II International Symposium on Positron Emission Tomography
September 21-24, 2014, Jagiellonian University, Kraków, Poland
Radiometals
for PET diagnostics
Renata Mikolajczak
NCBJ Radioisotope Centre POLATOM
05-400 Otwock, Poland
National Centre for Nuclear Research, Radioisotope Centre POLATOM
National Centre for Nuclear Research
MARIA
Research 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
Radionuclides in medicine
National Centre for Nuclear Research Radioisotope Centre POLATOM
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
3-integrins
CD20,
CD22
NIS
transcription
important
target for
radiopeptides
translation
GPCRs
m-RNA
DNA
protein
LAT
GLUT-1
18FDG
extracellular
matrix
pO2↓
Norep-T
[131I]MIBG
soluble protein
EGFRs
MMP
Credit to H.R.Maecke
pH↓
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
pharmacokinetic
modifier
Ligand
Chelator
Linker
Target
Molecular Address
Reporting Unit
• Antigens
(CD20,
HER2)
• Antibodies, their
fragments and
modifications
• GPCRs
• Regulatory peptides
and analogs thereof
• 99mTc, 111In, 67Ga
• 64Cu, 68Ga
• Gd3+
Cytotoxic Unit
• Transporters
• Amino Acids
•
•
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 of
Production
Decay Mode
Eβ+ (keV)
60Cu
0.4
cyclotron,
60Ni(p,n)60Cu
β+ (93%)
EC (7%)
3920, 3000
2000
61Cu
3.3
cyclotron,
61Ni(p,n)61Cu
β+ (62%)
EC (38%)
1220, 1150
940, 560
62Cu
0.16
62Zn/62Cu
β+ (98%)
2910
generator
EC (2%)
cyclotron,
64Ni(p,n)64Cu
β+ 19(%)
EC (41%)
β− (40%)
656
9.5
cyclotron,
63Cu(α,nγ)66Ga
β+ (56%)
EC (44%)
4150, 935
1.1
68Ge/68Ga
β+ (90%)
EC (10%)
1880, 770
64Cu
12.7
66Ga
68Ga
generator
86Y
14.7
cyclotron,
86Sr(p,n)86Y
β+ (33%)
EC (66%)
2335, 2019
1603, 1248
1043
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
186Re
188Re
Half-life
Eβ- (max) meV
Eγ (%) keV
3.7 d
17 hr
1.07
2.11
137 (9)
155 (15)
Production method
185Re(n,γ)186Re
187Re(n,
γ)
188Re,
188W/188Re
177Lu
generator
γ)177Lu,
2.7 d
1.4 d
2.27
0.57, 0.25
1.07
0.69, 0.64
286 (3)
103 (30), 70 (5)
148Nd
153Sm
2.2 d
1.95 d
(n,γ)149Nd→149Pm
152Sm(n, γ)153Sm
3
2
166Ho
1.1 d
1.85, 1.77
80 (6), 1379 (1)
164Dy (n,
9
14.3 d
9.6 d
8.0 d
1.71
0.34
0.6
364 (81), 637 (7)
32S(n,p) 32P
0.81
0.57
342 (6)
184 (48), 92 (23)
110Pd
67Cu
7.5 d
2.4 d
(n, γ) 111Pd→111Ag
67Zn(n,p)67Cu
2
2
47Sc
3.35d
0.6, 0.44
159 (68)
47Ti(n,p)47Sc,
2
105Rh
149Pm
32P
169Er
131I
111Ag
0.5
3
8
113 (6.4), 208
(11)
319 (19), 306 (5)
90 Y
6.7 d
176Lu
Approx. max range
in tissue [mm]
(n,
(n,γ) 177Yb→177Lu
90Sr/90Y generator
104Rn(n,γ)105Rn→105Rh
2
176Yb
γ)165Dy (n,γ)166Dy→166Ho
168Er(n,γ)169Er
130Te
(n, γ)131Te→131I
12
2
8.2
2
2
46Ca(n,)47Ca→47Sc
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
47Sc
and 67Cu can be
produced in nuclear
reactor and in cyclotron
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.
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
Chelators
chelator 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
DOTA-TATE
DOTA-somatostatin analogue
Zn2+
68Ga
Fe3+
177Lu3+
90Y
National Centre for Nuclear Research Radioisotope Centre POLATOM
Radiopeptide Therapy in Neuroendocrine Tumors
68Gallium
– DOTATATE
90Yttrium
– DOTATATE
Ga
Image
Y
Treat
Credit to H.R. Maecke
Ga-68, an innovative radionuclide?
GLEASONG,. I. : A PositronCow, Intl.
J. Appi.Radiation Isotopes 8:90,
1960.
ANGER, H. 0., AND GOTTSCHALK, A. : Localization
of Brain Tumors with the Positron Scintillation
Camera, J. Nuci. Med. 4:326, 1963.
A GALLIUM-68 POSITRON COW FOR MEDICAL USE.
YANO Y, ANGER HO. J Nucl Med. 1964 Jun;5:484-7.
„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
18F
18F
+ 0.6
110 m
cyclotron
Organic synthesis
and
68Ga
for PET
68Ga
PET/
CT
+ 1.9
68.3 m
generator
coordination chemistry
Credit to F. Roesch
68Ge/68Ga
generator.
68Ge
(p,2n)
e
270.8 d
67Ga
e; no +
78.3 h
68Ga
+ 1.9
68.3 m
69Ga
60.1 %
66Zn
27.9 %
6.2 b
Credit to F. Roesch
Ga-68 DOTATOC vs.SPECT and CT
The added value in diagnostic
accuracy has an important
influence on patient
management
From
‘onesize
sizefits
fitsall’
all’toto
‘personalized
From ‘one
‘personalized
therapy’
therapy’
18FDG
PET-CT
before
89Zr-rituximab
before
89Zr
positron
emitter
with 72 h
half life
18FDG
PET-CT
3 months after
90Y-rituximab
treatment
Courtesy: K. Muylle, P. Flamen, Brussels and G. van Dongen, VUmc, Amsterdam
44Sc
and
47Sc
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
as matched pair for molecular imaging
44Sc
Due to the half life (T1/2 = 3.92h) almost 4 times as long as the half life of
68Ga (T
1/2 = 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
Mean range in tissue
47Sc
- 810 µm
177Lu – 670 µm
90Y –
3900 µm
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.
Matched Radionuclide Pairs for Imaging and Therapy (edited by A. Bockish)
Eur J Nucl Med Mol Imaging, Vol 38, Suppl 1, June 2011
0.005 M H2C2O4/
0.07 M HCl
44Ti/44Sc
44Ti
+
generator
45Ti
+
1.9
60.4 a
1.0
3.08 h
43Sc
44Sc
+ 1.2
3.89 h
+ 1.5
3.92 h
(p,2n)
45Sc
100 %
5 mCi = 185 MBq, elution possible
every day in 3 ml volume
M. Pruszyński et al.,
Appl. Radiat. Isot., 68 (2010) 1636
44Ti
Production at PSI, Zurich
 Irradiation of natural scandium
40  16 MeV energy range;
up to 50 A current;
water jet cooling.

44Ti
(p,2n)
ε
60.4 a
45Sc
44Ti
yield
0.002 – 0.003 MBq/Ah
 Chemical isolation via anionexchanger
100 %
encapsulated target
~2 g scandium
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. P150 19th International Symposium on Radiopharmaceutical
Sciences. 28.08-2.09.2011, Amsterdam
PSI-Cyclotron Injector II
72 MeV protons
Abbas et al. Cyclotron production of 44Sc - new radionuclide for PET
technique. 19th International Symposium on Radiopharmaceutical
Sciences. 28.08-2.09.2011, Amsterdam
Cyclotron production of
44Sc
44Sc
– 3,92 h
44mSc
44Ca(p,n)44Sc
44m
44Ca(p,n)44mSc
β
Sc  Sc  Ca(stable)
44
44
44Sc
44Sc
0,8
Data for activity calculation
intensity – 2 μA
0,7
time – 30 min
0,6
44CaCO
0,5
barn
– 58,6 h
0,4
0,3
0,2
0,1
44mSc
0
5 6 7 8
9 10 11 12 13 14 15 16 17 18 19 20
E(MeV)
Levkovskij, Act.Cs.By Protons and Alphas, Moscow 1991,
USSR
44mSc
3
target – 100 mg
Scandium-47
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
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;
Chromatographic separation of
from 44Ca
44Sc
E. Koumarianou et al. 44Sc-DOTA-BN[2-14]NH2 in comparison to 68Ga-DOTA-BN[214]NH2 in pre-clinical investigation. Is 44Sc a potential radionuclide for PET? App
Radiat Isot 70 (2012) 2669–2676
Binding affinity study in PC-3 cells
100
%B. rad. [ 125I-Tyr4]-BN
DOTA-BN[2-14]NH2
nat
80
Y-DOTA-BN[2-14]NH2
nat
Lu-DOTA-BN[2-14]NH2
60
nat
Ga-DOTA-BN[2-14]NH2
nat
40
Sc-DOTA-BN[2-14]NH2
IC50 values from
displacement study of
125I-[Tyr4]-BN
Derivative
IC50 (nM)
1.78 ± 0.12
DOTA-BN[2-14]NH2
natY-DOTA-BN[2-14]NH
1.99 ± 0.06
2
natLu-DOTA-BN[2-14]NH
20
natGa-DOTA-BN[2-14]NH
natSc-DOTA-BN[2-14]NH
0
-12
2
-11
-10
-9
-8
Log M
-7
-6
2
2
1.34 ± 0.11
0.85 ± 0.06
6.49 ± 0.13
-5
Receptor affinity of M-DOTA-BN[2-14]NH2 : Ga>Lu>Y>Sc
44Sc:
development of PET-tracers
44Sc-DOTA-TOC PET/CT: 18 h p.i.
44Ti
e
44Sc
94 %  +
0.60 MeV
3.97 h
44Sc-DOTA-TOC
for dosimetric interest
and long-term imaging
Pruszyński M, Majkowska-Pilip M, Loktionova NS, Rösch F
Radiolabeling 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 application
Appl Radiat Isot 68 (2010) 1636-1641
Dept. of Nuclear Medicine/P.E.T. Center, Zentralklinik Bad Berka
ca 60 a
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 44ScDOTA-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)47Sc
3.35 d
0.6 (32%)
0.44 (68%)
159 keV
(68%)
50Ti(p,2p2n)47Sc
47Ti(n,p)47Sc
46Ca(n,γ)47Sc
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)
3.89 h
0.825
(17.2%)
1.198
(70.9%)
511 keV
(100%)
47Ti(p,nα)
48Ti(p,2nα)
New collaborative project starting :
Institute of Nuclear Chemistry and
Technology, Heavy Ion Laboratory, UW,
POLATOM
Diagnostic Radionuclides
Positron-Emitters
Gamma-Emitters
89Zr, 68Ga, 64Cu, 11C, 13N, 15O, 18F
99mTc,111In, 67Ga, 201Tl, 123I
Therapeutic Radionuclides
Beta-Emitters
Alpha-Emitters
90Y, 186/188Re, 177Lu, 131I, 165Dy,
166Ho, 105Rh, 111Ag
212Bi, 213Bi, 211At, 255Fm, 225Ac
Theranostic pairs (matched pairs)
99mTc/ 186/188Re
123/124I/131I
111In/
lanthanides,
90Y
68Ga/67Ga
64Cu/ 67Cu
(Auger)
Development of multimodality probes
for theranostic aplications
Gd-complexes
Imaging
Gd based
neutron capture
therapy
Photodynamic therapy
Optical probes
MRI probes
Theranostics
Nuclear probes
PET/SPECT for imaging
Particle emitters for targeted radionuclide therapy
Courtesy H.R. Maecke
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
Production of Radiometals
at Helmholtz-Zentrum Dresden-Rossendorf, Germany
PET-Cyclotron „CYCLONE 18/9” (IBA, Belgium)
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
Zr-89
Hg-197(m)
86Sr(p,n)86Y
89Y(p,n)89Zr
197Au(p,n)197(m)Hg
dosimetry for
antibodies
90Y-labeled
peptides,
labeling of antibodies (long-term
targeting)
labeling of peptides, antibodies,
small molecules
Acknowledgements
Helmut R Maecke, Basel
Marion de Jong, Rotterdam
W.A.P. Breeman, Rotterdam
Richard Baum, Bad Berka
Alicja Hubalewska-Dydejczyk, Krakow
Katarzyna Fröss, Krakow
Anna Staszczak, Krakow
J
aroslaw Cwikla, Warsaw
Jolanta Kunikowska, Warsaw
Leszek Krolicki, Warsaw
Piotr Garnuszek, Warsaw
Clemens Decristoforo
and 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)