[211At]YC-I-27 for PSMA-Targeted Alpha-Particle Radiopharmaceutical Therapy

143 Objectives Alpha particle emitters such as 211At have a high linear energy transfer and short range, offering the potential to treat micrometastases effectively while sparing normal tissues. We synthesized and investigated a novel urea-based astatinated small molecule targeting the prostate-specific membrane antigen (PSMA) for treatment of prostate cancer (PC) micrometastases. Methods The PSMA-targeting alpha emitter (2S)-2-(3-(1-carboxy-5-(4-[211At]asatatobenzamido)pentyl)ureido)pentanedioic acid ([211At]YC-I-27) was synthesized. Cellular uptake and clonogenic survival were tested in PSMA-positive (PSMA+) PC3 PIP and PSMA-negative (PSMA-) PC3 flu human PC cells after treatment with [211At]YC-I-27. Antitumor efficacy was tested in mice bearing PSMA+ PC3 PIP and PSMA- PC3 flu flank xenografts after administration of 740 kBq (20 µCi), as well as in mice bearing micrometastases from a novel PSMA+ luciferase-expressing PC3-ML cell line after administration of doses ranging from 0 to 370 kBq (10 µCi). Biodistribution was tested in mice bearing PSMA+ PC3 PIP and PSMA- PC3 flu flank xenografts after administration of 185 kBq (5 µCi). Sub-organ distribution was evaluated using α-Camera images, and micro-scale dosimetry was modeled. Long-term toxicity was assessed in mice by serial weights and laboratory tests for up to 12 mo, as well as necropsy. Results Treatment with [211At]YC-I-27 resulted in PSMA-specific cellular uptake and decreased clonogenic survival in vitro in PSMA+ PC3 PIP cells. This agent also demonstrated significantly improved survival in the PSMA+ micrometastatic PC model (P Conclusions PSMA-targeted α-particle radiopharmaceutical therapy with [211At]YC-I-27 yielded significantly improved survival in mice bearing PC micrometastases after systemic administration. [211At]YC-I-27 also showed uptake in renal proximal tubules resulting in late nephrotoxicity, highlighting the importance of long-term toxicity studies and micro-scale dosimetry.