1. Novel diagnostic and therapeutic radionuclides
IS528-ADD1
Novel diagnostic and therapeutic radionuclides
for the development of innovative radiopharmaceuticals
Katharina Domnanich1, Catherine Ghezzi2, Ferid Haddad3, Mikael Jensen4, Christian Kesenheimer6, Ulli Köster5, Cristina Müller1, Bernd Pichler6,
Jean-Pierre Pouget7, Anna-Maria Rolle6, Roger Schibli1, Gregory Severin4, Andreas Türler1, Stefan Wiehr6, Nick van der Meulen1
Local contact: Karl Johnston
1 Paul Scherrer Institut, Villigen – Universität Bern – ETH Zürich, Switzerland
2 CHU – INSERM – Université Grenoble, France
3 ARRONAX – INSERM – CRCNA – Subatech Nantes, France
4 Risø National Laboratory, Roskilde, Denmark
5 Institut Laue Langevin, Grenoble, France
6 Universitätsklinik Tübingen, Germany
7Institut de Recherche en Cancérologie de Montpellier, France

2. Radiometals for diagnostic imaging and therapy
Objectives M☢
Receptor
Chelator
Peptide
Abs
Vitamins
Photon or positron emitters 99mTc, 68Ga, … for imaging
Particle emitters 90Y, 177Lu, … for radionuclide therapy
applicable only
with high specific activity and chemical purity

3. The Nuclear Medicine Alphabet
SPECT
Camera
PET-Scanner +
Auger-e-  -

4. Production of n.c.a. [149/152/155Tb]-Terbium ISOLDE CERN and PSI
Paul Scherrer Institute
Separation by means of cation exchange chromatography
Spallation of tantalum targets followed by resonant laser ionization of Dy precursor and mass separation
 149,152,155Tb with some oxide sidebands
Chemical removal of oxide sidebands performed at PSI 4

5. Tumor Tageting Agent for Tb-Coordination Chemical Structure with 3 Functionalities
albumin binder
folic acid
Tb-folate
Chracteristics:
stable coordination of Tb-isotopes
high affinity to the folate receptor
prolonged blood circulation time
Tb-DOTA

6. Terbium: the Swiss Army knife of Nuclear Medicine
Müller et al. 2012, J Nucl Med 53:1951.

8. Terbium-149: alpha-Emitter Folate Receptor Targeted a-Radionuclide Therapy
Group A: control
Group B: 149Tb-folate 2.2 MBq
Group C: 149Tb-folate 3.0 MBq
Increasing 149Tb activity leads to increased therapeutic efficacy. Optimum activity not yet reached though.
Müller et al. 2013, Pharmaceuticals, submitted

9. 155Tb: low-dose SPECT prior to therapy
155Tb is a theranostic match chemically similar to the rare earth therapy isotopes: 90Y, 166Ho, 177Lu and chemically identical to 161Tb.
Müller et al. 2013, Nucl Med Biol, in press: doi: /j.nucmedbio

10. in vivo validation with peptides, mAbs and vitamins
Peptides monoclonal antibody folate
MD DOTATATE chCE chCE7 cm09 cm09
Müller et al. 2013, Nucl Med Biol, in press: doi: /j.nucmedbio

11. Efficient parallel operation
152Tb
149Tb
155Tb
HRS setup

12. 140Nd/140Pr: an in vivo PET generator
β+ 2.4
3.4 m
140Ce
140Nd ε
3.37 d
For certain applications PET is better than SPECT, but there are no long-lived isotopes with high beta+ branching ratio. Instead a couple of a long-lived isotope decaying by electron capture to a short-lived daughter that emits positrons can be used, e.g. 140Nd/140Pr. The figure shows a gerbil injected with a 140Nd-labeled mab that highlights an infection in the intestine. Left 1 days after injection, right 9 days after injection.
Köster et al. 2014, Nucl Med Biol, submitted.

13. Understanding the Auger release from chelators
QEC = 437
140Nd
3.39 min Pr Ce Nd
140Pr
BR+ = 51%
stable
140Ce

14. Understanding the Auger release from chelators?
QEC = 437
140Nd
3.39 min Nd Pr
140Pr
BR+ = 51%
stable Pr
140Ce

15. Understanding the Auger release from chelators
QEC = 437
140Nd
3.39 min
140Pr
BR+ = 51%
134Ce
134La
134Ba
3.37 d
6.45 min
stable
QEC = 386
BR+ = 63.6%
stable
140Ce
44Sc
44Ca
2.44 d
stable E
BR+ = 94.3%
44mSc
3.97 h
1157

16. Theranostic of Invasive Aspergillosis and Echinococcus Multilocularis

17. Survival with anti-HER2 212Pb-mABS
212Pb-Trastuzumab
212Pb-Trastuzumab (0.37MBq)
212Pb-Trastuzumab (0.74MBq)
212Pb-Trastuzumab (1.48MBq)
Survival (%)
Boudousq et al., 2013; PLoS ONE 8(7):e69613.
Time post-graft (days)

18. Auger release of 212Bi ? 212Po 212Bi 212Pb 208Pb 208Tl
10.6 h
212Bi
212Po
208Pb
(Stable)
208Tl
0.3 s
60.5 min
3.05min a b
36%
45.1% conversion electrons
 Auger cascades
partial delabeling?

19. 169Er (beta-) vs. 165Er (Auger) radiobiology

20. Beam request Shifts 149Tb-cm09 dose escalation study 8
149Tb-PRRT pilot study 3
152Tb/155Tb companion diagnostics incl.
140Nd/134Ce chelator optimization 6
140Nd/134Ce immuno-PET 6
exploratory experiments (Pb, Bi,…) 3
mass separation of 169Er/168Er 6 (offline)
Total
Available
New request (offline)

22. Off-line separation of 169Er
Therapy study with 6 mice, 70 MBq 169Er-DOTATOC per mouse
factor 2 for decay losses and labeling yield
850 MBq needed (1E15 atoms collected)
LA[169Er]=5 MBq  up to 500 MBq can be handled in “class C” bat. 170
 collect and ship two separate samples of 425 MBq each
 ship as UN2910 (“excepted package”)
implantation current 1 nA of 169Er for 24 h (3 shifts per sample)
total current 1 A Er (168Er + 169Er) [cf. 7Be collections]
ionization potential 6.11 eV > 0.5% thermal ionization efficiency
RILIS efficiency >5%? (to be tested!)
ship 20 GBq from ILL (2% of A2 limit > “type A” transport)
Note: 169Er is a low-energy beta emitter, with very low emission of  rays: 0.16% 8 keV, 0.01% 110 keV
 very low dose rate: <1 Gy/h at 1 m from unshielded 1 GBq sample.

23. Indirect production of 203Pb, 205Bi

24. Imaging Studies Using PET and SPECT KB Tumor-Bearing Nude Mice
PET SPECT SPECT
152Tb-folate: 9 MBq
Scan Start: 24 h p.i.
Scan Time: h
155Tb-folate: 4 MBq
Scan Start: 24 h p.i.
Scan Time: h
161Tb-folate: 30 MBq
Scan Start: 24 h p.i.
Scan Time: 20 min
Müller et al. 2012, J Nucl Med 53:1951.

25. Arsenic: another theranostic multiplet
72As:
generator-produced + emitter for PET
71As:
low-energy + emitter for high-resolution PET ?
74As:
long-lived + emitter for longitudinal PET studies
77As:
reactor-produced - emitter for therapy
Arsenic is under study as another theranostic multiplet. So far 72As and 74As were tested as PET tracer, but 71As has the lowest average positron energy and could provide best resolution.

26. Excellent resolution with Derenzo phantom
18F
Eb+ = 0.25 MeV
71As
Eb+ = 0.35 MeV
Indeed 71As
Köster et al. 2014, Nucl Med Biol, submitted.