Prostate-specific membrane antigen (PSMA) is a promising target for metastatic castration-resistant prostate cancer. We previously reported the effectiveness of PSMA-DA1 as a PSMA-targeting radiotheranostic agent containing an albumin binder moiety. To further enhance tumor uptake, we newly designed PSMA-NAT-DA1 (PNT-DA1) by the introduction of a lipophilic linker into PSMA-DA1. The PSMA affinity of [In]In-PNT-DA1 was increased ( = 8.20 nM) compared with that of [In]In-PSMA-DA1 ( = 89.4 nM). [In]In-PNT-DA1 showed markedly high tumor accumulation (131.6% injected dose/g at 48 h post-injection), and [In]In-PNT-DA1 enabled the visualization of the tumor clearly at 24 h post-injection with SPECT/CT imaging. The administration of [Ac]Ac-PNT-DA1 (2.5 kBq) led to shrinkage of the tumor without marked toxicity, and the antitumor effects of [Ac]Ac-PNT-DA1 were superior to those of [Ac]Ac-PSMA-DA1 and [Ac]Ac-PSMA-617, which is the current gold standard for PSMA-targeting Ac-endoradiotherapy. These results suggest that the combination of [In]In-PNT-DA1 and [Ac]Ac-PNT-DA1 comprises a promising method of PSMA-targeting radiotheranostics.
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