225Ac-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 225Ac (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 111In, 90Y, and 225Ac. [111In]­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 [111In]­In-PSMA–DA1 produced clear tumor images, and the administration of [90Y]­Y-PSMA–DA1 or [225Ac]­Ac-PSMA–DA1 inhibited tumor growth. [225Ac]­Ac-PSMA–DA1 had antitumor effects in mice at a lower radioactivity level than [225Ac]­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.

We designed and synthesized a novel DOTA-based trifunctional agent containing a click ligation moiety and a pharmacological modifier for the development of a radiotheranostic platform.

No abstract

We have reported that the chelator-based clickable radiotheranostic platform, ADIBO-DOTADG-ALB (ADA), has favorable properties as a radiotheranostic platform for low-molecular-weight ligands. In this study, we evaluated the applicability of ADA to moderate-molecular-weight ligands to expand the utility of the ADA platform. As a moderate-molecular-weight ligand, we selected exendin-4, a peptide-based agonist to glucagon-like peptide-1 receptor (GLP-1R). An exendin-4-incorporated ADA derivative, exendin-4-Cys40-triazole-DOTADG-ALB (EtDA), was radiolabeled with 111In by the conjugation of exendin-4-Cys40 azide to [111In]­In-ADA. The click ligation of exendin-4-Cys40 azide to [111In]­In-ADA was quantitatively completed in 10 min under ambient conditions. In the in vitro cell-binding assay and albumin-binding assay, [111In]­In-EtDA showed strong binding to both a GLP-1R-expressing cell and albumin. In the biodistribution assay, [111In]­In-EtDA showed markedly protracted tumor uptake, which was significantly decreased by the coinjection of exendin-4-Cys40. The single photon emission computed tomography (SPECT) image of [111In]­In-EtDA visualized the tumor clearly. These results indicated the utility of [111In]­In-EtDA as a radiotheranostic agent, suggesting the applicability of the ADA platform to moderate-molecular-weight ligands.