Purpose <p>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.</p> Methods <p>We designed an α-MSH analog labeled with ²¹¹At using a&#xa0;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-GGN<b>4c</b> was prepared using a procedure similar to that of the ¹²⁵I-labeled counterpart, [¹²⁵I]NpG-GGN<b>4b</b>. The biodistribution profile of [²¹¹At]NpG-GGN<b>4c</b> in B16F10 tumor-bearing mice was compared with that of [¹²⁵I]NpG-GGN<b>4b</b>. B16F10 tumor-bearing mice were treated with a single dose of vehicle or [²¹¹At]NpG-GGN<b>4c</b> (1 or 0.4 MBq<b>)</b>.</p> Results <p>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-GGN<b>4c</b> showed tumor accumulation comparable to that of [¹²⁵I]NpG-GGN<b>4b</b> and maintained the tumor radioactivity retention from 1 to 3&#xa0;h postinjection. [²¹¹At]NpG-GGN<b>4c</b> exhibited a dose-dependent inhibitory effect on B16F10 xenograft growth without apparent body weight loss.</p> Conclusion <p>[²¹¹At]NpG-GGN<b>4c</b> showed dose-dependent efficacy against B16F10 xenografts, suggesting that [²¹¹At]NpG-GGN<b>4c</b> is a promising TAT agent for treating metastatic melanoma.</p>