Renata MikolajczakNCBJ Radioisotope Centre POLATOM05-400 Otwock, Poland

II International Symposium on Positron Emission TomographySeptember 21-24, 2014, Jagiellonian University, Kraków, Poland

Radiometals for PET diagnostics

National Centre for Nuclear Research, Radioisotope Centre POLATOM

National Centre for Nuclear Research

MARIAResearch Reactor

National Centre for Nuclear Research, Radioisotope Centre POLATOM

Radioisotope Centre POLATOM

Division in the National Centre for Nuclear Research

Research programs on the development of novel radiopharmaceuticals

Results of our research programs and innovation activities can be directly implemented in the GMP certified production and QC facilities.

National Centre for Nuclear Research, Radioisotope Centre POLATOM

Hot-cells for production of 90Y and 177Lu

National Centre for Nuclear Research Radioisotope Centre POLATOM

Radionuclides in medicine

Radiopharmaceuticals

Radiopharmaceutical is a substance formed in a chemical combination of two important components:

ligand, chemical compound, molecule or cell which is selectively taken up, metabolized or actively taking part in the physiological process in the imaged organ or tissue.

radionuclide, radioactive isotope of certain element – radiation emitted by this isotope is either registered and allows imaging of tracer distribution in the patient’s body or it can destroy the target tissue.

18F-FDG 18F (T1/2 = 110 min)

Fludeoxyglucose (18F) injection USP, Ph. Eur. (monograph 1325)

Potential targets for molecular imaging

important important target for target for

radiopeptidesradiopeptides

extracellular matrix

3-integrinsCD20, CD20, CD22CD22

DNA m-RNA

transcription translation

protein

neovasculature

pO2↓

pH↓

↻

repl

icati

on

GPCRsGPCRs

LATLATGLUT-1 GLUT-1 1818FDGFDG EGFRsEGFRs

soluble proteinNorep-TNorep-T

[[131131I]MIBGI]MIBG

NISNIS

MMPMMPCredit to H.R.Maecke

Principle of Positron Emission Tomography (PET)

Wadas TJ et al. Chem Rev 2010;110(5):2858-2902

Schematic Representation of a Drug for Imaging and Targeted Therapy

Molecular Address

• Antibodies, their fragments and modifications

• Regulatory peptides and analogs thereof

• Amino Acids

Target

• Antigens (CD20, HER2)

• GPCRs

• Transporters

pharmacokinetic modifier

LinkerLigand Chelator

Reporting Unit

• 99mTc, 111In, 67Ga• 64Cu, 68Ga • Gd3+

Cytotoxic Unit

• 90Y, 177Lu, 213Bi• 105Rh, 67Cu, 186,188Re

Credit to H.R. Maecke

Tailoring radionuclide half life (energy of emitted radiation) to pharmacokinetics of the ligand

The physical half-life of the radionuclide should match with the time required for the radiopharmaceutical to reach the disease/target site and the time required for the radioactivity to be cleared from the body (in vivo residence time)

The half-life must be long enough to ensure that the radioactivity of radiopharmaceutical reaching the disease/target localisation will provide the imaging or therapeutic effect.

The radionuclide must be attached to the carrier agent in a way that it is stable in vivo so that the radiation is deposited in the desired location. Hence the knowledge of chemical behaviour i.e. the properties of the element itself is important

Positron-Emitting Radiometals

Isotope T1/2 (h) Methods ofProduction

Decay Mode Eβ+ (keV)

60Cu 0.4 cyclotron,60Ni(p,n)60Cu

β+ (93%)EC (7%)

3920, 30002000

61Cu 3.3 cyclotron,61Ni(p,n)61Cu

β+ (62%)EC (38%)

1220, 1150940, 560

62Cu 0.16 62Zn/62Cugenerator

β+ (98%)

EC (2%)

2910

64Cu 12.7 cyclotron,64Ni(p,n)64Cu

β+ 19(%)EC (41%)β− (40%)

656

66Ga 9.5 cyclotron,63Cu(α,nγ)66Ga

β+ (56%)EC (44%)

4150, 935

68Ga 1.1 68Ge/68Gagenerator

β+ (90%)EC (10%)

1880, 770

86Y 14.7 cyclotron,86Sr(p,n)86Y

β+ (33%)EC (66%)

2335, 20191603, 12481043

89Zr 78.5 89Y(p,n)89Zr β+ (22.7%)EC (77%)

897,909, 1675,1713, 1744

Wadas TJ et al. Chem Rev 2010;110(5):2858-2902

β- radionuclides suitable for labelling molecules for targeted radiotherapy of tumors (produced in nuclear reactor)

Radioisotope Half-life Eβ- (max) meV Eγ (%) keV Production method Approx. max range in tissue [mm]

186Re 3.7 d 1.07 137 (9) 185Re(n,γ)186Re 3188Re 17 hr 2.11 155 (15) 187Re(n, γ) 188Re,

188W/188Re generator8

177Lu 6.7 d 0.5 113 (6.4), 208 (11)

176Lu (n, γ)177Lu, 176Yb (n,γ) 177Yb→177Lu

2

90 Y 2.7 d 2.27 - 90Sr/90Y generator 12105Rh 1.4 d 0.57, 0.25 319 (19), 306 (5) 104Rn(n,γ)105Rn→105Rh 2

149Pm 2.2 d 1.07 286 (3) 148Nd (n,γ)149Nd→149Pm 3153Sm 1.95 d 0.69, 0.64 103 (30), 70 (5) 152Sm(n, γ)153Sm 2

166Ho 1.1 d 1.85, 1.77 80 (6), 1379 (1) 164Dy (n, γ)165Dy (n,γ)166Dy→166Ho 9

32P 14.3 d 1.71 - 32S(n,p) 32P 8.2169Er 9.6 d 0.34 - 168Er(n,γ)169Er 2131I 8.0 d 0.6 364 (81), 637 (7) 130Te (n, γ)131Te→131I 2

111Ag 7.5 d 0.81 342 (6) 110Pd (n, γ) 111Pd→111Ag 267Cu 2.4 d 0.57 184 (48), 92 (23) 67Zn(n,p)67Cu 2

47Sc 3.35d 0.6, 0.44 159 (68) 47Ti(n,p)47Sc,46Ca(n,)47Ca→47Sc

2

199Au 3.2 d 0.46 158 (37), 208 (8) 198Pt(n,γ)199Pt→199Au 2

Matched +/- pairs 44Sc/47Sc 64Cu/67Cu 86Y/90Y 124I/123/131I

The „twin” isotope of the same element can be used for diagnostic imaging or therapy follow up, while the other is used for therapy using the same carrier molecules.

47Sc and 67Cu can be produced in nuclear reactor and in cyclotron

Matched Radionuclide Pairs for Imaging and Therapy (edited by A. Bockish) Eur J Nucl Med Mol Imaging, Vol 38, Suppl 1, June 2011

Theranostics: combination of diagnosis and therapy

Personalized medicine/tailored medicine/

Matching the right drug for the right patient

Chelatorschelator is used to tightly bind the a radiometal ion so that when injected into a patient, the targeting molecule can be delivered without any radiometal loss

Wadas TJ et al. Chem Rev 2010;110(5):2858-2902

National Centre for Nuclear Research Radioisotope Centre POLATOM

DOTA-somatostatin analogue

177Lu3+

Zn2+

Fe3+

68Ga

90Y

DOTA-TATE

Radiopeptide Therapy in Neuroendocrine Tumors

68Gallium – DOTATATE 90Yttrium – DOTATATE

Ga

Image Treat

Y

Credit to H.R. Maecke

Ga-6Ga-68, an innovative 8, an innovative radionuclideradionuclide??

GLEASONG,. I. : A PositronCow, Intl. J. Appi.Radiation Isotopes 8:90, 1960.

A GALLIUM-68 POSITRON COW FOR MEDICAL USE.YANO Y, ANGER HO. J Nucl Med. 1964 Jun;5:484-7.

ANGER, H. 0., AND GOTTSCHALK, A. : Localization of Brain Tumors with the Positron Scintillation Camera, J. Nuci. Med. 4:326, 1963.

„To date more than 100 patients have been examined with only a small number of false positives and few known missed tumors.“

Credit to C. Decristoforo

68Ga+ 1.968.3 m

cyclotron generatorOrganic synthesis coordination chemistry

18F+ 0.6110 m

18F and 68Ga for PET

Credit to F. Roesch

PET/CT

68Ge/68Ga generator.

67Ga; no +

78.3 h

69Ga60.1 %

68Ga+ 1.968.3 m

66Zn27.9 %6.2 b

68Ge

270.8 d

(p,2n)

Credit to F. Roesch

The added value in diagnostic

accuracy has an important

influence on patient

management

Ga-68 DOTATOC vs.SPECT and CT

From ‘one size fits all’ to ‘personalized therapy’From ‘one size fits all’ to ‘personalized therapy’

18FDG PET-CT

before

89Zr-rituximab

before

18FDG PET-CT

3 months after

Courtesy: K. Muylle, P. Flamen, Brussels and G. van Dongen, VUmc, Amsterdam

90Y-rituximab treatment

89Zr positron emitter with 72 h half life

44Sc is a positron emitter (Eβ+ 1475.4 keV with 94.27% positron branching) and gamma radiation component of 1157 keV(99.9%).

47Sc (T1/2 = 3.35 d) is emitting β- radiation with max. energy 0.600 MeV (31.6%) and 0.439 MeV (68.4%) radiation of 159.4 keV (63.3%) suitable for imaging.

44Sc and 47Sc

44ScDue to the half life (T1/2 = 3.92h) almost 4 times as long as the half life of 68Ga (T1/2 = 67.71 min) it is an attractive candidate for development of novel PET-radiopharmaceuticals.

47Sc can be utilized in radiotherapy using the same vector molecules

Both radionuclides can create a matched pair and their clinical application may bring additional value, particularly in combination with ligands requiring longer observation time than in case of 18F or 68Ga labeled molecules.

44Sc and 47Sc as matched pair for molecular imaging

Matched Radionuclide Pairs for Imaging and Therapy (edited by A. Bockish) Eur J Nucl Med Mol Imaging, Vol 38, Suppl 1, June 2011

Mean range in tissue 47Sc - 810 µm177Lu – 670 µm90Y – 3900 µm

44Ti/44Sc generator

(p,2n)

43Sc+ 1.23.89 h

45Sc100 %

44Sc+ 1.53.92 h

44Ti+ 1.960.4 a

45Ti+ 1.03.08 h

5 mCi = 185 MBq, elution possible every day in 3 ml volume

M. Pruszyński et al., Appl. Radiat. Isot., 68 (2010) 1636

0.005 M H2C2O4/ 0.07 M HCl

44Tiε

60.4 a

45Sc100 %

(p,2n)

44Ti Production at PSI, Zurich

PSI-Cyclotron Injector II72 MeV protons

encapsulated target~2 g scandium

Irradiation of natural scandium40 16 MeV energy range;up to 50 A current; water jet cooling.

44Ti yield0.002 – 0.003 MBq/Ah

Chemical isolation via anion-exchanger

Capacity needed for 1GBq of 44Ti equals amount of 68Ge of about 500 000 USD. 

Konstantin Zhernosekov et al.: Development and evaluation of 44Ti production on high energy protons. P-150 19th International Symposium on Radiopharmaceutical Sciences. 28.08-2.09.2011, Amsterdam

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

E(MeV)

barn

44Sc – 3,92 h

44Ca(p,n)44Sc

Cyclotron production of 44Sc

Ca(stable)ScSc 44β4444m

44mSc – 58,6 h

44Ca(p,n)44mSc

44Sc44Sc

44mSc44mSc

Data for activity calculation

intensity – 2 μA

time – 30 min 44CaCO3 target – 100 mg

Levkovskij, Act.Cs.By Protons and Alphas, Moscow 1991, USSR

Abbas et al. Cyclotron production of 44Sc - new radionuclide for PET technique. 19th International Symposium on Radiopharmaceutical Sciences. 28.08-2.09.2011, Amsterdam

The n.c.a. 47Sc can be produced by proton irradiation in accelerators and in a nuclear reactor.

In neutron irradiation there are 2 ways possible:

47Ti(n,p)47Sc

46Ca(n,)47Ca and consecutive -decay of 47Ca

both routes require further chemical separation

Scandium-47

L.F. Mausner, K.L. Kolsky, V.Joshi and S.C.Srivastava.Radionuclide development at BNL for nuclear medicine therapy. Appl Radiat Isot (1998) 49; 285-294

K. L. Kolsky, V. Joshi, L. F. Mausner and S. C. Srivastava. Radiochemical purification of no-carrier-added scandium-47 for radioimmunotherapy Appl Radiat Isot (1998) 49; 1541-1549

Chromatographic separation of 44Sc from 44Ca

Derivative IC50 (nM)

DOTA-BN[2-14]NH21.78 ± 0.12

natY-DOTA-BN[2-14]NH2

1.99 ± 0.06

natLu-DOTA-BN[2-14]NH2

1.34 ± 0.11

natGa-DOTA-BN[2-14]NH2

0.85 ± 0.06

natSc-DOTA-BN[2-14]NH2

6.49 ± 0.13

IC50 values from

displacement study of 125I-[Tyr4]-BN

-12 -11 -10 -9 -8 -7 -6 -50

20

40

60

80

100

natSc-DOTA-BN[2-14]NH2

natGa-DOTA-BN[2-14]NH2

DOTA-BN[2-14]NH2

natLu-DOTA-BN[2-14]NH2

natY-DOTA-BN[2-14]NH2

Log M

%B.

rad.

[12

5I-T

yr4 ]-B

N

Binding affinity study in PC-3 cells

Receptor affinity of M-DOTA-BN[2-14]NH2 : Ga>Lu>Y>Sc

E. Koumarianou et al. 44Sc-DOTA-BN[2-14]NH2 in comparison to 68Ga-DOTA-BN[2-14]NH2 in pre-clinical investigation. Is 44Sc a potential radionuclide for PET? App

Radiat Isot 70 (2012) 2669–2676

Dep

t. o

f N

ucle

ar

Med

icin

e/P

.E.T

. C

ente

r, Z

entr

alkl

inik

Bad

Ber

ka

44Sc-DOTA-TOC for dosimetric interest and long-term imaging

Pruszyński M, Majkowska-Pilip M, Loktionova NS, Rösch FRadiolabeling of DOTATOC with the longer-lived, generator-derived positron emitter 44Sc

Pruszyynski M, Loktionova NS, Filosofov DV, Rösch F,Post-elution processing of 44Ti/44Sc generator-derived 44Sc for clinical applicationAppl Radiat Isot 68 (2010) 1636-1641

44Ti

ca 60 a

44Sc+ 0.60 MeV

3.97 h

44Sc-DOTA-TOC PET/CT: 18 h p.i.

44Sc: development of PET-tracers

Development of Sc theranostic radiopharmaceuticals

C.Müller et al. Promises of cyclotron-produced 44Sc as a diagnostic match for trivalent - emitters: in vitro and in vivo study of a 44Sc-DOTA-folate conjugate, J.Nucl.Med. 54 (2013) 2168–217

C.Müller et al. Promises of cyclotron-produced 44Sc as a diagnostic match for trivalent - emitters: in vitro and in vivo study of a 44Sc-DOTA-folate conjugate, J.Nucl.Med. 54 (2013) 2168–217

C.Müller et al. Promises of cyclotron-produced 44Sc as a diagnostic match for trivalent - emitters: in vitro and in vivo study of a 44Sc-DOTA-folate conjugate, J.Nucl.Med. 54 (2013) 2168–217

Radioisotopes of Sc with medical potential

Radionuclide Reaction Half-life β energies γ energies

47Sc 48Ti(p,2p)47Sc50Ti(p,2p2n)47Sc47Ti(n,p)47Sc46Ca(n,γ)47Sc

3.35 d 0.6 (32%) 0.44 (68%)

159 keV (68%)

44/44mSc 44Ca(d,2n)44Sc 3.97 h /58.6 h

0.632 MeV 511 keV (94.72%) /511 keV (100%)

44Sc/44Ti Generator available 3.97 h 0.632 MeV 511 keV (94.72%)

43Sc natTi(p,x)47Ti(p,nα)48Ti(p,2nα)

3.89 h 0.825 (17.2%)1.198 (70.9%)

511 keV (100%)

New collaborative project starting : Institute of Nuclear Chemistry and Technology, Heavy Ion Laboratory, UW, POLATOM

Diagnostic RadionuclidesDiagnostic Radionuclides

Gamma-Emitters

99mTc,111In, 67Ga, 201Tl, 123I

Positron-Emitters

89Zr, 68Ga, 64Cu, 11C, 13N, 15O, 18F

Therapeutic RadionuclidesTherapeutic Radionuclides

Beta-Emitters

90Y, 186/188Re, 177Lu, 131I, 165Dy, 166Ho, 105Rh, 111Ag

Alpha-Emitters

212Bi, 213Bi, 211At, 255Fm, 225Ac

Theranostic pairsTheranostic pairs (matched pairs) (matched pairs)

64Cu/ 67Cu99mTc/ 186/188Re 111In/ lanthanides, 90Y

123/124I/131I 68Ga/67Ga (Auger)

Theranostics

Nuclear probes

PET/SPECT for imaging

Particle emitters for targeted radionuclide therapy

Optical probes

Photodynamic therapy

MRI probes

Gd-complexes

Gd based neutron capture therapy

Imaging

Courtesy H.R. Maecke

Development of multimodality probes for theranostic aplications

Developments in Nuclear Medicine

Improved access to radionuclides

Better understanding of targets

Variety of ligands designed for these targets

Imaging modalities – improved scanners, hybrid

systems SPECT, PET/CT, PET/MR

Multidisciplinary approach, collaboration between groups of various expertise – international programs

FP6, FP7, COST, EUREKA, IAEA

Cu-61 64Zn(p,a)61Cu labeling of peptides, antibodies (immuno-PET)

Cu-64 64Ni(p,n)64Cu labeling of peptides, antibodies, small molecules

Y-86 86Sr(p,n)86Y dosimetry for 90Y-labeled peptides, antibodies

Zr-89 89Y(p,n)89Zr labeling of antibodies (long-term targeting)

Hg-197(m) 197Au(p,n)197(m)Hg labeling of peptides, antibodies, small molecules

Production of Radiometals at Helmholtz-Zentrum Dresden-Rossendorf, Germany

PET-Cyclotron „CYCLONE 18/9” (IBA, Belgium)

AcknowledgementsHelmut R Maecke, BaselMarion de Jong, RotterdamW.A.P. Breeman, RotterdamRichard Baum, Bad Berka

Alicja Hubalewska-Dydejczyk, KrakowKatarzyna Fröss, Krakow Anna Staszczak, Krakow Jaroslaw Cwikla, WarsawJolanta Kunikowska, WarsawLeszek Krolicki, WarsawPiotr Garnuszek, WarsawClemens Decristoforoand Radiopharmacy Committee

D. Pawlak, B. Janota, W. Wojdowska, E. Koumarianou Radioisotope Centre POLATOM

COST TD1004 – Theragnostics Imaging and Therapy: An Action to Develop Novel Nanosized Systems for Imaging-Guided Drug Delivery (2011-2015), leader of WG1 Imaging reporters for theranostic agents and in COST CM1105 - Functional metal complexes that bind to biomolecules (2012–2016)