Targeted α-therapy using astatine (${}^{211}$At)-labeled PSMA1, 5, and 6: a preclinical evaluation as a novel compound

Targeted α-therapy (TAT) for prostate-specific membrane antigen (PSMA) is a promising treatment for metastatic castration-resistant prostate cancer (CRPC). Astatine is an α-emitter (half-life=7.2 h) that can be produced by a 30-MeV cyclotron. This study evaluated the treatment effect of ${}^{211}$At-labeled PSMA compounds in mouse xenograft models. Tumor xenograft models were established by subcutaneous transplantation of human prostate cancer cells (LNCaP) in NOD/SCID mouse. [${}^{211}$At]PSMA1, [${}^{211}$At]PSMA5, or [${}^{211}$At]PSMA6 was administered to LNCaP xenograft mice to evaluate biodistribution at 3 and 24 h. The treatment effect was evaluated by administering [${}^{211}$At]PSMA1 (0.40 ± 0.07 MBq), [${}^{211}$At]PSMA5 (0.39 ± 0.03 MBq), or saline. Histopathological evaluation was performed for the at-risk organs at 3 and 6 weeks after administration. [${}^{211}$At]PSMA5 resulted in higher tumor retention compared to [${}^{211}$At]PSMA1 and [${}^{211}$At]PSMA6 (30.6 ± 17.8, 12.4 ± 4.8, and 19.1 ± 4.5 %ID/g at 3 h versus 40.7 ± 2.6, 8.7 ± 3.5, and 18.1 ± 2.2%ID/g at 24 h, respectively), whereas kidney excretion was superior in [${}^{211}$At]PSMA1 compared to [${}^{211}$At]PSMA5 and [${}^{211}$At]PSMA6. An excellent treatment effect on tumor growth was observed after [${}^{211}$At]PSMA5 administration. [${}^{211}$At]PSMA1 also showed a substantial treatment effect; however, the tumor size was relatively larger compared to that with [${}^{211}$At]PSMA5. In the histopathological evaluation, regenerated tubules were detected in the kidneys at 3 and 6 weeks after the administration of [${}^{211}$At]PSMA5. TAT using [${}^{211}$At]PSMA5 resulted in excellent tumor growth suppression with minimal side effects in the normal organs. [${}^{211}$At]PSMA5 should be considered a new possible TAT for metastatic CRPC, and translational prospective trials are warranted.