TY - JOUR T1 - An improved <sup>211</sup>At-labeled agent for PSMA-targeted alpha therapy JF - Journal of Nuclear Medicine JO - J Nucl Med DO - 10.2967/jnumed.121.262098 SP - jnumed.121.262098 AU - Ronnie C Mease AU - Choongmo Kang AU - Vivek Kumar AU - Sangeeta Ray AU - IL Minn AU - Mary Brummet AU - Kathleen Gabrielson AU - Yutian Feng AU - Andrew Park AU - Ana Kiess AU - George Sgouros AU - Ganesan Vaidyanathan AU - Michael Zalutsky AU - Martin G. Pomper Y1 - 2021/06/01 UR - http://jnm.snmjournals.org/content/early/2021/06/04/jnumed.121.262098.abstract N2 - 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 211At-labeled radiotracer targeting PSMA that resulted from the search for a pharmacokinetically optimized agent. Methods: A small series of 125I-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, 211At-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 211At-VK-02-90-Lu, including tissue chemistries and histopathology. Results: The radiochemical yield of 211At-VK-02-90-Lu was 17.8 ± 8.2%. Lead compound 211At-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, 211At-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 (&gt;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. Conclusion: Compound 211At-VK-02-90-Lu or close analogs may provide limited and acceptable toxicity while retaining efficacy in management of prostate cancer. ER -