Radiotheranostics Using a Novel Ac-Labeled Radioligand with Improved Pharmacokinetics Targeting Prostate-Specific Membrane Antigen.

Ac-based radiotheranostics targeting prostate-specific membrane antigen (PSMA) has induced impressive responses in patients with metastatic castration-resistant prostate cancer. To enhance the therapeutic effects of radioligands labeled with Ac (half-life: 10 days), a radioligand that shows longer tumor retention would be useful. Here, we designed and synthesized a straight-chain PSMA-targeting radioligand, PSMA-DA1, which includes an (iodophenyl)butyric acid derivative as an albumin binder (ALB). We performed preclinical evaluations of PSMA-DA1 as a tool for PSMA-targeting radiotheranostics using In, Y, and Ac. [In]In-PSMA-DA1 demonstrated significantly greater tumor uptake and retention than a corresponding non-ALB-conjugated compound. In mice, single-photon emission computed tomography performed with [In]In-PSMA-DA1 produced clear tumor images, and the administration of [Y]Y-PSMA-DA1 or [Ac]Ac-PSMA-DA1 inhibited tumor growth. [Ac]Ac-PSMA-DA1 had antitumor effects in mice at a lower radioactivity level than [Ac]Ac-PSMA-617, which has been reported to be clinically useful. These results indicate that PSMA-DA1 may be a useful PSMA-targeting radiotheranostic agent.