In vivo stable ²¹¹At-labeled prostate-specific membrane antigen-targeted tracer using a neopentyl glycol structure

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 (²¹¹At) is a versatile α-emitting radionuclide that can be produced using a cyclotron. Therefore, ²¹¹At-labeled PSMA compounds could be useful for TAT; however, ²¹¹At-labeled compounds are unstable against deastatination in vivo. In this study, to develop in vivo stable ²¹¹At-labeled PSMA derivatives, we designed and synthesized ²¹¹At-labeled PSMA derivatives using a neopentyl glycol (NpG) structure that can stably retain ²¹¹At in vivo. We also evaluated their biodistribution in normal and tumor-bearing mice.

We designed and synthesized ²¹¹At-labeled PSMA derivatives containing two glutamic acid (Glu) linkers between the NpG structure and asymmetric urea (NpG-L-PSMA ((L-Glu)₂ linker used) and NpG-D-PSMA ((D-Glu)₂ linker used)). First, we evaluated the characteristics of ¹²⁵I-labeled NpG derivatives because ¹²⁵I was readily available. [¹²⁵I]I-NpG-L-PSMA and [¹²⁵I]I-NpG-D-PSMA showed low accumulation in the stomach and thyroid, indicating their high in vivo stability against deiodination. [¹²⁵I]I-NpG-L-PSMA was excreted in urine as hydrophilic radiometabolites in addition to the intact form. Meanwhile, [¹²⁵I]I-NpG-D-PSMA was excreted in urine in an intact form. In both cases, no radioactivity was observed in the free iodine fraction. [¹²⁵I]I-NpG-D-PSMA showed higher tumor accumulation than [¹²⁵I]I-NpG-L-PSMA. We then developed ²¹¹At-labeled PSMA using the NpG-D-PSMA structure. [²¹¹At]At-NpG-D-PSMA showed low accumulation in the stomach and thyroid in normal mice, indicating its high stability against deastatination in vivo. Moreover, [²¹¹At]At-NpG-D-PSMA showed high accumulation in tumor similar to that of [¹²⁵I]I-NpG-D-PSMA.

[²¹¹At]At-NpG-D-PSMA showed high in vivo stability against deastatination and high tumor accumulation. [²¹¹At]At-NpG-D-PSMA should be considered as a potential new TAT for mCRPC.