeboom and E P KrenningldquoRole of somatostatins in gastroenteropancreatic neuroen-docrine tumor development and therapyrdquoGastroenterology vol139 no 3 pp 753-753 2010
[179] K Oberg ldquoGallium-68 somatostatin receptor PETCT Is ittime to replace 111Indium DTPA octreotide for patients withneuroendocrine tumorsrdquo Endocrine Journal vol 42 no 1 pp3-4 2012
[180] R Srirajaskanthan I Kayani A M Quigley J Soh M ECaplin and J Bomanji ldquoThe role of 68Ga-DOTATATE PET inpatients with neuroendocrine tumors and negative or equivocalfindings on 111In-DTPA-octreotide scintigraphyrdquo Journal ofNuclear Medicine vol 51 no 6 pp 875ndash882 2010
[181] A Kroiss D Putzer and C Uprimny ldquoFunctional imag-ing in phaeochromocytoma and neuroblastoma with 68Ga-DOTA-Tyr3-octreotide positron emission tomography and123I-metaiodobenzylguanidinerdquo European Journal of NuclearMedicine and Molecular Imaging vol 38 no 5 pp 865ndash8732011
[182] M Naji C Zhao S J Welsh et al ldquo68Ga-DOTA-TATE PETvs 123I-MIBG in identifying malignant neural crest tumoursrdquoMolecular Imaging and Biology vol 13 no 4 pp 769ndash775 2011
[183] V Ambrosini P Tomassetti P Castellucci et al ldquoComparisonbetween 68Ga-DOTA-NOC and 18F-DOPA PET for the detec-tion of gastro-entero-pancreatic and lung neuro-endocrinetumoursrdquo European Journal of Nuclear Medicine and MolecularImaging vol 35 no 8 pp 1431ndash1438 2008
[184] D Putzer M Gabriel B Henninger et al ldquoBone metastasesin patients with neuroendocrine tumor 68Ga- DOTA-Tyr3-octreotide PET in comparison to CT and bone scintigraphyrdquoJournal of Nuclear Medicine vol 50 no 8 pp 1214ndash1221 2009
[185] L K Anzola-Fuentes M Chianelli F Galli et al ldquoSomatostatinreceptor scintigraphy in patients with rheumatoid arthritis andsecondary Sjogrenrsquos syndrome treated with Infliximab a pilotstudyrdquo EJNMMI Research vol 6 no 1 article no 49 2016
[186] T Nobashi Y Nakamoto T Kubo et al ldquoThe utility of PETCTwith 68Ga-DOTATOC in sarcoidosis comparison with 67Ga-scintigraphyrdquoAnnals ofNuclearMedicine vol 30 no 8 pp 544ndash552 2016
[187] C Boy T A Heusner T D Poeppel et al ldquo68Ga-DOTATOCPETCT and somatostatin receptor (sst1-sst5) expression innormal human tissue Correlation of sst2mRNAand SUVmaxrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 38 no 7 pp 1224ndash1236 2011
[188] P Rinne S Hellberg M Kiugel et al ldquoComparison of Somato-statin Receptor 2-Targeting PET Tracers in the Detection ofMouse Atherosclerotic Plaquesrdquo Molecular Imaging and Biol-ogy vol 18 no 1 pp 99ndash108 2016
[189] M Asti E Ferrari S Croci et al ldquoSynthesis and characteri-zation of 68Ga-labeled curcumin and curcuminoid complexesas potential radiotracers for imaging of cancer and alzheimersdiseaserdquo Inorganic Chemistry vol 53 no 10 pp 4922ndash49332014
[190] A Signore I Santino and A W J M Glaudemans ldquoIn vivoimaging of microorganismsrdquo Clinical and Translational Imag-ing vol 4 no 3 pp 161-162 2016
[191] S Auletta F Galli C Lauri D Martinelli I Santino andA Signore ldquoImaging bacteria with radiolabelled quinolones
22 Contrast Media amp Molecular Imaging
cephalosporins and siderophores for imaging infection a sys-tematic reviewrdquo Clinical and Translational Imaging vol 4 no 4pp 229ndash252 2016
[192] X Ning S Lee Z Wang et al ldquoMaltodextrin-based imagingprobes detect bacteria in vivo with high sensitivity and speci-ficityrdquo Nature Materials vol 10 no 8 pp 602ndash607 2011
[193] J Ady andY Fong ldquoImaging for infection Fromvisualization ofinflammation to visualization of microbesrdquo Surgical Infectionsvol 15 no 6 pp 700ndash707 2014
[194] J M Sierra D Rodriguez-Puig A Soriano J Mensa C Pieraand J Vila ldquoAccumulation of 99mTc-ciprofloxacin in Staphy-lococcus aureus and Pseudomonas aeruginosardquo AntimicrobialAgents and Chemotherapy vol 52 no 7 pp 2691-2692 2008
[195] D I Andersson and D Hughes ldquoMicrobiological effects ofsublethal levels of antibioticsrdquoNature ReviewsMicrobiology vol12 no 7 pp 465ndash478 2014
[196] N Dumarey D Blocklet T Appelboom L Tant and ASchoutens ldquoInfecton is not specific for bacterial osteo-articularinfective pathologyrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 29 no 4 pp 530ndash535 2002
[197] K E Britton D W Wareham S S Das et al ldquoImaging bacte-rial infection with 99mTc-ciprofloxacin (Infecton)rdquo Journal ofClinical Pathology vol 55 no 11 pp 817ndash823 2002
[198] G Ferro-Flores M A Avila-Rodrıguez and F O Garcıa-PerezldquoImaging of bacteria with radiolabeled ubiquicidin by SPECTand PET techniquesrdquo Clinical and Translational Imaging vol 4no 3 pp 175ndash182 2016
[199] P S Hiemstra M T van den Barselaar M Roest P H Nibber-ing and R van Furth ldquoUbiquicidin a novel murine microbi-cidal protein present in the cytosolic fraction of macrophagesrdquoJournal of Leukocyte Biology vol 66 no 3 pp 423ndash428 1999
[200] M S Akhtar A Qaisar J Irfanullah et al ldquoAntimicrobialpeptide 99mTc-ubiquicidin 29ndash41 as human infection-imagingagent clinical trialrdquo Journal of Nuclear Medicne vol 46 no 4pp 567ndash573 2005
[201] M Assadi K Vahdat I Nabipour et al ldquoDiagnostic value of99mTc-ubiquicidin scintigraphy for osteomyelitis and compar-isons with 99mTc-methylene diphosphonate scintigraphy andmagnetic resonance imagingrdquo Nuclear Medicine Communica-tions vol 32 no 8 pp 716ndash723 2011
[202] T Emery ldquoExchange of Iron by Gallium in SiderophoresrdquoBiochemistry vol 25 no 16 pp 4629ndash4633 1986
[203] M Petrik C Zhai H Haas and C Decristoforo ldquoSiderophoresfor molecular imaging applicationsrdquo Clinical and TranslationalImaging vol 5 no 1 pp 15ndash27 2017
[204] H J Flint E A BayerM T Rincon R Lamed and B AWhiteldquoPolysaccharide utilization by gut bacteria potential for newinsights from genomic analysisrdquo Nature Reviews Microbiologyvol 6 no 2 pp 121ndash131 2008
[205] GGowrishankarMNamavari E B Jouannot et al ldquoInvestiga-tion of 6-[18F]-fluoromaltose as a novel PET tracer for imagingbacterial infectionrdquo PLoS ONE vol 9 no 9 Article ID e1079512014
[206] N Gholipour M Akhlaghi A M Kheirabadi et al ldquoChelator-free radiolabeling of dextran with 68Ga for PET studiesrdquoJournal of Radioanalytical and Nuclear Chemistry vol 311 no3 pp 1811ndash1817 2017
[207] C Bettegowda C A Foss I Cheong et al ldquoImaging bac-terial infections with radiolabeled 1-(21015840-deoxy-21015840- fluoro-120573-D-arabinofuranosyl)-5-iodouracilrdquo Proceedings of the NationalAcadamy of Sciences of the United States of America vol 102 no4 pp 1145ndash1150 2005
[208] S A Soghomonyan M Doubrovin J Pike et al ldquoPositronemission tomography (PET) imaging of tumor-localizedSalmonella expressing HSV1-TKrdquo Cancer GeneTherapy vol 12no 1 pp 101ndash108 2005
[209] C Palestro K Nichols S Sheikh-Fayyaz S Dewey P Singhaland K Bhargava ldquoCan Gallium-68 PET differentiate acuteinterstitial nephritis from acute tubular necrosisrdquo Journal ofNuclear Medicne vol 57 Supplement 2 p 551 2016
[210] A J Morguet D L Munz V Ivancevic et al ldquoImmunoscintig-raphy using technetium-99m-labeled anti-NCA-95 antigranu-locyte antibodies as an adjunct to echocardiography in subacuteinfective endocarditisrdquo Journal of the American College ofCardiology vol 23 no 5 pp 1171ndash1178 1994
[211] C van der Laken O Boerman W Oyen et al ldquoIn Vivo Expres-sion of Interleukin-1 Receptors during Various ExperimentallyInduced Inflammatory Conditionsrdquo The Journal of InfectiousDiseases vol 177 no 5 pp 1398ndash1401 1998
[212] C J Van Der Laken O C Boerman W J G Oyen M T PVan De Ven J W M Van Der Meer and F H M CorstensldquoScintigraphic detection of infection and inflammation Newdevelopments with special emphasis on receptor interactionrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 25 no 5 pp 535ndash546 1998
[213] C J van der LakenOC BoermanW J GOyenM T P van deVen J W M van der Meer and F H M Corstens ldquoImaging ofinfection in rabbits with radioiodinated interleukin-1 (120572 and 120573)its receptor antagonist and a chemotactic peptide a comparativestudyrdquo European Journal of Nuclear Medicine and MolecularImaging vol 25 no 4 pp 347ndash352 1998
[214] C J Van Der Laken O C BoermanW J G Oyen M T P VanDe Ven F H M Corstens and J W M Ven Der Meer ldquoThekinetics of radiolabelled interleukin-8 in infection and sterileinflammationrdquo Nuclear Medicine Communications vol 19 no3 pp 271ndash282 1998
[215] E Lazzeri P Erba M Perri et al ldquoScintigraphic imaging ofvertebral osteomyelitis with 111in-biotinrdquoThe Spine Journal vol33 no 7 pp E198ndashE204 2008
[216] E Blom B Langstrom and I Velikyan ldquo68Ga-labeling of biotinanalogues and their characterizationrdquo Bioconjugate Chemistryvol 20 no 6 pp 1146ndash1151 2009
[217] O Eriksson F Carlsson E Blom et al ldquoPreclinical evaluationof a 68Ga-labeled biotin analogue for applications in islettransplantationrdquo Nuclear Medicine and Biology vol 39 no 3pp 415ndash421 2012
[218] E A Weinstein A A Ordonez V P DeMarco et alldquoImaging Enterobacteriaceae infection in vivo with 18F-fluoro-deoxysorbitol positron emission tomographyrdquo Science Transla-tional Medicine vol 6 no 259 p 259ra146 2014
[219] K M Nielsen M H Kyneb A K O Alstrup et alldquo68Ga-labeled phage-display selected peptides as tracers forpositron emission tomography imaging of Staphylococcusaureus biofilm-associated infections Selection radiolabellingand preliminary biological evaluationrdquo Nuclear Medicine andBiology vol 43 no 10 pp 593ndash605 2016
[220] T J Makinen P Lankinen T Poyhonen J Jalava H T Aroand A Roivainen ldquoComparison of 18F-FDG and 68Ga PETimaging in the assessment of experimental osteomyelitis due toStaphylococcus aureusrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 32 no 11 pp 1259ndash1268 2005
[221] JMU Silvola I LaitinenH J Sipila et al ldquoUptake of 68galliumin atherosclerotic plaques in LDLRminusminusApoB100100micerdquo EJN-MMI Research vol 1 no 1 pp 1ndash8 2011
Contrast Media amp Molecular Imaging 23
[222] T A Wynn ldquoCellular and molecular mechanisms of fibrosisrdquoThe Journal of Pathology vol 214 no 2 pp 199ndash210 2008
[223] T Derlin D Jonigk J Bauersachs and FM Bengel ldquoMolecularImaging of Chemokine Receptor CXCR4 in NonndashSmall CellLung Cancer Using 68Ga-Pentixafor PETCT ComparisonWith 18F-FDGrdquo Clinical Nuclear Medicine 2016
[224] I Velikyan U Rosenstrom T N Bulenga O Eriksson andG Antoni ldquoFeasibility of multiple examinations using68ga-labelled collagelin analogues Organ distribution in rat forextrapolation to human organ and whole-body radiationdosimetryrdquo Pharmaceuticals vol 9 no 2 article no 31 2016
[225] S Jadhav M Kakela J Makila et al ldquoSynthesis and in VivoPET Imaging of Hyaluronan Conjugates of OligonucleotidesrdquoBioconjugate Chemistry vol 27 no 2 pp 391ndash403 2016
[226] A Autio A Saraste N Kudomi et al ldquoAssessment of bloodflow with (68) Ga-DOTA PET in experimental inflammation avalidation study using (15) O-waterrdquo American Journal ofNuclear Medicine and Molecular Imaging vol 4 no 6 pp 571ndash579 2014
[227] G Davies A Rolle A Maurer et al ldquoTowards translationalimmunoPETMR imaging of invasive pulmonary aspergillosisthe Humanised Monoclonal Antibody JF5 detects in vivordquoTheranostics vol 7 no 14 pp 3398ndash3414 2017
[228] DGoodwin CMeares GDavid et al ldquoMonoclonal antibodiesas reversible equilibrium carriers of radiopharmaceuticalsrdquoInternational Journal of Radiation Applications and Instrumen-tation Part B Nuclear Medicine and Biology vol 13 no 4 pp383ndash391 1986
[229] D A Goodwin C F Mears M McTigue and G S DavidldquoMonoclonal antibody hapten radiopharmaceutical deliveryrdquoNuclear Medicine Communications vol 7 no 8 pp 569ndash5801986
[230] S E Halpern and R O Dillman ldquoProblems associated withradioimmunodetection and possibilities for future solutionsrdquo JBiol Response Mod vol 6 no 3 pp 235ndash262 1987
[231] H Hong J Sun and W Cai ldquoRadionuclide-based cancerimaging targeting the carcinoembryonic antigenrdquo BiomarkerInsights vol 3 pp 435ndash451 2008
[232] G J Forster E B Santos P M Smith-Jones P Zanzonico andS M Larson ldquoPretargeted radioimmunotherapy with a single-chain antibodystreptavidin construct and radiolabeledDOTA-biotin Strategies for reduction of the renal doserdquo Journal ofNuclear Medicine vol 47 no 1 pp 140ndash149 2006
[233] Z Yao M Zhang H Kobayashi et al ldquoImproved targeting ofradiolabeled streptavidin in tumors pretargeted with biotiny-lated monoclonal antibodies through an avidin chaserdquo Journalof Nuclear Medicine vol 36 no 5 pp 837ndash841 1995
[234] C-H Chang R M Sharkey E A Rossi et al ldquoMolecularAdvances in Pretargeting Radioimunotherapy with BispecificAntibodies 1 Supported in part by USPHS Grant R01-CA-84379from the NIH and Department of Energy Grant DE-FG01-00NE22941 (both to R M S)1rdquo Mol Cancer Ther vol 1 no 7pp 553ndash563 2002
[235] R M Sharkey E A Rossi W J McBride C-H Chang andD M Goldenberg ldquoRecombinant Bispecific Monoclonal Anti-bodies Prepared by theDock-and-Lock Strategy for PretargetedRadioimmunotherapyrdquo Seminars in Nuclear Medicine vol 40no 3 pp 190ndash203 2010
[236] R M Sharkey E A Rossi C-H Chang and D M Golden-berg ldquoImproved cancer therapy and molecular imaging withmultivalent multispecific antibodiesrdquo Cancer Biotherapy andRadiopharmaceuticals vol 25 no 1 pp 1ndash12 2010
[237] D M Goldenberg R M Sharkey G Paganelli J Barbet andJ Chatal ldquoAntibody pretargeting advances cancer radioim-munodetection and radioimmunotherapyrdquo Journal of ClinicalOncology vol 24 no 5 pp 823ndash834 2006
[238] O C Boerman F G van Schaijk W J G Oyen and FH M Corstens ldquoPretargeted radioimmunotherapy of cancerprogress step by steprdquo Journal of Nuclear Medicine vol 44 no3 pp 400ndash411 2003
[239] J Schuhmacher S Kaul G Klivenyi et al ldquoImmunoscintigra-phy with positron emission tomography Gallium-68 chelateimaging of breast cancer pretargeted with bispecific anti-MUC1anti-Ga chelate antibodiesrdquo Cancer Research vol 61 no9 pp 3712ndash3717 2001
[240] J Schuhmacher G Klivenyi S Kaul et al ldquoPretargeting ofhuman mammary carcinoma xenografts with bispecific anti-MUC1anti-Ga chelate antibodies and immunoscintigraphywith PETrdquo Nuclear Medicine and Biology vol 28 no 7 pp 821ndash828 2001
[241] C Somasundaram S Matzku J Schuhmacher and M ZollerldquoDevelopment of a bispecific monoclonal antibody against agallium-67 chelate and the human melanoma-associated anti-gen p97 for potential use in pretargeted immunoscintigraphyrdquoCancer Immunology Immunotherapy vol 36 no 5 pp 337ndash3451993
[242] E A Rossi D L Rossi R Stein D M Goldenberg and C-H Chang ldquoA bispecific antibody-IFN1205722b immunocytokine tar-geting CD20 and HLA-DR is highly toxic to human lymphomaandmultiplemyeloma cellsrdquoCancer Research vol 70 no 19 pp7600ndash7609 2010
[243] R M Sharkey H Karacay S Litwin et al ldquoImproved ther-apeutic results by pretargeted radioimmunotherapy of non-Hodgkinrsquos lymphoma with a new recombinant trivalent anti-CD20 bispecific antibodyrdquo Cancer Research vol 68 no 13 pp5282ndash5290 2008
[244] G L Griffiths C-H Chang W J McBride et al ldquoReagentsandmethods for PETusing bispecific antibody pretargeting and68Ga-radiolabeled bivalent hapten-peptide-chelate conjugatesrdquoJournal of Nuclear Medicine vol 45 no 1 pp 30ndash39 2004
[245] J Watine M Miedouge and B Friedberg ldquoCarcinoembryonicantigen as an independent prognostic factor of recurrence andsurvival in patients resected for colorectal liver metastases Asystematic reviewrdquo Diseases of the Colon amp Rectum vol 44 no12 pp 1791ndash1799 2001
[246] M J Goldstein and E P Mitchell ldquoCarcinoembryonic antigenin the staging and follow-up of patients with colorectal cancerrdquoCancer Investigation vol 23 no 4 pp 338ndash351 2005
[247] D V Gold D M Goldenberg H Karacay et al ldquoA novelbispecific trivalent antibody construct for targeting pancreaticcarcinomardquo Cancer Research vol 68 no 12 pp 4819ndash48262008
[248] J Schuhmacher G Klivenyi R Matys et al ldquoMultistep tumortargeting in nudemice using bispecific antibodies and a galliumchelate suitable for immunoscintigraphy with positron emis-sion tomographyrdquo Cancer Research vol 55 no 1 pp 115ndash1231995
[249] G Klivenyi J Schuhmacher E Patzelt et al ldquoGallium-68chelate imaging of human colon carcinoma xenografts pre-targeted with bispecific anti-CD44(V6)anti-gallium chelateantibodiesrdquo Journal ofNuclearMedicine vol 39 no 10 pp 1769ndash1776 1998
[250] M Zoller J Schuhmacher J Reed W Maier-Borst and SMatzku ldquoEstablishment and characterization of monoclonal
24 Contrast Media amp Molecular Imaging
antibodies against an octahedral gallium chelate suitable forimmunoscintigraphy with PETrdquo Journal of Nuclear Medicinevol 33 no 7 pp 1366ndash1372 1992
[251] R M Sharkey T M Cardillo E A Rossi et al ldquoSignal ampli-fication in molecular imaging by pretargeting a multivalentbispecific antibodyrdquo Nature Medicine vol 11 no 11 pp 1250ndash1255 2005
[252] D M Goldenberg and R M Sharkey ldquoNovel radiolabeledantibody conjugatesrdquo Oncogene vol 26 no 25 pp 3734ndash37442007
[253] D M Goldenberg E A Rossi R M Sharkey W J McBrideand C-H Chang ldquoMultifunctional antibodies by the dock-and-lock method for improved cancer imaging and therapy bypretargetingrdquo Journal of NuclearMedicine vol 49 no 1 pp 158ndash163 2008
[254] R Schoffelen R M Sharkey D M Goldenberg et al ldquoPre-targeted immuno-positron emission tomography imaging ofcarcinoembryonic antigen-expressing tumors with a bispecificantibody and a68Ga- And18F-labeled hapten peptide in micewith human tumor xenograftsrdquoMolecular Cancer Therapeuticsvol 9 no 4 pp 1019ndash1027 2010
[255] E S Bos W H Kuijpers M Meesters-Winters et al ldquoIn vitroevaluation of DNA-DNA hybridization as a two-step approachin radioimmunotherapy of cancerrdquoCancer Research vol 54 no13 pp 3479ndash3486 1994
[256] G Paganelli M Bartolomei M Ferrari et al ldquoPre-TargetedLocoregional Radioimmunotherapy withrdquo Cancer biotherapyand radiopharmaceuticals vol 16 no 3 pp 227ndash235 2001
[257] A Forero P L Weiden J M Vose et al ldquoPhase 1 trial of a novelanti-CD20 fusion protein in pretargeted radioimmunotherapyfor B-cell non-Hodgkin lymphomardquo Blood vol 104 no 1 pp227ndash236 2004
[258] DM Goldenberg C-H Chang E A RossiW J McBride andR M Sharkey ldquoPretargeted molecular imaging and radioim-munotherapyrdquoTheranostics vol 2 no 5 pp 523ndash540 2012
[259] H Karacay R M Sharkey W J McBride E A Rossi C-HChang and D M Goldenberg ldquoOptimization of hapten-peptide labeling for pretargeted immunoPET of bispecificantibody using generator-produced 68Gardquo Journal of NuclearMedicine vol 52 no 4 pp 555ndash559 2011
[260] J R Oh and B C Ahn ldquoFalse-positive uptake on radioiodinewhole-body scintigraphy physiologic and pathologic variantsunrelated to thyroid cancerrdquo American Journal of NuclearMedicine and Molecular Imaging vol 2 no 2 pp 141ndash150 2012
[261] E Frampas C Rousseau C Bodet-Milin J Barbet J-F Chataland F Kraeber-Bodere ldquoImprovement of radioimmunotherapyusing pretargetingrdquo Frontiers in Oncology vol 3 Article ID00159 2013
[262] C S McKay and M G Finn ldquoClick chemistry in complexmixtures Bioorthogonal bioconjugationrdquo Chemistry amp Biologyvol 21 no 9 pp 1075ndash1101 2014
[263] B L Oliveira Z Guo and G J Bernardes ldquoInverse electrondemand DielsndashAlder reactions in chemical biologyrdquo ChemicalSociety Reviews vol 46 no 16 pp 4895ndash4950 2017
[264] B Nichols Z Qin J Yang D R Vera and N K Devaraj ldquo68Gachelating bioorthogonal tetrazine polymers for the multisteplabeling of cancer biomarkersrdquo Chemical Communications vol50 no 40 pp 5215ndash5217 2014
[265] R Rossin P R Verkerk S M van den Bosch et al ldquoInvivo chemistry for pretargeted tumor imaging in live micerdquoAngewandte Chemie International Edition vol 49 no 19 pp3375ndash3378 2010
[266] B M Zeglis K K Sevak T Reiner et al ldquoA pretargetedPET imaging strategy based on bioorthogonal diels-alder clickchemistryrdquo Journal of Nuclear Medicine vol 54 no 8 pp 1389ndash1396 2013
[267] J L Houghton R Membreno D Abdel-Atti et al ldquoEstablish-ment of the invivo efficacy of pretargeted radioimmunotherapyutilizing inverse electron demand diels-alder click chemistryrdquoMolecular Cancer Therapeutics vol 16 no 1 pp 124ndash133 2017
[268] J Funkhouser ldquoReinventing pharma the theranostic revolu-tionrdquo Current Drug Discovery pp 17ndash19 2002
[269] J Sorensen I Velikyan A Wennborg et al ldquoMeasuring HER2-expression in metastatic breast cancer using 68Ga-ABY025PETCTrdquo European Journal of Nuclear Medicine and MolecularImaging vol 41 pp S226ndashS226 2014
[270] I Velikyan A Wennborg J Feldwisch et al ldquoGMP compliantpreparation of a 68Gallium-labeled Affibody analogue forbreast cancer patient examination first-in-manrdquoEur JNuclMedMol Imaging vol 41 pp S228ndashS229 2014
[271] K Oberg ldquoMolecular imaging radiotherapy Theranostics forpersonalized patient management of neuroendocrine tumors(NETs)rdquoTheranostics vol 2 no 5 pp 448ndash458 2012
[272] I Velikyan AWennborg J FeldwischH Lindman J Carlssonand J Sorensen ldquoGood manufacturing practice production of [(68) Ga]Ga-ABY-025 for HER2 specific breast cancer imagingrdquoAmerican Journal of Nuclear Medicine and Molecular Imagingvol 6 no 2 pp 135ndash153 2016
[273] M Sandstrom K Lindskog I Velikyan et al ldquoBiodistributionand radiation dosimetry of the anti-HER2 Affibody molecule68Ga-ABY-025 in breast cancer patientsrdquo Journal of NuclearMedicine vol 57 no 6 pp 867ndash871 2016
[274] D Sandberg V Tolmachev I Velikyan et al ldquoIntra-imagereferencing for simplified assessment of HER2-expression inbreast cancer metastases using the Affibody molecule ABY-025with PET and SPECTrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 44 no 8 pp 1337ndash1346 2017
[275] H ZhangM AMoroz I Serganova et al ldquoImaging expressionof the human somatostatin receptor subtype-2 reporter genewith 68Ga-DOTATOCrdquo Journal ofNuclearMedicine vol 52 no1 pp 123ndash131 2011
[276] M Naji and A Al-Nahhas ldquo68Ga-labelled peptides in themanagement of neuroectodermal tumoursrdquo European Journalof Nuclear Medicine and Molecular Imaging vol 39 no 1 ppS61ndashS67 2012
[277] I Velikyan ldquoThe diversity of 68Ga-Based imaging agentsrdquoRecent Results in Cancer Research vol 194 pp 101ndash131 2013
[278] K Ferreira H-Y Hu V Fetz et al ldquoMultivalent siderophore-dotam conjugates as theranostics for imaging and treatment ofbacterial infectionsrdquo Angewandte Chemie International Editionvol 56 no 28 pp 8272ndash8276 2017
Computational and Mathematical Methods in Medicine
Hindawiwwwhindawicom Volume 2018
Behavioural Neurology
OphthalmologyJournal of
Hindawiwwwhindawicom Volume 2018
Diabetes ResearchJournal of
Hindawiwwwhindawicom Volume 2018
Hindawiwwwhindawicom Volume 2018
Research and TreatmentAIDS
Hindawiwwwhindawicom Volume 2018
Gastroenterology Research and Practice
Hindawiwwwhindawicom Volume 2018
Parkinsonrsquos Disease
Evidence-Based Complementary andAlternative Medicine
Volume 2018Hindawiwwwhindawicom
Submit your manuscripts atwwwhindawicom
22 Contrast Media amp Molecular Imaging
cephalosporins and siderophores for imaging infection a sys-tematic reviewrdquo Clinical and Translational Imaging vol 4 no 4pp 229ndash252 2016
[192] X Ning S Lee Z Wang et al ldquoMaltodextrin-based imagingprobes detect bacteria in vivo with high sensitivity and speci-ficityrdquo Nature Materials vol 10 no 8 pp 602ndash607 2011
[193] J Ady andY Fong ldquoImaging for infection Fromvisualization ofinflammation to visualization of microbesrdquo Surgical Infectionsvol 15 no 6 pp 700ndash707 2014
[194] J M Sierra D Rodriguez-Puig A Soriano J Mensa C Pieraand J Vila ldquoAccumulation of 99mTc-ciprofloxacin in Staphy-lococcus aureus and Pseudomonas aeruginosardquo AntimicrobialAgents and Chemotherapy vol 52 no 7 pp 2691-2692 2008
[195] D I Andersson and D Hughes ldquoMicrobiological effects ofsublethal levels of antibioticsrdquoNature ReviewsMicrobiology vol12 no 7 pp 465ndash478 2014
[196] N Dumarey D Blocklet T Appelboom L Tant and ASchoutens ldquoInfecton is not specific for bacterial osteo-articularinfective pathologyrdquo European Journal of Nuclear Medicine andMolecular Imaging vol 29 no 4 pp 530ndash535 2002
[197] K E Britton D W Wareham S S Das et al ldquoImaging bacte-rial infection with 99mTc-ciprofloxacin (Infecton)rdquo Journal ofClinical Pathology vol 55 no 11 pp 817ndash823 2002
[198] G Ferro-Flores M A Avila-Rodrıguez and F O Garcıa-PerezldquoImaging of bacteria with radiolabeled ubiquicidin by SPECTand PET techniquesrdquo Clinical and Translational Imaging vol 4no 3 pp 175ndash182 2016
[199] P S Hiemstra M T van den Barselaar M Roest P H Nibber-ing and R van Furth ldquoUbiquicidin a novel murine microbi-cidal protein present in the cytosolic fraction of macrophagesrdquoJournal of Leukocyte Biology vol 66 no 3 pp 423ndash428 1999
[200] M S Akhtar A Qaisar J Irfanullah et al ldquoAntimicrobialpeptide 99mTc-ubiquicidin 29ndash41 as human infection-imagingagent clinical trialrdquo Journal of Nuclear Medicne vol 46 no 4pp 567ndash573 2005
[201] M Assadi K Vahdat I Nabipour et al ldquoDiagnostic value of99mTc-ubiquicidin scintigraphy for osteomyelitis and compar-isons with 99mTc-methylene diphosphonate scintigraphy andmagnetic resonance imagingrdquo Nuclear Medicine Communica-tions vol 32 no 8 pp 716ndash723 2011
[202] T Emery ldquoExchange of Iron by Gallium in SiderophoresrdquoBiochemistry vol 25 no 16 pp 4629ndash4633 1986
[203] M Petrik C Zhai H Haas and C Decristoforo ldquoSiderophoresfor molecular imaging applicationsrdquo Clinical and TranslationalImaging vol 5 no 1 pp 15ndash27 2017
[204] H J Flint E A BayerM T Rincon R Lamed and B AWhiteldquoPolysaccharide utilization by gut bacteria potential for newinsights from genomic analysisrdquo Nature Reviews Microbiologyvol 6 no 2 pp 121ndash131 2008
[205] GGowrishankarMNamavari E B Jouannot et al ldquoInvestiga-tion of 6-[18F]-fluoromaltose as a novel PET tracer for imagingbacterial infectionrdquo PLoS ONE vol 9 no 9 Article ID e1079512014
[206] N Gholipour M Akhlaghi A M Kheirabadi et al ldquoChelator-free radiolabeling of dextran with 68Ga for PET studiesrdquoJournal of Radioanalytical and Nuclear Chemistry vol 311 no3 pp 1811ndash1817 2017
[207] C Bettegowda C A Foss I Cheong et al ldquoImaging bac-terial infections with radiolabeled 1-(21015840-deoxy-21015840- fluoro-120573-D-arabinofuranosyl)-5-iodouracilrdquo Proceedings of the NationalAcadamy of Sciences of the United States of America vol 102 no4 pp 1145ndash1150 2005
[208] S A Soghomonyan M Doubrovin J Pike et al ldquoPositronemission tomography (PET) imaging of tumor-localizedSalmonella expressing HSV1-TKrdquo Cancer GeneTherapy vol 12no 1 pp 101ndash108 2005
[209] C Palestro K Nichols S Sheikh-Fayyaz S Dewey P Singhaland K Bhargava ldquoCan Gallium-68 PET differentiate acuteinterstitial nephritis from acute tubular necrosisrdquo Journal ofNuclear Medicne vol 57 Supplement 2 p 551 2016
[210] A J Morguet D L Munz V Ivancevic et al ldquoImmunoscintig-raphy using technetium-99m-labeled anti-NCA-95 antigranu-locyte antibodies as an adjunct to echocardiography in subacuteinfective endocarditisrdquo Journal of the American College ofCardiology vol 23 no 5 pp 1171ndash1178 1994
[211] C van der Laken O Boerman W Oyen et al ldquoIn Vivo Expres-sion of Interleukin-1 Receptors during Various ExperimentallyInduced Inflammatory Conditionsrdquo The Journal of InfectiousDiseases vol 177 no 5 pp 1398ndash1401 1998
[212] C J Van Der Laken O C Boerman W J G Oyen M T PVan De Ven J W M Van Der Meer and F H M CorstensldquoScintigraphic detection of infection and inflammation Newdevelopments with special emphasis on receptor interactionrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 25 no 5 pp 535ndash546 1998
[213] C J van der LakenOC BoermanW J GOyenM T P van deVen J W M van der Meer and F H M Corstens ldquoImaging ofinfection in rabbits with radioiodinated interleukin-1 (120572 and 120573)its receptor antagonist and a chemotactic peptide a comparativestudyrdquo European Journal of Nuclear Medicine and MolecularImaging vol 25 no 4 pp 347ndash352 1998
[214] C J Van Der Laken O C BoermanW J G Oyen M T P VanDe Ven F H M Corstens and J W M Ven Der Meer ldquoThekinetics of radiolabelled interleukin-8 in infection and sterileinflammationrdquo Nuclear Medicine Communications vol 19 no3 pp 271ndash282 1998
[215] E Lazzeri P Erba M Perri et al ldquoScintigraphic imaging ofvertebral osteomyelitis with 111in-biotinrdquoThe Spine Journal vol33 no 7 pp E198ndashE204 2008
[216] E Blom B Langstrom and I Velikyan ldquo68Ga-labeling of biotinanalogues and their characterizationrdquo Bioconjugate Chemistryvol 20 no 6 pp 1146ndash1151 2009
[217] O Eriksson F Carlsson E Blom et al ldquoPreclinical evaluationof a 68Ga-labeled biotin analogue for applications in islettransplantationrdquo Nuclear Medicine and Biology vol 39 no 3pp 415ndash421 2012
[218] E A Weinstein A A Ordonez V P DeMarco et alldquoImaging Enterobacteriaceae infection in vivo with 18F-fluoro-deoxysorbitol positron emission tomographyrdquo Science Transla-tional Medicine vol 6 no 259 p 259ra146 2014
[219] K M Nielsen M H Kyneb A K O Alstrup et alldquo68Ga-labeled phage-display selected peptides as tracers forpositron emission tomography imaging of Staphylococcusaureus biofilm-associated infections Selection radiolabellingand preliminary biological evaluationrdquo Nuclear Medicine andBiology vol 43 no 10 pp 593ndash605 2016
[220] T J Makinen P Lankinen T Poyhonen J Jalava H T Aroand A Roivainen ldquoComparison of 18F-FDG and 68Ga PETimaging in the assessment of experimental osteomyelitis due toStaphylococcus aureusrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 32 no 11 pp 1259ndash1268 2005
[221] JMU Silvola I LaitinenH J Sipila et al ldquoUptake of 68galliumin atherosclerotic plaques in LDLRminusminusApoB100100micerdquo EJN-MMI Research vol 1 no 1 pp 1ndash8 2011
Contrast Media amp Molecular Imaging 23
[222] T A Wynn ldquoCellular and molecular mechanisms of fibrosisrdquoThe Journal of Pathology vol 214 no 2 pp 199ndash210 2008
[223] T Derlin D Jonigk J Bauersachs and FM Bengel ldquoMolecularImaging of Chemokine Receptor CXCR4 in NonndashSmall CellLung Cancer Using 68Ga-Pentixafor PETCT ComparisonWith 18F-FDGrdquo Clinical Nuclear Medicine 2016
[224] I Velikyan U Rosenstrom T N Bulenga O Eriksson andG Antoni ldquoFeasibility of multiple examinations using68ga-labelled collagelin analogues Organ distribution in rat forextrapolation to human organ and whole-body radiationdosimetryrdquo Pharmaceuticals vol 9 no 2 article no 31 2016
[225] S Jadhav M Kakela J Makila et al ldquoSynthesis and in VivoPET Imaging of Hyaluronan Conjugates of OligonucleotidesrdquoBioconjugate Chemistry vol 27 no 2 pp 391ndash403 2016
[226] A Autio A Saraste N Kudomi et al ldquoAssessment of bloodflow with (68) Ga-DOTA PET in experimental inflammation avalidation study using (15) O-waterrdquo American Journal ofNuclear Medicine and Molecular Imaging vol 4 no 6 pp 571ndash579 2014
[227] G Davies A Rolle A Maurer et al ldquoTowards translationalimmunoPETMR imaging of invasive pulmonary aspergillosisthe Humanised Monoclonal Antibody JF5 detects in vivordquoTheranostics vol 7 no 14 pp 3398ndash3414 2017
[228] DGoodwin CMeares GDavid et al ldquoMonoclonal antibodiesas reversible equilibrium carriers of radiopharmaceuticalsrdquoInternational Journal of Radiation Applications and Instrumen-tation Part B Nuclear Medicine and Biology vol 13 no 4 pp383ndash391 1986
[229] D A Goodwin C F Mears M McTigue and G S DavidldquoMonoclonal antibody hapten radiopharmaceutical deliveryrdquoNuclear Medicine Communications vol 7 no 8 pp 569ndash5801986
[230] S E Halpern and R O Dillman ldquoProblems associated withradioimmunodetection and possibilities for future solutionsrdquo JBiol Response Mod vol 6 no 3 pp 235ndash262 1987
[231] H Hong J Sun and W Cai ldquoRadionuclide-based cancerimaging targeting the carcinoembryonic antigenrdquo BiomarkerInsights vol 3 pp 435ndash451 2008
[232] G J Forster E B Santos P M Smith-Jones P Zanzonico andS M Larson ldquoPretargeted radioimmunotherapy with a single-chain antibodystreptavidin construct and radiolabeledDOTA-biotin Strategies for reduction of the renal doserdquo Journal ofNuclear Medicine vol 47 no 1 pp 140ndash149 2006
[233] Z Yao M Zhang H Kobayashi et al ldquoImproved targeting ofradiolabeled streptavidin in tumors pretargeted with biotiny-lated monoclonal antibodies through an avidin chaserdquo Journalof Nuclear Medicine vol 36 no 5 pp 837ndash841 1995
[234] C-H Chang R M Sharkey E A Rossi et al ldquoMolecularAdvances in Pretargeting Radioimunotherapy with BispecificAntibodies 1 Supported in part by USPHS Grant R01-CA-84379from the NIH and Department of Energy Grant DE-FG01-00NE22941 (both to R M S)1rdquo Mol Cancer Ther vol 1 no 7pp 553ndash563 2002
[235] R M Sharkey E A Rossi W J McBride C-H Chang andD M Goldenberg ldquoRecombinant Bispecific Monoclonal Anti-bodies Prepared by theDock-and-Lock Strategy for PretargetedRadioimmunotherapyrdquo Seminars in Nuclear Medicine vol 40no 3 pp 190ndash203 2010
[236] R M Sharkey E A Rossi C-H Chang and D M Golden-berg ldquoImproved cancer therapy and molecular imaging withmultivalent multispecific antibodiesrdquo Cancer Biotherapy andRadiopharmaceuticals vol 25 no 1 pp 1ndash12 2010
[237] D M Goldenberg R M Sharkey G Paganelli J Barbet andJ Chatal ldquoAntibody pretargeting advances cancer radioim-munodetection and radioimmunotherapyrdquo Journal of ClinicalOncology vol 24 no 5 pp 823ndash834 2006
[238] O C Boerman F G van Schaijk W J G Oyen and FH M Corstens ldquoPretargeted radioimmunotherapy of cancerprogress step by steprdquo Journal of Nuclear Medicine vol 44 no3 pp 400ndash411 2003
[239] J Schuhmacher S Kaul G Klivenyi et al ldquoImmunoscintigra-phy with positron emission tomography Gallium-68 chelateimaging of breast cancer pretargeted with bispecific anti-MUC1anti-Ga chelate antibodiesrdquo Cancer Research vol 61 no9 pp 3712ndash3717 2001
[240] J Schuhmacher G Klivenyi S Kaul et al ldquoPretargeting ofhuman mammary carcinoma xenografts with bispecific anti-MUC1anti-Ga chelate antibodies and immunoscintigraphywith PETrdquo Nuclear Medicine and Biology vol 28 no 7 pp 821ndash828 2001
[241] C Somasundaram S Matzku J Schuhmacher and M ZollerldquoDevelopment of a bispecific monoclonal antibody against agallium-67 chelate and the human melanoma-associated anti-gen p97 for potential use in pretargeted immunoscintigraphyrdquoCancer Immunology Immunotherapy vol 36 no 5 pp 337ndash3451993
[242] E A Rossi D L Rossi R Stein D M Goldenberg and C-H Chang ldquoA bispecific antibody-IFN1205722b immunocytokine tar-geting CD20 and HLA-DR is highly toxic to human lymphomaandmultiplemyeloma cellsrdquoCancer Research vol 70 no 19 pp7600ndash7609 2010
[243] R M Sharkey H Karacay S Litwin et al ldquoImproved ther-apeutic results by pretargeted radioimmunotherapy of non-Hodgkinrsquos lymphoma with a new recombinant trivalent anti-CD20 bispecific antibodyrdquo Cancer Research vol 68 no 13 pp5282ndash5290 2008
[244] G L Griffiths C-H Chang W J McBride et al ldquoReagentsandmethods for PETusing bispecific antibody pretargeting and68Ga-radiolabeled bivalent hapten-peptide-chelate conjugatesrdquoJournal of Nuclear Medicine vol 45 no 1 pp 30ndash39 2004
[245] J Watine M Miedouge and B Friedberg ldquoCarcinoembryonicantigen as an independent prognostic factor of recurrence andsurvival in patients resected for colorectal liver metastases Asystematic reviewrdquo Diseases of the Colon amp Rectum vol 44 no12 pp 1791ndash1799 2001
[246] M J Goldstein and E P Mitchell ldquoCarcinoembryonic antigenin the staging and follow-up of patients with colorectal cancerrdquoCancer Investigation vol 23 no 4 pp 338ndash351 2005
[247] D V Gold D M Goldenberg H Karacay et al ldquoA novelbispecific trivalent antibody construct for targeting pancreaticcarcinomardquo Cancer Research vol 68 no 12 pp 4819ndash48262008
[248] J Schuhmacher G Klivenyi R Matys et al ldquoMultistep tumortargeting in nudemice using bispecific antibodies and a galliumchelate suitable for immunoscintigraphy with positron emis-sion tomographyrdquo Cancer Research vol 55 no 1 pp 115ndash1231995
[249] G Klivenyi J Schuhmacher E Patzelt et al ldquoGallium-68chelate imaging of human colon carcinoma xenografts pre-targeted with bispecific anti-CD44(V6)anti-gallium chelateantibodiesrdquo Journal ofNuclearMedicine vol 39 no 10 pp 1769ndash1776 1998
[250] M Zoller J Schuhmacher J Reed W Maier-Borst and SMatzku ldquoEstablishment and characterization of monoclonal
24 Contrast Media amp Molecular Imaging
antibodies against an octahedral gallium chelate suitable forimmunoscintigraphy with PETrdquo Journal of Nuclear Medicinevol 33 no 7 pp 1366ndash1372 1992
[251] R M Sharkey T M Cardillo E A Rossi et al ldquoSignal ampli-fication in molecular imaging by pretargeting a multivalentbispecific antibodyrdquo Nature Medicine vol 11 no 11 pp 1250ndash1255 2005
[252] D M Goldenberg and R M Sharkey ldquoNovel radiolabeledantibody conjugatesrdquo Oncogene vol 26 no 25 pp 3734ndash37442007
[253] D M Goldenberg E A Rossi R M Sharkey W J McBrideand C-H Chang ldquoMultifunctional antibodies by the dock-and-lock method for improved cancer imaging and therapy bypretargetingrdquo Journal of NuclearMedicine vol 49 no 1 pp 158ndash163 2008
[254] R Schoffelen R M Sharkey D M Goldenberg et al ldquoPre-targeted immuno-positron emission tomography imaging ofcarcinoembryonic antigen-expressing tumors with a bispecificantibody and a68Ga- And18F-labeled hapten peptide in micewith human tumor xenograftsrdquoMolecular Cancer Therapeuticsvol 9 no 4 pp 1019ndash1027 2010
[255] E S Bos W H Kuijpers M Meesters-Winters et al ldquoIn vitroevaluation of DNA-DNA hybridization as a two-step approachin radioimmunotherapy of cancerrdquoCancer Research vol 54 no13 pp 3479ndash3486 1994
[256] G Paganelli M Bartolomei M Ferrari et al ldquoPre-TargetedLocoregional Radioimmunotherapy withrdquo Cancer biotherapyand radiopharmaceuticals vol 16 no 3 pp 227ndash235 2001
[257] A Forero P L Weiden J M Vose et al ldquoPhase 1 trial of a novelanti-CD20 fusion protein in pretargeted radioimmunotherapyfor B-cell non-Hodgkin lymphomardquo Blood vol 104 no 1 pp227ndash236 2004
[258] DM Goldenberg C-H Chang E A RossiW J McBride andR M Sharkey ldquoPretargeted molecular imaging and radioim-munotherapyrdquoTheranostics vol 2 no 5 pp 523ndash540 2012
[259] H Karacay R M Sharkey W J McBride E A Rossi C-HChang and D M Goldenberg ldquoOptimization of hapten-peptide labeling for pretargeted immunoPET of bispecificantibody using generator-produced 68Gardquo Journal of NuclearMedicine vol 52 no 4 pp 555ndash559 2011
[260] J R Oh and B C Ahn ldquoFalse-positive uptake on radioiodinewhole-body scintigraphy physiologic and pathologic variantsunrelated to thyroid cancerrdquo American Journal of NuclearMedicine and Molecular Imaging vol 2 no 2 pp 141ndash150 2012
[261] E Frampas C Rousseau C Bodet-Milin J Barbet J-F Chataland F Kraeber-Bodere ldquoImprovement of radioimmunotherapyusing pretargetingrdquo Frontiers in Oncology vol 3 Article ID00159 2013
[262] C S McKay and M G Finn ldquoClick chemistry in complexmixtures Bioorthogonal bioconjugationrdquo Chemistry amp Biologyvol 21 no 9 pp 1075ndash1101 2014
[263] B L Oliveira Z Guo and G J Bernardes ldquoInverse electrondemand DielsndashAlder reactions in chemical biologyrdquo ChemicalSociety Reviews vol 46 no 16 pp 4895ndash4950 2017
[264] B Nichols Z Qin J Yang D R Vera and N K Devaraj ldquo68Gachelating bioorthogonal tetrazine polymers for the multisteplabeling of cancer biomarkersrdquo Chemical Communications vol50 no 40 pp 5215ndash5217 2014
[265] R Rossin P R Verkerk S M van den Bosch et al ldquoInvivo chemistry for pretargeted tumor imaging in live micerdquoAngewandte Chemie International Edition vol 49 no 19 pp3375ndash3378 2010
[266] B M Zeglis K K Sevak T Reiner et al ldquoA pretargetedPET imaging strategy based on bioorthogonal diels-alder clickchemistryrdquo Journal of Nuclear Medicine vol 54 no 8 pp 1389ndash1396 2013
[267] J L Houghton R Membreno D Abdel-Atti et al ldquoEstablish-ment of the invivo efficacy of pretargeted radioimmunotherapyutilizing inverse electron demand diels-alder click chemistryrdquoMolecular Cancer Therapeutics vol 16 no 1 pp 124ndash133 2017
[268] J Funkhouser ldquoReinventing pharma the theranostic revolu-tionrdquo Current Drug Discovery pp 17ndash19 2002
[269] J Sorensen I Velikyan A Wennborg et al ldquoMeasuring HER2-expression in metastatic breast cancer using 68Ga-ABY025PETCTrdquo European Journal of Nuclear Medicine and MolecularImaging vol 41 pp S226ndashS226 2014
[270] I Velikyan A Wennborg J Feldwisch et al ldquoGMP compliantpreparation of a 68Gallium-labeled Affibody analogue forbreast cancer patient examination first-in-manrdquoEur JNuclMedMol Imaging vol 41 pp S228ndashS229 2014
[271] K Oberg ldquoMolecular imaging radiotherapy Theranostics forpersonalized patient management of neuroendocrine tumors(NETs)rdquoTheranostics vol 2 no 5 pp 448ndash458 2012
[272] I Velikyan AWennborg J FeldwischH Lindman J Carlssonand J Sorensen ldquoGood manufacturing practice production of [(68) Ga]Ga-ABY-025 for HER2 specific breast cancer imagingrdquoAmerican Journal of Nuclear Medicine and Molecular Imagingvol 6 no 2 pp 135ndash153 2016
[273] M Sandstrom K Lindskog I Velikyan et al ldquoBiodistributionand radiation dosimetry of the anti-HER2 Affibody molecule68Ga-ABY-025 in breast cancer patientsrdquo Journal of NuclearMedicine vol 57 no 6 pp 867ndash871 2016
[274] D Sandberg V Tolmachev I Velikyan et al ldquoIntra-imagereferencing for simplified assessment of HER2-expression inbreast cancer metastases using the Affibody molecule ABY-025with PET and SPECTrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 44 no 8 pp 1337ndash1346 2017
[275] H ZhangM AMoroz I Serganova et al ldquoImaging expressionof the human somatostatin receptor subtype-2 reporter genewith 68Ga-DOTATOCrdquo Journal ofNuclearMedicine vol 52 no1 pp 123ndash131 2011
[276] M Naji and A Al-Nahhas ldquo68Ga-labelled peptides in themanagement of neuroectodermal tumoursrdquo European Journalof Nuclear Medicine and Molecular Imaging vol 39 no 1 ppS61ndashS67 2012
[277] I Velikyan ldquoThe diversity of 68Ga-Based imaging agentsrdquoRecent Results in Cancer Research vol 194 pp 101ndash131 2013
[278] K Ferreira H-Y Hu V Fetz et al ldquoMultivalent siderophore-dotam conjugates as theranostics for imaging and treatment ofbacterial infectionsrdquo Angewandte Chemie International Editionvol 56 no 28 pp 8272ndash8276 2017
Computational and Mathematical Methods in Medicine
Hindawiwwwhindawicom Volume 2018
Behavioural Neurology
OphthalmologyJournal of
Hindawiwwwhindawicom Volume 2018
Diabetes ResearchJournal of
Hindawiwwwhindawicom Volume 2018
Hindawiwwwhindawicom Volume 2018
Research and TreatmentAIDS
Hindawiwwwhindawicom Volume 2018
Gastroenterology Research and Practice
Hindawiwwwhindawicom Volume 2018
Parkinsonrsquos Disease
Evidence-Based Complementary andAlternative Medicine
Volume 2018Hindawiwwwhindawicom
Submit your manuscripts atwwwhindawicom
Contrast Media amp Molecular Imaging 23
[222] T A Wynn ldquoCellular and molecular mechanisms of fibrosisrdquoThe Journal of Pathology vol 214 no 2 pp 199ndash210 2008
[223] T Derlin D Jonigk J Bauersachs and FM Bengel ldquoMolecularImaging of Chemokine Receptor CXCR4 in NonndashSmall CellLung Cancer Using 68Ga-Pentixafor PETCT ComparisonWith 18F-FDGrdquo Clinical Nuclear Medicine 2016
[224] I Velikyan U Rosenstrom T N Bulenga O Eriksson andG Antoni ldquoFeasibility of multiple examinations using68ga-labelled collagelin analogues Organ distribution in rat forextrapolation to human organ and whole-body radiationdosimetryrdquo Pharmaceuticals vol 9 no 2 article no 31 2016
[225] S Jadhav M Kakela J Makila et al ldquoSynthesis and in VivoPET Imaging of Hyaluronan Conjugates of OligonucleotidesrdquoBioconjugate Chemistry vol 27 no 2 pp 391ndash403 2016
[226] A Autio A Saraste N Kudomi et al ldquoAssessment of bloodflow with (68) Ga-DOTA PET in experimental inflammation avalidation study using (15) O-waterrdquo American Journal ofNuclear Medicine and Molecular Imaging vol 4 no 6 pp 571ndash579 2014
[227] G Davies A Rolle A Maurer et al ldquoTowards translationalimmunoPETMR imaging of invasive pulmonary aspergillosisthe Humanised Monoclonal Antibody JF5 detects in vivordquoTheranostics vol 7 no 14 pp 3398ndash3414 2017
[228] DGoodwin CMeares GDavid et al ldquoMonoclonal antibodiesas reversible equilibrium carriers of radiopharmaceuticalsrdquoInternational Journal of Radiation Applications and Instrumen-tation Part B Nuclear Medicine and Biology vol 13 no 4 pp383ndash391 1986
[229] D A Goodwin C F Mears M McTigue and G S DavidldquoMonoclonal antibody hapten radiopharmaceutical deliveryrdquoNuclear Medicine Communications vol 7 no 8 pp 569ndash5801986
[230] S E Halpern and R O Dillman ldquoProblems associated withradioimmunodetection and possibilities for future solutionsrdquo JBiol Response Mod vol 6 no 3 pp 235ndash262 1987
[231] H Hong J Sun and W Cai ldquoRadionuclide-based cancerimaging targeting the carcinoembryonic antigenrdquo BiomarkerInsights vol 3 pp 435ndash451 2008
[232] G J Forster E B Santos P M Smith-Jones P Zanzonico andS M Larson ldquoPretargeted radioimmunotherapy with a single-chain antibodystreptavidin construct and radiolabeledDOTA-biotin Strategies for reduction of the renal doserdquo Journal ofNuclear Medicine vol 47 no 1 pp 140ndash149 2006
[233] Z Yao M Zhang H Kobayashi et al ldquoImproved targeting ofradiolabeled streptavidin in tumors pretargeted with biotiny-lated monoclonal antibodies through an avidin chaserdquo Journalof Nuclear Medicine vol 36 no 5 pp 837ndash841 1995
[234] C-H Chang R M Sharkey E A Rossi et al ldquoMolecularAdvances in Pretargeting Radioimunotherapy with BispecificAntibodies 1 Supported in part by USPHS Grant R01-CA-84379from the NIH and Department of Energy Grant DE-FG01-00NE22941 (both to R M S)1rdquo Mol Cancer Ther vol 1 no 7pp 553ndash563 2002
[235] R M Sharkey E A Rossi W J McBride C-H Chang andD M Goldenberg ldquoRecombinant Bispecific Monoclonal Anti-bodies Prepared by theDock-and-Lock Strategy for PretargetedRadioimmunotherapyrdquo Seminars in Nuclear Medicine vol 40no 3 pp 190ndash203 2010
[236] R M Sharkey E A Rossi C-H Chang and D M Golden-berg ldquoImproved cancer therapy and molecular imaging withmultivalent multispecific antibodiesrdquo Cancer Biotherapy andRadiopharmaceuticals vol 25 no 1 pp 1ndash12 2010
[237] D M Goldenberg R M Sharkey G Paganelli J Barbet andJ Chatal ldquoAntibody pretargeting advances cancer radioim-munodetection and radioimmunotherapyrdquo Journal of ClinicalOncology vol 24 no 5 pp 823ndash834 2006
[238] O C Boerman F G van Schaijk W J G Oyen and FH M Corstens ldquoPretargeted radioimmunotherapy of cancerprogress step by steprdquo Journal of Nuclear Medicine vol 44 no3 pp 400ndash411 2003
[239] J Schuhmacher S Kaul G Klivenyi et al ldquoImmunoscintigra-phy with positron emission tomography Gallium-68 chelateimaging of breast cancer pretargeted with bispecific anti-MUC1anti-Ga chelate antibodiesrdquo Cancer Research vol 61 no9 pp 3712ndash3717 2001
[240] J Schuhmacher G Klivenyi S Kaul et al ldquoPretargeting ofhuman mammary carcinoma xenografts with bispecific anti-MUC1anti-Ga chelate antibodies and immunoscintigraphywith PETrdquo Nuclear Medicine and Biology vol 28 no 7 pp 821ndash828 2001
[241] C Somasundaram S Matzku J Schuhmacher and M ZollerldquoDevelopment of a bispecific monoclonal antibody against agallium-67 chelate and the human melanoma-associated anti-gen p97 for potential use in pretargeted immunoscintigraphyrdquoCancer Immunology Immunotherapy vol 36 no 5 pp 337ndash3451993
[242] E A Rossi D L Rossi R Stein D M Goldenberg and C-H Chang ldquoA bispecific antibody-IFN1205722b immunocytokine tar-geting CD20 and HLA-DR is highly toxic to human lymphomaandmultiplemyeloma cellsrdquoCancer Research vol 70 no 19 pp7600ndash7609 2010
[243] R M Sharkey H Karacay S Litwin et al ldquoImproved ther-apeutic results by pretargeted radioimmunotherapy of non-Hodgkinrsquos lymphoma with a new recombinant trivalent anti-CD20 bispecific antibodyrdquo Cancer Research vol 68 no 13 pp5282ndash5290 2008
[244] G L Griffiths C-H Chang W J McBride et al ldquoReagentsandmethods for PETusing bispecific antibody pretargeting and68Ga-radiolabeled bivalent hapten-peptide-chelate conjugatesrdquoJournal of Nuclear Medicine vol 45 no 1 pp 30ndash39 2004
[245] J Watine M Miedouge and B Friedberg ldquoCarcinoembryonicantigen as an independent prognostic factor of recurrence andsurvival in patients resected for colorectal liver metastases Asystematic reviewrdquo Diseases of the Colon amp Rectum vol 44 no12 pp 1791ndash1799 2001
[246] M J Goldstein and E P Mitchell ldquoCarcinoembryonic antigenin the staging and follow-up of patients with colorectal cancerrdquoCancer Investigation vol 23 no 4 pp 338ndash351 2005
[247] D V Gold D M Goldenberg H Karacay et al ldquoA novelbispecific trivalent antibody construct for targeting pancreaticcarcinomardquo Cancer Research vol 68 no 12 pp 4819ndash48262008
[248] J Schuhmacher G Klivenyi R Matys et al ldquoMultistep tumortargeting in nudemice using bispecific antibodies and a galliumchelate suitable for immunoscintigraphy with positron emis-sion tomographyrdquo Cancer Research vol 55 no 1 pp 115ndash1231995
[249] G Klivenyi J Schuhmacher E Patzelt et al ldquoGallium-68chelate imaging of human colon carcinoma xenografts pre-targeted with bispecific anti-CD44(V6)anti-gallium chelateantibodiesrdquo Journal ofNuclearMedicine vol 39 no 10 pp 1769ndash1776 1998
[250] M Zoller J Schuhmacher J Reed W Maier-Borst and SMatzku ldquoEstablishment and characterization of monoclonal
24 Contrast Media amp Molecular Imaging
antibodies against an octahedral gallium chelate suitable forimmunoscintigraphy with PETrdquo Journal of Nuclear Medicinevol 33 no 7 pp 1366ndash1372 1992
[251] R M Sharkey T M Cardillo E A Rossi et al ldquoSignal ampli-fication in molecular imaging by pretargeting a multivalentbispecific antibodyrdquo Nature Medicine vol 11 no 11 pp 1250ndash1255 2005
[252] D M Goldenberg and R M Sharkey ldquoNovel radiolabeledantibody conjugatesrdquo Oncogene vol 26 no 25 pp 3734ndash37442007
[253] D M Goldenberg E A Rossi R M Sharkey W J McBrideand C-H Chang ldquoMultifunctional antibodies by the dock-and-lock method for improved cancer imaging and therapy bypretargetingrdquo Journal of NuclearMedicine vol 49 no 1 pp 158ndash163 2008
[254] R Schoffelen R M Sharkey D M Goldenberg et al ldquoPre-targeted immuno-positron emission tomography imaging ofcarcinoembryonic antigen-expressing tumors with a bispecificantibody and a68Ga- And18F-labeled hapten peptide in micewith human tumor xenograftsrdquoMolecular Cancer Therapeuticsvol 9 no 4 pp 1019ndash1027 2010
[255] E S Bos W H Kuijpers M Meesters-Winters et al ldquoIn vitroevaluation of DNA-DNA hybridization as a two-step approachin radioimmunotherapy of cancerrdquoCancer Research vol 54 no13 pp 3479ndash3486 1994
[256] G Paganelli M Bartolomei M Ferrari et al ldquoPre-TargetedLocoregional Radioimmunotherapy withrdquo Cancer biotherapyand radiopharmaceuticals vol 16 no 3 pp 227ndash235 2001
[257] A Forero P L Weiden J M Vose et al ldquoPhase 1 trial of a novelanti-CD20 fusion protein in pretargeted radioimmunotherapyfor B-cell non-Hodgkin lymphomardquo Blood vol 104 no 1 pp227ndash236 2004
[258] DM Goldenberg C-H Chang E A RossiW J McBride andR M Sharkey ldquoPretargeted molecular imaging and radioim-munotherapyrdquoTheranostics vol 2 no 5 pp 523ndash540 2012
[259] H Karacay R M Sharkey W J McBride E A Rossi C-HChang and D M Goldenberg ldquoOptimization of hapten-peptide labeling for pretargeted immunoPET of bispecificantibody using generator-produced 68Gardquo Journal of NuclearMedicine vol 52 no 4 pp 555ndash559 2011
[260] J R Oh and B C Ahn ldquoFalse-positive uptake on radioiodinewhole-body scintigraphy physiologic and pathologic variantsunrelated to thyroid cancerrdquo American Journal of NuclearMedicine and Molecular Imaging vol 2 no 2 pp 141ndash150 2012
[261] E Frampas C Rousseau C Bodet-Milin J Barbet J-F Chataland F Kraeber-Bodere ldquoImprovement of radioimmunotherapyusing pretargetingrdquo Frontiers in Oncology vol 3 Article ID00159 2013
[262] C S McKay and M G Finn ldquoClick chemistry in complexmixtures Bioorthogonal bioconjugationrdquo Chemistry amp Biologyvol 21 no 9 pp 1075ndash1101 2014
[263] B L Oliveira Z Guo and G J Bernardes ldquoInverse electrondemand DielsndashAlder reactions in chemical biologyrdquo ChemicalSociety Reviews vol 46 no 16 pp 4895ndash4950 2017
[264] B Nichols Z Qin J Yang D R Vera and N K Devaraj ldquo68Gachelating bioorthogonal tetrazine polymers for the multisteplabeling of cancer biomarkersrdquo Chemical Communications vol50 no 40 pp 5215ndash5217 2014
[265] R Rossin P R Verkerk S M van den Bosch et al ldquoInvivo chemistry for pretargeted tumor imaging in live micerdquoAngewandte Chemie International Edition vol 49 no 19 pp3375ndash3378 2010
[266] B M Zeglis K K Sevak T Reiner et al ldquoA pretargetedPET imaging strategy based on bioorthogonal diels-alder clickchemistryrdquo Journal of Nuclear Medicine vol 54 no 8 pp 1389ndash1396 2013
[267] J L Houghton R Membreno D Abdel-Atti et al ldquoEstablish-ment of the invivo efficacy of pretargeted radioimmunotherapyutilizing inverse electron demand diels-alder click chemistryrdquoMolecular Cancer Therapeutics vol 16 no 1 pp 124ndash133 2017
[268] J Funkhouser ldquoReinventing pharma the theranostic revolu-tionrdquo Current Drug Discovery pp 17ndash19 2002
[269] J Sorensen I Velikyan A Wennborg et al ldquoMeasuring HER2-expression in metastatic breast cancer using 68Ga-ABY025PETCTrdquo European Journal of Nuclear Medicine and MolecularImaging vol 41 pp S226ndashS226 2014
[270] I Velikyan A Wennborg J Feldwisch et al ldquoGMP compliantpreparation of a 68Gallium-labeled Affibody analogue forbreast cancer patient examination first-in-manrdquoEur JNuclMedMol Imaging vol 41 pp S228ndashS229 2014
[271] K Oberg ldquoMolecular imaging radiotherapy Theranostics forpersonalized patient management of neuroendocrine tumors(NETs)rdquoTheranostics vol 2 no 5 pp 448ndash458 2012
[272] I Velikyan AWennborg J FeldwischH Lindman J Carlssonand J Sorensen ldquoGood manufacturing practice production of [(68) Ga]Ga-ABY-025 for HER2 specific breast cancer imagingrdquoAmerican Journal of Nuclear Medicine and Molecular Imagingvol 6 no 2 pp 135ndash153 2016
[273] M Sandstrom K Lindskog I Velikyan et al ldquoBiodistributionand radiation dosimetry of the anti-HER2 Affibody molecule68Ga-ABY-025 in breast cancer patientsrdquo Journal of NuclearMedicine vol 57 no 6 pp 867ndash871 2016
[274] D Sandberg V Tolmachev I Velikyan et al ldquoIntra-imagereferencing for simplified assessment of HER2-expression inbreast cancer metastases using the Affibody molecule ABY-025with PET and SPECTrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 44 no 8 pp 1337ndash1346 2017
[275] H ZhangM AMoroz I Serganova et al ldquoImaging expressionof the human somatostatin receptor subtype-2 reporter genewith 68Ga-DOTATOCrdquo Journal ofNuclearMedicine vol 52 no1 pp 123ndash131 2011
[276] M Naji and A Al-Nahhas ldquo68Ga-labelled peptides in themanagement of neuroectodermal tumoursrdquo European Journalof Nuclear Medicine and Molecular Imaging vol 39 no 1 ppS61ndashS67 2012
[277] I Velikyan ldquoThe diversity of 68Ga-Based imaging agentsrdquoRecent Results in Cancer Research vol 194 pp 101ndash131 2013
[278] K Ferreira H-Y Hu V Fetz et al ldquoMultivalent siderophore-dotam conjugates as theranostics for imaging and treatment ofbacterial infectionsrdquo Angewandte Chemie International Editionvol 56 no 28 pp 8272ndash8276 2017
Computational and Mathematical Methods in Medicine
Hindawiwwwhindawicom Volume 2018
Behavioural Neurology
OphthalmologyJournal of
Hindawiwwwhindawicom Volume 2018
Diabetes ResearchJournal of
Hindawiwwwhindawicom Volume 2018
Hindawiwwwhindawicom Volume 2018
Research and TreatmentAIDS
Hindawiwwwhindawicom Volume 2018
Gastroenterology Research and Practice
Hindawiwwwhindawicom Volume 2018
Parkinsonrsquos Disease
Evidence-Based Complementary andAlternative Medicine
Volume 2018Hindawiwwwhindawicom
Submit your manuscripts atwwwhindawicom
24 Contrast Media amp Molecular Imaging
antibodies against an octahedral gallium chelate suitable forimmunoscintigraphy with PETrdquo Journal of Nuclear Medicinevol 33 no 7 pp 1366ndash1372 1992
[251] R M Sharkey T M Cardillo E A Rossi et al ldquoSignal ampli-fication in molecular imaging by pretargeting a multivalentbispecific antibodyrdquo Nature Medicine vol 11 no 11 pp 1250ndash1255 2005
[252] D M Goldenberg and R M Sharkey ldquoNovel radiolabeledantibody conjugatesrdquo Oncogene vol 26 no 25 pp 3734ndash37442007
[253] D M Goldenberg E A Rossi R M Sharkey W J McBrideand C-H Chang ldquoMultifunctional antibodies by the dock-and-lock method for improved cancer imaging and therapy bypretargetingrdquo Journal of NuclearMedicine vol 49 no 1 pp 158ndash163 2008
[254] R Schoffelen R M Sharkey D M Goldenberg et al ldquoPre-targeted immuno-positron emission tomography imaging ofcarcinoembryonic antigen-expressing tumors with a bispecificantibody and a68Ga- And18F-labeled hapten peptide in micewith human tumor xenograftsrdquoMolecular Cancer Therapeuticsvol 9 no 4 pp 1019ndash1027 2010
[255] E S Bos W H Kuijpers M Meesters-Winters et al ldquoIn vitroevaluation of DNA-DNA hybridization as a two-step approachin radioimmunotherapy of cancerrdquoCancer Research vol 54 no13 pp 3479ndash3486 1994
[256] G Paganelli M Bartolomei M Ferrari et al ldquoPre-TargetedLocoregional Radioimmunotherapy withrdquo Cancer biotherapyand radiopharmaceuticals vol 16 no 3 pp 227ndash235 2001
[257] A Forero P L Weiden J M Vose et al ldquoPhase 1 trial of a novelanti-CD20 fusion protein in pretargeted radioimmunotherapyfor B-cell non-Hodgkin lymphomardquo Blood vol 104 no 1 pp227ndash236 2004
[258] DM Goldenberg C-H Chang E A RossiW J McBride andR M Sharkey ldquoPretargeted molecular imaging and radioim-munotherapyrdquoTheranostics vol 2 no 5 pp 523ndash540 2012
[259] H Karacay R M Sharkey W J McBride E A Rossi C-HChang and D M Goldenberg ldquoOptimization of hapten-peptide labeling for pretargeted immunoPET of bispecificantibody using generator-produced 68Gardquo Journal of NuclearMedicine vol 52 no 4 pp 555ndash559 2011
[260] J R Oh and B C Ahn ldquoFalse-positive uptake on radioiodinewhole-body scintigraphy physiologic and pathologic variantsunrelated to thyroid cancerrdquo American Journal of NuclearMedicine and Molecular Imaging vol 2 no 2 pp 141ndash150 2012
[261] E Frampas C Rousseau C Bodet-Milin J Barbet J-F Chataland F Kraeber-Bodere ldquoImprovement of radioimmunotherapyusing pretargetingrdquo Frontiers in Oncology vol 3 Article ID00159 2013
[262] C S McKay and M G Finn ldquoClick chemistry in complexmixtures Bioorthogonal bioconjugationrdquo Chemistry amp Biologyvol 21 no 9 pp 1075ndash1101 2014
[263] B L Oliveira Z Guo and G J Bernardes ldquoInverse electrondemand DielsndashAlder reactions in chemical biologyrdquo ChemicalSociety Reviews vol 46 no 16 pp 4895ndash4950 2017
[264] B Nichols Z Qin J Yang D R Vera and N K Devaraj ldquo68Gachelating bioorthogonal tetrazine polymers for the multisteplabeling of cancer biomarkersrdquo Chemical Communications vol50 no 40 pp 5215ndash5217 2014
[265] R Rossin P R Verkerk S M van den Bosch et al ldquoInvivo chemistry for pretargeted tumor imaging in live micerdquoAngewandte Chemie International Edition vol 49 no 19 pp3375ndash3378 2010
[266] B M Zeglis K K Sevak T Reiner et al ldquoA pretargetedPET imaging strategy based on bioorthogonal diels-alder clickchemistryrdquo Journal of Nuclear Medicine vol 54 no 8 pp 1389ndash1396 2013
[267] J L Houghton R Membreno D Abdel-Atti et al ldquoEstablish-ment of the invivo efficacy of pretargeted radioimmunotherapyutilizing inverse electron demand diels-alder click chemistryrdquoMolecular Cancer Therapeutics vol 16 no 1 pp 124ndash133 2017
[268] J Funkhouser ldquoReinventing pharma the theranostic revolu-tionrdquo Current Drug Discovery pp 17ndash19 2002
[269] J Sorensen I Velikyan A Wennborg et al ldquoMeasuring HER2-expression in metastatic breast cancer using 68Ga-ABY025PETCTrdquo European Journal of Nuclear Medicine and MolecularImaging vol 41 pp S226ndashS226 2014
[270] I Velikyan A Wennborg J Feldwisch et al ldquoGMP compliantpreparation of a 68Gallium-labeled Affibody analogue forbreast cancer patient examination first-in-manrdquoEur JNuclMedMol Imaging vol 41 pp S228ndashS229 2014
[271] K Oberg ldquoMolecular imaging radiotherapy Theranostics forpersonalized patient management of neuroendocrine tumors(NETs)rdquoTheranostics vol 2 no 5 pp 448ndash458 2012
[272] I Velikyan AWennborg J FeldwischH Lindman J Carlssonand J Sorensen ldquoGood manufacturing practice production of [(68) Ga]Ga-ABY-025 for HER2 specific breast cancer imagingrdquoAmerican Journal of Nuclear Medicine and Molecular Imagingvol 6 no 2 pp 135ndash153 2016
[273] M Sandstrom K Lindskog I Velikyan et al ldquoBiodistributionand radiation dosimetry of the anti-HER2 Affibody molecule68Ga-ABY-025 in breast cancer patientsrdquo Journal of NuclearMedicine vol 57 no 6 pp 867ndash871 2016
[274] D Sandberg V Tolmachev I Velikyan et al ldquoIntra-imagereferencing for simplified assessment of HER2-expression inbreast cancer metastases using the Affibody molecule ABY-025with PET and SPECTrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 44 no 8 pp 1337ndash1346 2017
[275] H ZhangM AMoroz I Serganova et al ldquoImaging expressionof the human somatostatin receptor subtype-2 reporter genewith 68Ga-DOTATOCrdquo Journal ofNuclearMedicine vol 52 no1 pp 123ndash131 2011
[276] M Naji and A Al-Nahhas ldquo68Ga-labelled peptides in themanagement of neuroectodermal tumoursrdquo European Journalof Nuclear Medicine and Molecular Imaging vol 39 no 1 ppS61ndashS67 2012
[277] I Velikyan ldquoThe diversity of 68Ga-Based imaging agentsrdquoRecent Results in Cancer Research vol 194 pp 101ndash131 2013
[278] K Ferreira H-Y Hu V Fetz et al ldquoMultivalent siderophore-dotam conjugates as theranostics for imaging and treatment ofbacterial infectionsrdquo Angewandte Chemie International Editionvol 56 no 28 pp 8272ndash8276 2017
![Review The Search for an Alternative to [ Ga]Ga-DOTA-TATE ...thno.org/v09p1336.pdf · [68Ga]Ga-DOTA-TATE, [68Ga]Ga-DOTA-TOC, and [68Ga]Ga-DOTA-NOC allows for NET staging with high](https://static.documents.pub/doc/80x56/5e2a1b5b2104573c786ad22c/review-the-search-for-an-alternative-to-gaga-dota-tate-thnoorg-68gaga-dota-tate.jpg)
![[68Ga]PSMA-HBED-CC Uptake in Osteolytic, Osteoblastic, and ... · Conclusions: [68Ga]PSMA-HBED-CC uptake is higher in osteolytic and bone marrow metastases compared to osteoblastic](https://static.documents.pub/doc/80x56/607572caf32e2d79681dbd86/68gapsma-hbed-cc-uptake-in-osteolytic-osteoblastic-and-conclusions-68gapsma-hbed-cc.jpg)
