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IS528-ADD1 Novel diagnostic and therapeutic radionuclides

IS528-ADD1 Novel diagnostic and therapeutic radionuclides for the development of innovative radiopharmaceuticals. Katharina Domnanich 1 , Catherine Ghezzi 2 , Ferid Haddad 3 , Mikael Jensen 4 , Christian Kesenheimer 6 , Ulli Köster 5 , Cristina Müller 1 , Bernd Pichler 6 ,

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IS528-ADD1 Novel diagnostic and therapeutic radionuclides

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  1. 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]-TerbiumISOLDE 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

  5. Tumor Tageting Agent for Tb-CoordinationChemical 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.

  7. Terbium-149: alpha-EmitterFolate Receptor Targeted a-Radionuclide Therapy Group A: control Group B: 149Tb-folate 2.2 MBq Group C: 149Tb-folate 3.0 MBq Müller et al. 2013, Pharmaceuticals, submitted

  8. 155Tb: low-dose SPECT prior to therapy Müller et al. 2013, Nucl Med Biol, in press: doi:10.1016/j.nucmedbio.2013.11.002

  9. 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

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

  11. 140Nd ε 3.37 d 140Pr β+ 2.4 3.4 m 140Ce 140Nd/140Pr: an in vivo PET generator Köster et al. 2014, Nucl Med Biol, submitted.

  12. Understanding the Auger release from chelators 3.37 d QEC = 437 140Nd 3.39 min Nd Pr Ce 140Pr BR+ = 51% stable 140Ce

  13. Understanding the Auger release from chelators 3.37 d QEC = 437 140Nd 3.39 min ? Pr Nd 140Pr BR+ = 51% stable Pr 140Ce

  14. Understanding the Auger release from chelators 3.37 d QEC = 437 140Nd 134Ce 3.39 min 140Pr 134La BR+ = 51% 3.37 d stable QEC = 386 6.45 min 140Ce 134Ba BR+ = 63.6% stable 44mSc 2.44 d E4 271 3.97 h 44Sc BR+ = 94.3% 1157 stable 44Ca

  15. Theranostic of Invasive Aspergillosisand Echinococcus Multilocularis

  16. Survival with anti-HER2 212Pb-mABS 212Pb-Trastuzumab HER2 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)

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

  18. 169Er (beta-) vs. 165Er (Auger) radiobiology 169Er

  19. 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)

  20. 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.

  21. Indirect production of 203Pb, 205Bi

  22. Imaging Studies Using PET and SPECTKB 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.

  23. Arsenic: another theranostic multiplet 71As: low-energy +emitter for high-resolution PET ? 74As: long-lived + emitter for longitudinal PET studies 77As: reactor-produced - emitter for therapy 72As: generator-produced +emitter for PET

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

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