Radiotheranostics Using a Novel 225Ac-Labeled Radioligand with Improved Pharmacokinetics Targeting Prostate-Specific Membrane Antigen

Ac-225-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-225 (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, PSMADA1, 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-111, 90Y, and Ac-225. [In-111]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-111]In-PSMA-DA1 produced clear tumor images, and the administration of [Y-90]Y-PSMA-DA1 or [Ac-225]Ac-PSMA-DA1 inhibited tumor growth. [Ac-225]Ac-PSMA-DA1 had antitumor effects in mice at a lower radioactivity level than [Ac-225]Ac-PSMA617, which has been reported to be clinically useful. These results indicate that PSMA-DA1 may be a useful PSMA-targeting radiotheranostic agent.

Automated summary

The radioligand PSMA-DA1 shows promising potential as a PSMA-targeting radiotheranostic agent, with significant tumor uptake and retention capabilities in preclinical studies. PSMA-DA1 produced clear tumor images in mice and inhibited tumor growth, indicating its potential as an effective radiotherapeutic agent.