1. Novel diagnostic and therapeutic radionuclides for the development
of innovative radiopharmaceuticals
Holger Dorrer, Catherine Ghezzi, Ferid Haddad, Mikael Jensen, Ulli Köster, Cristina Müller, Bernd Pichler, Anna-Maria Rolle, Roger Schibli, Jonathan Siikanen, Andreas Türler, Stefan Wiehr, Konstantin Zhernosekov

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. Suitable Radionuclides
established
investigational
High-energy proton induced reactions can produce most of the isotopes of the chart of nuclides.

4. Do we need so many Radionuclides?

5. Do we need so many Radionuclides?
Radionucide Therapy
delivery of therapeutic dose of ionizing radiation to the malignant cell
Alpha, beta, electrons
cytotoxicity and therapeutic efficiency;
side-effects and limiting doses.

6. 149Tb for targeted alpha therapy
New Terbium isotopes for therapy and diagnosis
A Multi-Purpose Element
149Tb for targeted alpha therapy

7. Progress report Terbium-radioisotopes
Physics and Chemistry
separation of
isobar/pseudo-isobar ions
Deposition of lanthanide ions onto zinc covered gold foil
(15 mm x 8 mm)
50 mm
Foil holder for deposition of ion beam 9
Progress report Terbium-radioisotopes 7

8. Preliminary Results 152Tb-PET 155Tb-SPECT ISOLDE ISOLDE 24 h p.i
the first in vivo application
ISOLDE
Tumor
Kidney
24 h p.i
ISOLDE
Tumor
Kidney
155Tb-SPECT
the first in vivo application
19 h p.i

9. Therapy: Alfa vs Beta Alpha emitter 149Tb can be available from ISOLDE
Untreated Mice
149Tb
therapy with alpha
ISOLDE
Alpha emitter 149Tb can be available from ISOLDE
Day 16 after the Therapy
Tumor
Treated Mice
investigation of the biological response to the different characteristics of the decay radiation in the same system
Tumor
PSI
Tumor
Kidney
Beta emitter 161Tb available at PSI
161Tb
therapy with beta
the first therapy studies! Followed up by SPECT imaging

10. 140Nd 140Pr 140Ce Long-lived radionuclides for imaging
140Nd radiolabelled DOTA-mAb at day 12 post injection
140Pr
β+ 2.4
3.4 m
140Ce
140Nd ε
3.37 d

11. Towards Auger electron therapy
M. Jensen et al.,
Hevesy Lab,
DTU Risø,
Denmark
produce 71Ge with high specific activity at ILL
micro-injection of 0.1 pl Na2GeO3 into the cell
Incubate 1 hour
Read out double strand breaks by gamma-H2AX assay
Control cells injected with "cold" germanate solution
...work in progress: needs 131Cs, 140Nd, 165Er... from ISOLDE

12. Spallation production of 149Tb
1.4 GeV ISOLDE PSB
1.0 GeV ISOLDE PSB
0.6 GeV ISOLDE SC
With proton energy rising from 0.6 to 1 to 1.4 GeV the cross-sections increase and so should the yields.

13. Yields of 149Tb
ISOLDE facility
Proton energy (GeV)
Target # or thickn.
(g/cm2)
Yield
(ions/uC)
T target (°C)
T ionizer
(°C)
Overall efficiency (%)
Reference SC
0.6
122
2E8
2200
2500
1.2%
Yellow book, Kluge 1986
PSB
1.0
112
5E8
Beyer et al., Radiochim. Acta 90 (2002) 247.
1.4 42
1.2E7
2.1E7
1900
Tb-RILIS
0.07%
0.12%
U.K. et al., NIM B204 (2003) 347.
Ta.436
3E6
1950
1850
0.015%
This work
6E6
2000
0.03%
Ta.443
3e7
2050
0.17%
Overall efficiency is calculated by the ratio of the experimental yield and the in-target production calculated from published experimental cross-sections.
(As expected) the target and ionizer temperature have a crucial influence on the yields (valid for all surface-ionized lanthanides!), a high temperature of the tungsten ionizer is essential. 13

14. Ways to optimize the 149Tb activity
Action Gain factor
Heat tungsten line more (2300–2400 °C)  5
Dy/Tb RILIS with setting optimized for A=  2 ?
Collect for 6 hours instead of 3 or 4 hours
Run with 2 A protons on target  2
Reduce delay until parcel leaves CERN 2
Estimated gain factors for 2012 with respect to collections performed in June 2011.
Comments:
Yield history shows that the line temperature has the strongest influence on the yields. Despite the higher cross-section at 1.4 GeV the previous yields could never be reproduced due to too low line temperature.
Resonant ionization of Tb and Dy was tried, showing an increase of <2 in both cases. The former experiment (Tb) was handicapped by too low target and line temperature and the absence of a mass marker for tuning. In the latter experiment (Dy) the collection was performed parasitically with the RILIS set for A=168 for ISOLTRAP (isotope shift?). While this factor 2 gain does not seem to be impressive compared to the first factor (heating the line more), it is very useful since it improves the beam purity (only Tb is enhanced but not the cerium oxide sidebands).
Straightforward gain (closer to saturation).
Test shifts in 2011 were operated in proton sharing with HRS.
Reduction in delay between EOI and shipping from 5 to 1 hour should be achievable. 14

15. Dedicated shielded transport containers
Our collaboration just invested over thirty thousand Swiss Francs into reusable transport containers dedicated to facilitate the shipping of exotic Tb isotopes.
We urge CERN's radioactive shipping service to optimize their procedures and assure an accelerated shipping of these valuable short-lived radioisotopes."
tungsten shielded POSISAFE from Lemer-Pax
certified as “Type A” for 90 MBq “unknown α activity”, i.e. 0.5 GBq 149Tb
“type B” certification for much higher activities under preparation
10 reusable container available from PSI/Uni Bern/ILL

16. Beam request : 25 shifts total in 2012
Ta foil target + W surface ionizer, if possible with Dy/Tb RILIS :
16 shifts in two beam times (8 shifts each) for 149Tb/152Tb/155Tb:
5 nights (12 hours each) for collections to be shipped to PSI:
20:00 – 02:00 collection of 152Tb
02:00 – 08:00 collection of 149Tb
09:00 shipment leaves to PSI
5 x 12 hours = 60 hours = 8 shifts (incl. preparation)
155Tb is collected in parallel on GHM (no extra shifts counted)
Ta foil target + W surface ionizer
5 shifts to collect 134Ce, 140Nd and 165Tm/165Er
UCx, ThCx, LaCx or La target with surface ionizer
1 shift to collect 131Cs
various targets/ion sources
3 shifts to collect test samples of 47Sc, 71Ge, 71,72,74As, 73Se, 84Rb, 117mSn, 200,203Pb and Bi

17. Thank you
for your attention!

18. Therapy planing