Synthesis of [225Ac]PSMA-617 for preclinical evaluation

1126 Objectives: Alpha-emitting radionuclides such as actinium-225 (225Ac) can be used to treat cancers showing resistance to beta-radiotherapy using lutetium-177, or progressive cancers in patients undergoing chemotherapy.1 Ongoing studies using 225Ac-PSMA-617 have shown great promise in treatment of metastatic and/or resistant prostate cancers. As it is not commercially available, it is necessary to produce 225Ac-PSMA-617 on-site. The objective of this work is to communicate a repeatable, reliable synthesis with complete experimental information for better advancement of radiotherapy using 225Ac. Methods: Production chemistry was adapted from select previously published methods.2-4 Free actinium-225 was received from Oak Ridge National Lab in the form of [225Ac]Ac(NO3)3 and was solvated in 0.05 M HCl. PSMA-617 precursor was dissolved in 25 μL metal free water (0.67 mg/mL), and combined with 500 μL 0.05M Tris buffer, pH 9. [225Ac]Ac(NO3)3 (15 μL, ~30-65 μCi) was then combined with the PSMA-617 precursor in Tris buffer. After heating for 40-50 minutes at 120°C, the reaction was allowed to cool. To stabilize the product and adjust the pH, 0.6 mL gentistic acid solution (4 mg/mL gentisic acid in 0.2 M NH4OAc) was added. The final product was analyzed by radio TLC (eluent: 9% NaCl, 10 mM NaOH). Results: Incorporation of 225Ac into the PSMA-617 precursor was successful, with yields over 90% (27µCi). Conclusions: This work demonstrates a reliable, consistent, straightforward procedure for the radiosynthesis of 225Ac-PSMA-617. Pre-clinical therapeutic studies in prostate cancer models are underway. Acknowledgements: The authors wish to thank Clemens Kratochwil (University Hospital Heidelberg), Alfred Morgenstern (Joint Research Centre, Eurpean Commission), and Sophie Poty (Memorial Sloan Kettering) for their valuable assistance with experimental details. We also thank Michigan Medicine and the Department of Radiology for Pilot Grants References:1. Sathekge, M.; Bruchertseifer, F.; Knoesen, O.; Reyneke, F.; Lawal, I.; Lengana, T.; Davis, C.; Mahapane, J.; Corbett, C.; Vorster, M.; Morgenstern, A., (225)Ac-PSMA-617 in chemotherapy-naive patients with advanced prostate cancer: a pilot study. Eur J Nucl Med Mol Imaging 2019,46 (1), 129-138.2. Kratochwil, C.; Bruchertseifer, F.; Giesel, F. L.; Weis, M.; Verburg, F. A.; Mottaghy, F.; Kopka, K.; Apostolidis, C.; Haberkorn, U.; Morgenstern, A., 225Ac-PSMA-617 for PSMA-Targeted alpha-Radiation Therapy of Metastatic Castration-Resistant Prostate Cancer. J Nucl Med 2016,57 (12), 1941-1944.3. Maguire, W. F.; McDevitt, M. R.; Smith-Jones, P. M.; Scheinberg, D. A., Efficient 1-step radiolabeling of monoclonal antibodies to high specific activity with 225Ac for alpha-particle radioimmunotherapy of cancer. J Nucl Med 2014,55 (9), 1492-8.4. Poty, S.; Membreno, R.; Glaser, J. M.; Ragupathi, A.; Scholz, W. W.; Zeglis, B. M.; Lewis, J. S., The inverse electron-demand Diels-Alder reaction as a new methodology for the synthesis of (225)Ac-labelled radioimmunoconjugates. Chem Commun (Camb) 2018,54 (21), 2599-2602.