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

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

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

Do we need so many Radionuclides?

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.

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

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

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

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

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

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

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.

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

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=149  2 ? Collect for 6 hours instead of 3 or 4 hours 1.3-1.6 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

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

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 202-206Bi

Thank you for your attention!

Therapy planing