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

Abstract 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 ( 211 At) is a versatile α-emitting radionuclide that can be produced using a cyclotron. Therefore, 211 At-labeled PSMA compounds could be useful for TAT; however, 211 At-labeled compounds are unstable against deastatination in vivo. In this study, to develop in vivo stable 211 At-labeled PSMA derivatives, we designed and synthesized 211 At-labeled PSMA derivatives using a neopentyl glycol (NpG) structure that can stably retain 211 At in vivo. We also evaluated their biodistribution in normal and tumor-bearing mice. Results We designed and synthesized 211 At-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 125 I-labeled NpG derivatives because 125 I was readily available. 125 II-NpG-L-PSMA and 125 II-NpG-D-PSMA showed low accumulation in the stomach and thyroid, indicating their high in vivo stability against deiodination. 125 II-NpG-L-PSMA was excreted in urine as hydrophilic radiometabolites in addition to the intact form. Meanwhile, 125 II-NpG-D-PSMA was excreted in urine in an intact form. In both cases, no radioactivity was observed in the free iodine fraction. 125 II-NpG-D-PSMA showed higher tumor accumulation than 125 II-NpG-L-PSMA. We then developed 211 At-labeled PSMA using the NpG-D-PSMA structure. 211 AtAt-NpG-D-PSMA showed low accumulation in the stomach and thyroid in normal mice, indicating its high stability against deastatination in vivo. Moreover, 211 AtAt-NpG-D-PSMA showed high accumulation in tumor similar to that of 125 II-NpG-D-PSMA. Conclusions 211 AtAt-NpG-D-PSMA showed high in vivo stability against deastatination and high tumor accumulation. 211 AtAt-NpG-D-PSMA should be considered as a potential new TAT for mCRPC.