An Improved <sup>211</sup>At-Labeled Agent for PSMA-Targeted α-Therapy
Ronnie C. Mease, Choong Mo Kang, Vivek Kumar, Sangeeta Ray Banerjee, Il Minn, Mary Brummet, Kathleen L. Gabrielson, Yutian Feng, Andrew Park, Ana P. Kiess, George Sgouros, Ganesan Vaidyanathan, Michael R. Zalutsky, Martin G. Pomper
Abstract
α-Particle emitters targeting the prostate-specific membrane antigen (PSMA) proved effective in treating patients with prostate cancer who were unresponsive to the corresponding β-particle therapy. Astatine-211 is an α-emitter that may engender less toxicity than other α-emitting agents. We synthesized a new <sup>211</sup>At-labeled radiotracer targeting PSMA that resulted from the search for a pharmacokinetically optimized agent. <b>Methods:</b> A small series of <sup>125</sup>I-labeled compounds were synthesized from their tin precursors to evaluate the effect of location of radiohalogen within the molecule and the presence of lutetium in the chelate on biodistribution. On that basis, <sup>211</sup>At-VK-02-90-Lu was selected and evaluated in cell uptake and internalization studies, biodistribution and PSMA+ PC3 PIP tumor growth control in experimental flank and metastatic (PC3-ML-Luc) models. A long-term (13-month) toxicity study was performed for <sup>211</sup>At-VK-02-90-Lu, including tissue chemistries and histopathology. <b>Results:</b> The radiochemical yield of <sup>211</sup>At-VK-02-90-Lu was 17.8 ± 8.2%. Lead compound <sup>211</sup>At-VK-02-90-Lu demonstrated total uptake within PSMA+ PC3 PIP cells of 13.4 ± 0.5% of the input dose after 4 h of incubation with little uptake in control cells. In SCID mice, <sup>211</sup>At-VK-02-90-Lu provided 30.6 ± 4.8 percentage of injected dose per gram (%ID/g) of uptake in PSMA+ PC3 PIP tumor at 1 h post-injection that decreased to 9.46 ± 0.96 %ID/g by 24 h. Tumor-to-salivary gland and tumor-to-kidney ratios were 129 ± 99 at 4 h and 130 ± 113 at 24 h, respectively. De-astatination was not significant (stomach 0.34 ± 0.20%ID/g at 4 h). Dose-dependent survival was demonstrated at higher doses (>1.48 MBq) in both flank and metastatic models. There was little off-target toxicity as demonstrated by hematopoietic stability, unchanged tissue chemistries, weight gain rather than loss throughout treatment, and favorable histopathology. <b>Conclusion:</b> Compound <sup>211</sup>At-VK-02-90-Lu or close analogs may provide limited and acceptable toxicity while retaining efficacy in management of prostate cancer.