In vivo stable At-labeled prostate-specific membrane antigen-targeted tracer using a neopentyl glycol structure.

Background: Prostate cancer is a common cancer among men worldwide that has a very poor prognosis, especially when it progresses to metastatic castration-resistant prostate cancer (mCRPC). Therefore, novel therapeutic agents for mCRPC are urgently required. Because prostate-specific membrane antigen (PSMA) is overexpressed in mCRPC, targeted alpha therapy (TAT) for PSMA is a promising treatment for mCRPC. Astatine-211 (At) is a versatile α-emitting radionuclide that can be produced using a cyclotron. Therefore, At-labeled PSMA compounds could be useful for TAT; however, At-labeled compounds are unstable against deastatination in vivo. In this study, to develop in vivo stable At-labeled PSMA derivatives, we designed and synthesized At-labeled PSMA derivatives using a neopentyl glycol (NpG) structure that can stably retain At in vivo. We also evaluated their biodistribution in normal and tumor-bearing mice.

Results: We designed and synthesized At-labeled PSMA derivatives containing two glutamic acid (Glu) linkers between the NpG structure and asymmetric urea (NpG-L-PSMA ((L-Glu) linker used) and NpG-D-PSMA ((D-Glu) linker used)). First, we evaluated the characteristics of I-labeled NpG derivatives because I was readily available. [I]I-NpG-L-PSMA and [I]I-NpG-D-PSMA showed low accumulation in the stomach and thyroid, indicating their high in vivo stability against deiodination. [I]I-NpG-L-PSMA was excreted in urine as hydrophilic radiometabolites in addition to the intact form. Meanwhile, [I]I-NpG-D-PSMA was excreted in urine in an intact form. In both cases, no radioactivity was observed in the free iodine fraction. [I]I-NpG-D-PSMA showed higher tumor accumulation than [I]I-NpG-L-PSMA. We then developed At-labeled PSMA using the NpG-D-PSMA structure. [At]At-NpG-D-PSMA showed low accumulation in the stomach and thyroid in normal mice, indicating its high stability against deastatination in vivo. Moreover, [At]At-NpG-D-PSMA showed high accumulation in tumor similar to that of [I]I-NpG-D-PSMA.

Conclusions: [At]At-NpG-D-PSMA showed high in vivo stability against deastatination and high tumor accumulation. [At]At-NpG-D-PSMA should be considered as a potential new TAT for mCRPC.