鈴木 博元

<jats:title>Abstract</jats:title><jats:sec> <jats:title>Background</jats:title> <jats:p>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 (<jats:sup>211</jats:sup>At) is a versatile α-emitting radionuclide that can be produced using a cyclotron. Therefore, <jats:sup>211</jats:sup>At-labeled PSMA compounds could be useful for TAT; however, <jats:sup>211</jats:sup>At-labeled compounds are unstable against deastatination in vivo. In this study, to develop in vivo stable <jats:sup>211</jats:sup>At-labeled PSMA derivatives, we designed and synthesized <jats:sup>211</jats:sup>At-labeled PSMA derivatives using a neopentyl glycol (NpG) structure that can stably retain <jats:sup>211</jats:sup>At in vivo. We also evaluated their biodistribution in normal and tumor-bearing mice.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>We designed and synthesized <jats:sup>211</jats:sup>At-labeled PSMA derivatives containing two glutamic acid (Glu) linkers between the NpG structure and asymmetric urea (NpG-L-PSMA ((L-Glu)<jats:sub>2</jats:sub> linker used) and NpG-D-PSMA ((D-Glu)<jats:sub>2</jats:sub> linker used)). First, we evaluated the characteristics of <jats:sup>125</jats:sup>I-labeled NpG derivatives because <jats:sup>125</jats:sup>I was readily available. [<jats:sup>125</jats:sup>I]I-NpG-L-PSMA and [<jats:sup>125</jats:sup>I]I-NpG-D-PSMA showed low accumulation in the stomach and thyroid, indicating their high in vivo stability against deiodination. [<jats:sup>125</jats:sup>I]I-NpG-L-PSMA was excreted in urine as hydrophilic radiometabolites in addition to the intact form. Meanwhile, [<jats:sup>125</jats:sup>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. [<jats:sup>125</jats:sup>I]I-NpG-D-PSMA showed higher tumor accumulation than [<jats:sup>125</jats:sup>I]I-NpG-L-PSMA. We then developed <jats:sup>211</jats:sup>At-labeled PSMA using the NpG-D-PSMA structure. [<jats:sup>211</jats:sup>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, [<jats:sup>211</jats:sup>At]At-NpG-D-PSMA showed high accumulation in tumor similar to that of [<jats:sup>125</jats:sup>I]I-NpG-D-PSMA.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusions</jats:title> <jats:p>[<jats:sup>211</jats:sup>At]At-NpG-D-PSMA showed high in vivo stability against deastatination and high tumor accumulation. [<jats:sup>211</jats:sup>At]At-NpG-D-PSMA should be considered as a potential new TAT for mCRPC.</jats:p> </jats:sec>

In this study we developed a neopentyl 211At‐labeled activated ester that incorporates a triazole spacer and applied it to the synthesis of an 211At‐labeled cetuximab. The activated ester was synthesized via the nucleophilic 211At‐astatination of a neopentyl sulfonate carrying two long alkyl chains that serve as a lipid tag, which was followed by the hydrolysis of an acetal. Additionally, we developed a novel Resin‐Assisted Purification and Deprotection (RAPD) protocol involving a solid‐phase extraction of the protected 211At‐labeled compound from the mixture of the labeling reaction, hydrolysis of the acetal on the resin, and finally an elution of the 211At‐labeled activator from the resin. This method allows the synthesis of an 211At‐labeled activated ester with high purity through a simplified procedure that circumvents the need for HPLC purification. Using this 211At‐labeled activated ester, we efficiently synthesized 211At‐labeled cetuximab in 27±1% radiochemical yield with 95% radiochemical purity. This 211At‐activated ester demonstrated high reactivity, and enabled the completion of the reaction with the antibody within 10 min. In comparative biodistribution studies between 211At‐labeled cetuximab and the corresponding 125I‐labeled cetuximab in normal mice, both the thyroid and stomach showed radioactivity levels that were less than 1.0% of the injected dose.

Abstract Background L-type amino acid transporter 1 (LAT1) is overexpressed in various cancers; therefore, radiohalogen-labeled amino acid derivatives targeting LAT1 have emerged as promising candidates for cancer radiotheranostics. However, ²¹¹At-labeled amino acid derivatives exhibit instability against deastatination in vivo, making it challenging to use ²¹¹At for radiotherapy. In this study, radiohalogen-labeled amino acid derivatives with high dehalogenation stability were developed. Results We designed and synthesized new radiohalogen-labeled amino acid derivatives ([²¹¹At]At-NpGT, [¹²⁵I]I-NpGT, and [¹⁸F]F-NpGT) in which L-tyrosine was introduced into the neopentyl glycol (NpG) structure. The radiolabeled amino acid derivatives were recognized as substrates of LAT1 in the in vitro studies using C6 glioma cells. In a biodistribution study using C6 glioma-bearing mice, these agents exhibited high stability against in vivo dehalogenation and similar biodistributions. The similarity of [²¹¹At]At-NpGT and [¹⁸F]F-NpGT indicated that these pairs of radiolabeled compounds would be helpful in radiotheranostics. Moreover, [²¹¹At]At-NpGT exhibited a dose-dependent inhibitory effect on the growth of C6 glioma-bearing mice. Conclusions [²¹¹At]At-NpGT exhibited a dose-dependent inhibitory effect on the tumor growth of glioma-bearing mice, and its biodistribution was similar to that of other radiohalogen-labeled amino acid derivatives. These findings suggest that radiotheranostics using [¹⁸F]F-NpGT and [^123/131I]I-NpGT for diagnostic applications and [²¹¹At]At-NpGT and [¹³¹I]I-NpGT for therapeutic applications are promising.