Synthesis and Preliminary Evaluation of the ²¹¹ At-Labeled PARP Inhibitor [ ²¹¹ At]Talazoparib as a Targeted Alpha-Particle Emitting Therapeutic

Poly(ADP-ribose) polymerase-1 (PARP1) has become a crucial target in cancer therapy. In recent years, derivatives of olaparib and rucaparib have been radiolabeled for noninvasive imaging of PARP1 expression and targeted radionuclide therapy of PARP-expressing tumors. Motivated by the superior potency of talazoparib, we developed a novel radiolabeling approach for [ 211 At]talazoparib and report its in vitro and in vivo evaluation. The tin precursors and iodo standards were synthesized, separated on a chiral column, and [ 211 At]talazoparib and its inactive. [ 211 At]LT-674 enantiomer were synthesized in a single step from their respective tin precursor. Radiochemical yield (RCY) and radiochemical purity RCP were determined using RP-HPLC. Cell uptake and internalization were performed on PSMA-positive PC-3 PIP prostate carcinoma cells and U87MG glioma cells and in vitro cytotoxicity (MTT) was evaluated on PC-3 PIP cells. Biodistribution studies were performed in athymic mice with subcutaneous PC-3 PIP xenografts and the therapeutic efficacy of [ 211 At]talazoparib was evaluated in the same animal model. The syntheses of tin precursors and iodo standards was developed and optimized. A one-step and scalable radiolabeling method was developed for the synthesis of [ 211 At]talazoparib with 70 ± 7% (n = 10) RCY in 1 h and >95% RCP. The maximum activity of [ 211 At]talazoparib produced was 370 MBq. High cell uptake and internalization were observed for [ 211 At]talazoparib but not [ 211 At]LT-674 with PC-3 PIP cells, and [ 211 At]talazoparib was cytotoxic to PC3 PIP cells in vitro. High tumor uptake and prolonged retention, and rapid clearance from normal tissues were seen for [ 211 At]talazoparib after intratumoral injection. Tumor growth inhibition and survival benefit were observed with a single dose of intratumorally injected [ 211 At]talazoparib. Methods for the chiral separation of precursor permitted radiolabeling of [ 211 At]talazoparib without the need for separation from its inactive 211 At-labeled enantiomer after radiolabeling, and scaled-up production was optimized. [ 211 At]talazoparib exhibited promising potential as a targeted radiotherapeutic, particularly for settings where locoregional administration is warranted.