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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)