Probes for Nuclear Imaging

MEng Lecture

• History of nuclear imaging• Why nuclear imaging• Types of nuclear imaging- PET and SPECT• Principles of PET and SPECT• PET agents• Specific examples- Cancer• Specific examples- Cardiovascular• Specific examples- Neuro

Topics to Cover

History of Nuclear Imaging

• George Charles de Hevesy was first to identify the radioisotope tracer principle.

• In 1923, he used 10.6 hour lead-212 to study the uptake of solutions in bean plants, noninvasively. Used small, non-toxic amounts given the sensitivity of the radioactivity techniques.

• The first experiment in animals used Bi-210 to label and follow the circulation of Bi-containing antisyphilitic drugs in rabbits.

• In a later book with Fritz Paneth, the tracer method was introduced as the use of radioelements as indicators.

•The first practical application of a radioisotope was made by George de Hevesy in 1911.•He suspected that meals that appeared regularly might be made from leftovers.•To confirm these suspicions de Hevesy put a small amount of radioactive material into the remains of a meal.•When the same meal was served, it was radioactive!

George de Hevesy : Nobel prize in 1943 and the Atoms for Peace award in 1959.

1934 photo of Livingston and Lawrence with the 27” cyclotron

The Advantage of Radionuclides for Targeted Imaging, especially Low Density Sites (<20 nM)

If 10 mCi at a specific activity of >1000 µCi/nmol: 10 nmol/70 Kg

<0.2 nM

For Gd MRI: Iron oxide (T2) increases sensitivity.

10-100 µM

For CT:Iodinated contrast media

>100 µM

Optical imaging and Ultrasound ?

Schematic view of a detector block and ring of a PET scanner

• Nuclear imaging technique that produces a 3D image of functional processes in the body• Detects pairs of rays emitted indirectly by a positron-emitting radionuclide (tracer)• 3D-images of tracer concentration within the body are then constructed by computer analysis. • In PET-CT or PET-MR scanners, 3D-imaging is accomplished with the aid of a CT X-ray/MR scan performed on the patient during the same session, in the same machine.

First, a targeted imaging agent containing a positron emitting radioisotope is administered to the subject. Positrons are emitted from each imaging agent only once; these positrons travel short distances and collide with electrons in the surrounding tissues (annihilation), resulting in the production of two rays, (energy 511 keV), traveling at opposite directions to one another (180° apart). Following the detection of gamma rays by the PET detector, the location of annihilation events are calculated by observing multiple events. The resulting electrical signals are converted into sinograms that are reconstructed into tomographic images.

Images demonstrating the noninvasive visualization of an orthotopic brain tumor (2.5 mm in diameter) in a rat via the use of ([18F]FDG), as early as 10 days (D10) after implantation. Pinks arrows show tumor, and red arrow shows wound due to intracerebral implantation of tumor cells

Principles of PET

First, a targeted SPECT imaging agent (containing a emitting radioisotope) is administered to the subject and the gamma rays are detected via a gamma camera (rotated around the subject). The detected gamma rays are then reconstructed into tomographic images, providing information on the location of the imaging agent in the subject.

B: SPECT images demonstrating the utility of visualizing gastrin-releasing peptide receptor (GRPR), a receptor often found in high levels in prostate cancer, via the administration of [99mTc]-HABN in mice bearing human prostate xenografts. Arrows point to tumor; clear visualization of tumor is possible at 4 h post-injection (p.i.)

Principles of SPECT

PET Scan vs. Stress Echocardiogram for Cardiovascular Disease

www.cms.gov

Comparative Lung Cancer Detection with using 18F-FDG

Transaxial images of CT (left) and FDG-PET/CT (right) in three different patients. A: A male smoker with 2 cm lump in left lung (red cross hair). With CT alone the risk of this lump being cancer is 50%. The lump has a very high FDG uptake, which is typical for fast growing cancers and the combined image indicates an 80% risk of cancer.

B: A non-smoking female with a 1.5 cm lesion that has no FDG uptake (the large yellow area is the heart muscle). The negative predictive value of the combined image is 99%.

C: CT with a bone window setting is negative for bone metastases. PET shows two small metastases with very intense uptake.

Combined coronal [18F]-FDG PET/CT images from a 25-year old woman, who was diagnosed with aggressive Non-Hodgkins Lymphoma. Prior to PET/CT the patient was known to have disease in the neck and mediastinum. The left image was obtained before treatment and showed extensive growth of tumors not only in the neck and mediastinum, but also in abdominal lymph nodes, bone marrow, liver and spleen. This image dramatically changed the disease stage and the associated treatment.

(Right Image) After chemotherapy: The mediastinal lumps remain visible on CT, termed ”partial anatomical remission”, but neither these lumps nor any of the previously diagnosed lymphoma locations show pathological FDG uptake, a pattern of findings termed ”complete metabolic remission”. This finding after treatment is highly predictive of treatment success without any need of therapy changes. On the other hand, remaining FDG uptake in any of the known lumps is associated with a high likelihood of recurrence.

FDG-PET/CT for Staging and Treatment in Lymphoma

Isotopes with short half-lives such as C-11 (~20 min), N-13 (~10 min), O-15 (~2 min), F-18 (~110 min)., or Rb-82(~1.27 min).

Incorporated either into compounds normally used by the body such as glucose (or glucose analogues), water, or ammonia, or into molecules that bind to receptors or other sites of drug action.

Trace biologic pathways of tracers in humans.

Clinical PET scanning uses fluorodeoxyglucose (FDG or fludeoxyglucose), an analogue of glucose that is labeled with F-18 essentially in all scans (>95%) for oncology and most scans in neurology.

Due to the short half-lives of most positron-emitting radioisotopes, the radiotracers have traditionally been produced using a cyclotron in close proximity to the PET imaging facility.

Rb-82 generators have become commercially available. These contain strontium-82, which decays by electron capture to produce positron-emitting rubidium-82.

Nuclear Imaging Contrast Agent Essentials

PET Radionucleotides

T1/2 (min) E+ (kev) Nuclear Reaction

82Rb 1.3 3350 82Sr generator11C 20 960 14N (p,) w. 6 ppm O2

13N 10 1190 16O (p,)15O 2.05 1720 14N (d,n) w. 2% O2

18F 109.6 635 20Ne (d,) w. 0.5%F2

18F 109.6 635 18O (p,n)

76Br 966 3980 75As (a,3n)64Cu 762 571 64Ni (p,n)124I 5976 2134 124Te (p,n)

FDG: 18F-fluorodeoxyglucose (FDG) is a radioactive sugar molecule, that, when used with PET imaging, produces images that show the metabolic activity of tissues. In FDG-PET scanning, the high consumption of the sugar by tumor cells, as compared to the lower consumption by normal surrounding tissues, identifies these cells as cancer cells. FDG is also used to study tumor response to treatment.

PET and Nuclear Medicine Imaging AgentsElimination half-life: 110 min (at 70%)16 min (at 20%)

Excretion 20% Radioactivity renally excreted in 2 h

Mechanism of [18F]FDG signal amplification

James M L , and Gambhir S S Physiol Rev 2012;92:897-965

©2012 by American Physiological Society

The small molecule imaging agent [18F]FDG is an analog of glucose, whereby the 2-carbon hydroxyl group of glucose is substituted with a fluorine atom. Like glucose, [18F]FDG is taken up by cells via the glucose transporter (GLUT1) and phosphorylated by hexokinase II (HKII) to form [18F]FDG-6-PO4; however, (unlike glucose), further metabolism is prevented due to the absence of the required 2-carbon hydroxyl, and hence [18F]FDG remains trapped within the cell. [18F]FDG-6-PO4 accumulates in cells over time, leading to signal amplification and making this imaging agent a suitable indicator of hexokinase II activity as well as a cell's need for glucose.

64Cu-ATSM: 64Cu diacetyl-bis(N4-methylthiosemicarbazone), also called ATSM or Copper 64, is an imaging agent used in PET or PET/CT for its ability to identify hypoxic tissue (tissue with low oxygen).

PET and Nuclear Medicine Imaging Agents64Cu half-life - 12.7h Decays: 17.86 (± 0.14)% by positron emission to 64Ni, 39.0 (± 0.3)% by beta decay to 64Zn, 43.075 (± 0.500)% by electron capture to 64Ni, and 0.475 (± 0.010)% gamma radiation/internal conversion.

PET/CT shows decreased retention of 64Cu-ATSM in ArKO tumor–bearing mice. Whole-body PET/CT images were acquired for wild-type (A) and ArKO tumor–bearing (B) mice 1 h after the intravenous injection of 3.7 MBq (100 μCi) of 64Cu-ATSM. Images show protuberant abdomen in ArKO tumor–bearing mouse and clearly decreased activity in right side of enlarged liver (circles).

18F-fluoride: 18F-fluoride is an imaging agent for PET imaging of new bone formation. It can assess changes both in normal bone as well as bone tumors. As a result, it can be used to measure response to treatment.

http://pubs.rsc.org/en/content/articlelanding/2011/dt/c0dt01618g#!divAbstract

Normal distribution of the tracer was visualized throughout the entire skeletal system, except for mild degenerative changes in the lower lumbar vertebrae (arrows). There was no evidence of skeletal metastatic disease.

Gallium: Gallium attaches to areas of inflammation, such as infection. It also attaches to areas of rapid cell division, such as cancer cells. It can take gallium a few days to accumulate in the affected tissue, so the scan may be done 2-3 days after the gallium is administered. (Gallium Citrate or Nitrate)

Gallium Scans

•Produced by a cyclotron. •Charged particle bombardment of enriched 68Zn. •The 67gallium is then complexed with citric acid•The half life of gallium-67 is 78 hours.

Gallium-67 photo-peaks:Energy Abundance93 keV 40%184 keV 20%300 keV 17%393 keV 5%

Imaging og biopsy-proven enteococcus faecalis spondylodiscitis at L4-L5.

Left: increased uptake at vertebral endplates adjacent to L4-L5 disc space on bone scan SPECT/CT.

Middle: discordant increased Ga uptake within disc space itself.

Right: corresponding hyperintensity in verbral bodies and L4-L5 intervertebral disc space on T2-weighted MR imaging

Technetium (99mTc) tetrofosminHalf-life: 6.0058 h; Parent isotopes 99Mo (65.976 h); Decay products: 99Tc

Tc-99m tetrofosmin is rapidly taken up by myocardial tissue and reaches its maximum level in approximately 5 minutes.

About 66% of the total injected dose is excreted within 48 hours after injection (40% urine, 26% feces)

The severity of Diabetic Foot Infection can be best measured by determining the anatomic and physiologic parameters by utilizing 99mTc-WBC SPECT/CT images.

This gives information regarding intensity, number, and location of lesions, as well as radiographic evidence of adjacent disrupted bone architecture)

Evaluation of a radiolabeled binding aptamer ([99mTc]-TTA1) specific for extracellular matrix protein tenascin-C, vs a radiolabeled nonbinding aptamer, in mice either bearing glioblastoma (U251) or breast cancer (MDA-MB-435) tumor xenografts using planar scintigraphy. The results show rapid tumor uptake and fast blood clearance of the binding aptamer [99mTc]-TTA1, affording a tumor-to-blood ratio of 50 within 3 h. Scintigraphic images obtained at 18 h depict the tumor as the brightest structure and demonstrate the almost complete clearance of [99mTc]-TTA1 from the body, whereas the tumor cannot be visualized using the radiolabeled nonbinding aptamer. [99mTc]-TTA1 could also be used to detect breast tumor xenografts (MDA-MB-435) at 20 h, illustrating the use of this aptamer for detecting different tumor types.

Example of a clinical (AD) using [11C]PK11195, positron emission tomography (PET), and magnetic resonance imaging (MRI). This figure shows brain PET images coregistered with MRI images for a normal elderly subject (A) and a patient with mild AD (B). Arrows represent regions of increased [11C]PK11195 binding found in mild AD patient and not in elderly control.

Molecular imaging of neuro-inflammation in patients with mild Alzheimer's disease

MicroPET images (coronal) of mice with BT-474 tumors with Ga-68-DOTAcHF at 3 h before and 24 h

after 17-AAG

Tum

or &

kid

ney

Nat Biotechnol. 2004;22:701-6

Nuclear imaging of Detecting Cardiovascular disease

coronal PET (left), transverse PET (top middle), and transverse PET/CT (bottom middle) images of 18F-FDG–labeled circulating progenitor cells 4h after intracoronary infusion via the left anterior descending coronary artery in a patient with 92-day-old anteroseptal wall infarction. Cell accumulation (grayscale for the coronal image; color scale for the transverse images) is clearly visualized in the anteroseptal wall of heart (H; 2% at 4 hours), liver (L), spleen (S), and bone marrow within the skeleton. Images courtesy of Won Jun Kang at Yonsei University, South Korea.132 B, PET imaging of reporter gene/probe-labeled embryonic stem cells. A mouse underwent intramyocardial injection of mouse embryonic stem cells expressing HSV1-sr39tk PET reporter gene, followed by 18F-FHBG and 18F-FDG scans 2 weeks later to assess cell viability and myocardial glucose metabolism. Representative transverse 18F-FHBG (top right), 18F-FDG (middle right), and18F-FHBG/18F-FDG fusion (bottom right) images show the location of implanted cells (arrowheads) in the anterolateral wall of the LV, where cells were implanted.

Clinical and preclinical PET imaging of stem cell transplantation

A, Human PET imaging of the engraftment of 18F-FDG–labeled circulating progenitor cells after intracoronary infusion. Representative

18F-FDG uptake of human carotid and aortic atherosclerotic plaques in response to simvastatin therapy. Coronal 18F-FDG PET images (top 2 rows) of human carotid (upper white arrows) and aortic (lower white arrows) atherosclerotic plaques at baseline (left column) and 3 months after treatment (right column) with either dietary management (top row) or simvastatin (bottom 2 rows). 18F-FDG uptake is attenuated in both carotid and aortic atherosclerotic plaques treated with simvastatin, as clearly demonstrated in the transverse PET/CT images (bottom row) of a left carotid plaque (black box). Plaque 18F-FDG uptake is not influenced by dietary management.

Monitoring Therapy with Nuclear Imaging

Effects of Nuclear Radiation• We are surrounded by natural radiation coming from the sky, the

ground and even the foods we eat.

• Radiation generated from a nuclear bomb or reactor can be highly concentrated, which may deliver lethal dose in a very short span of time.

What are the Possible Health Effects of a Radiation Exposure?