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.

Radiolabeled antibodies are powerful tools for both imaging and therapy in the field of nuclear medicine. Radiolabeling methods that do not release radionuclides from parent antibodies are essential for radiolabeling antibodies, and practical radiolabeling protocols that provide high in vivo stability have been established for many radionuclides, with a few exceptions. However, several limitations remain, including undesirable side effects on the biodistribution profiles of antibodies. This review summarizes the numerous efforts made to tackle this problem and the recent advances, mainly in preclinical studies. These include pretargeting approaches, engineered antibody fragments and constructs, the secondary injection of clearing agents, and the insertion of metabolizable linkages. Finally, we discuss the potential of these approaches and their prospects for further clinical application.

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. The triazole spacer significantly enhanced the reactivity of the neopentyl sulfonate towards nucleophilic substitution. 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 activated ester demonstrated high reactivity, and enabled the completion of the reaction with the antibody within 10 minutes. In comparative biodistribution studies between 211At-labeled cetuximab and the corresponding 125I-labeled cetuximab in normal mice, we observed equivalent radioactivity distribution after administration, and both the thyroid and stomach showed radioactivity levels that were less than 1.0% of the injected dose. These findings indicate a suppressed dehalogenation of the 211At-labeled cetuximab, which emphasizes the effectiveness of the 211At-labeled activated ester.