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Abstract Purpose Patients who develop metastatic melanoma have a very poor prognosis, and new treatments are needed to improve the response rates. Melanocortin-1 receptor (MC1R) is a promising target for radionuclide therapy of metastatic melanoma, and alpha-melanocyte stimulating hormone (α-MSH) peptide analogs show high affinities to MC1Rs. Because targeted alpha therapy (TAT) can be a desirable treatment for metastatic melanoma, this study aimed to develop an ²¹¹At-labeled α-MSH peptide analog for TAT of metastatic melanoma. Methods We designed an α-MSH analog labeled with ²¹¹At using a neopentyl glycol scaffold via a hydrophilic linker. Preliminary studies using ¹²⁵I-labeled α-MSH analogs were performed to identify suitable hydrophilic linkers. Then, [²¹¹At]NpG-GGN4c was prepared using a procedure similar to that of the ¹²⁵I-labeled counterpart, [¹²⁵I]NpG-GGN4b. The biodistribution profile of [²¹¹At]NpG-GGN4c in B16F10 tumor-bearing mice was compared with that of [¹²⁵I]NpG-GGN4b. B16F10 tumor-bearing mice were treated with a single dose of vehicle or [²¹¹At]NpG-GGN4c (1 or 0.4 MBq). Results The D-Glu-D-Arg linker was identified as the optimal hydrophilic linker because of its high affinity for MC1R and good biodistribution profile, especially with low accumulation in the liver and intestine. [²¹¹At]NpG-GGN4c showed tumor accumulation comparable to that of [¹²⁵I]NpG-GGN4b and maintained the tumor radioactivity retention from 1 to 3 h postinjection. [²¹¹At]NpG-GGN4c exhibited a dose-dependent inhibitory effect on B16F10 xenograft growth without apparent body weight loss. Conclusion [²¹¹At]NpG-GGN4c showed dose-dependent efficacy against B16F10 xenografts, suggesting that [²¹¹At]NpG-GGN4c is a promising TAT agent for treating metastatic melanoma.

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 (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. Results 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. Conclusions [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.

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.