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Meeting ReportMolecular Targeting Probes - Radioactive & Nonradioactive

PSMA-targeted18F-labeled Radiohybrid Inhibitors: Concept, preclinical evaluation and first proof of concept study in men

Alexander Wurzer, Daniel Di Carlo, Alexander Schmidt, Roswitha Beck, Matthias Eiber, Markus Schwaiger and Hans Wester
Journal of Nuclear Medicine May 2019, 60 (supplement 1) 344;
Alexander Wurzer
3Pharmaceutical Radiochemistry Technical University Munich Garching Germany
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Daniel Di Carlo
3Pharmaceutical Radiochemistry Technical University Munich Garching Germany
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Alexander Schmidt
3Pharmaceutical Radiochemistry Technical University Munich Garching Germany
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Roswitha Beck
3Pharmaceutical Radiochemistry Technical University Munich Garching Germany
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Matthias Eiber
1Klinikum rechts der Isar Munich Germany
2Klinikum rechts der Isar Munich Germany
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Markus Schwaiger
1Klinikum rechts der Isar Munich Germany
2Klinikum rechts der Isar Munich Germany
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Hans Wester
3Pharmaceutical Radiochemistry Technical University Munich Garching Germany
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Abstract

344

Objectives: With the aim to develop a platform technology that allows for fast and efficient labeling of peptide and peptide-like radiopharmaceuticals with either 18F or radiometals, we have synthesized and evaluated novel radiohybrid PSMA (rhPSMA) ligands. A unique feature of such rhPSMA-ligands is that both, fluorine and the metal, are always present, but only one of them as radioactive isotope (e.g. [18F,natGa]rhPSMA or [19F,68Ga]rhPSMA). In this study we present the results of the development and evaluation of a series of F/Ga-rhPSMA ligands. Methods: Six different radiohybrid-PSMA ligands that contain a PSMA-addressing urea motif, a silicon fluoride acceptor moiety for 18F-labeling by isotopic exchange (IE) and a chelator for complexation with trivalent metal ions were synthesized by SPPS. 18F-labeling of [19F,natGa]rhPSMA-7 by IE was carried out at room temperature within 5 min. The overall production was completed in less than 15 min (80±5% RCY). PSMA-affinities (IC50) and internalization studies (37°C, 60 min) were carried out on LNCaP cells. In addition, binding to human serum albumin and log P values were quantified. μPET imaging and biodistribution was carried out on LNCaP tumor-bearing SCID mice. Proof of concept (PoC) in men was performed by [18F,natGa]rhPSMA-7 in a patient suffering from mCRPC. Results: All compounds showed suitable hydrophilicity (log P: -2.6 to -3.5) and >94% binding to human serum albumin. The novel rhPSMA inhibitors showed PSMA affinities between 3.0 and 11 nM and rapid cell internalization (33-177%). Biodistribution and μPET-scans of rhPSMA-7 and 10 in mice showed high tumor accumulation, fast renal excretion, low activity accumulation in non-target tissues and no elevated 18F-uptake in bone. Based on their high affinity, fast internalization and excellent biodistribution, the DOTA- and DOTAGA-derived inhibitors rhPSMA-7 and 10 were found to be the most promising candidates for first PoC studies in men. In the proof of concept study in a patient [18F,natGa]rhPSMA-7 demonstrated fast blood clearance via the kidneys, showed almost no activity transfer into the bladder (up to 120 min p.i.) and allowed high-contrast imaging of LN and bone metastasis. Conclusion: Radiohybrid PSMA ligands represent a unique class of either paired diagnostic (e.g. F/Ga-rhPSMA) or true theranostic (e.g. F/Lu-rhPSMA) ligands. [18F,natGa]rhPSMA-7 and [18F,natGa]rhPSMA-10 were found to have favorable pharmacokinetic profiles in men, show high stability towards in-vivo defluorination (no bone uptake) and almost no activity in the ureters and bladder. Based on these characteristics and the simple high yield production, [18F,natGa]rhPSMA-7 has been transferred into detailed clinical studies. Noteworthy, due to the identity of 18F- and 68Ga-labeled rhPSAM-7, experiences obtained with one of these compounds can be transferred to the other twin.

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Journal of Nuclear Medicine
Vol. 60, Issue supplement 1
May 1, 2019
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PSMA-targeted18F-labeled Radiohybrid Inhibitors: Concept, preclinical evaluation and first proof of concept study in men
Alexander Wurzer, Daniel Di Carlo, Alexander Schmidt, Roswitha Beck, Matthias Eiber, Markus Schwaiger, Hans Wester
Journal of Nuclear Medicine May 2019, 60 (supplement 1) 344;

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PSMA-targeted18F-labeled Radiohybrid Inhibitors: Concept, preclinical evaluation and first proof of concept study in men
Alexander Wurzer, Daniel Di Carlo, Alexander Schmidt, Roswitha Beck, Matthias Eiber, Markus Schwaiger, Hans Wester
Journal of Nuclear Medicine May 2019, 60 (supplement 1) 344;
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