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

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

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

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

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

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

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

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:10.1016/j.nucmedbio.2013.11.002

in vivo validation with peptides, mAbs and vitamins Peptides monoclonal antibody folate MD DOTATATE chCE7 chCE7 cm09 cm09 Müller et al. 2013, Nucl Med Biol, in press: doi:10.1016/j.nucmedbio.2013.11.002

Efficient parallel operation 152Tb 149Tb 155Tb HRS setup

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.

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

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

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 E4 271 BR+ = 94.3% 44mSc 3.97 h 1157

Theranostic of Invasive Aspergillosis and Echinococcus Multilocularis

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)

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?

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

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 26 + 6 Available -10 New request 16 + 6 (offline)

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.

Indirect production of 203Pb, 205Bi

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: 4 h 155Tb-folate: 4 MBq Scan Start: 24 h p.i. Scan Time: 1 h 161Tb-folate: 30 MBq Scan Start: 24 h p.i. Scan Time: 20 min Müller et al. 2012, J Nucl Med 53:1951.

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.

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.