An At-labeled alpha-melanocyte stimulating hormone peptide analog for targeted alpha therapy of metastatic melanoma.

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 At-labeled α-MSH peptide analog for TAT of metastatic melanoma.

Methods: We designed an α-MSH analog labeled with At using a neopentyl glycol scaffold via a hydrophilic linker. Preliminary studies using I-labeled α-MSH analogs were performed to identify suitable hydrophilic linkers. Then, [At]NpG-GGN4c was prepared using a procedure similar to that of the I-labeled counterpart, [I]NpG-GGN4b. The biodistribution profile of [At]NpG-GGN4c in B16F10 tumor-bearing mice was compared with that of [I]NpG-GGN4b. B16F10 tumor-bearing mice were treated with a single dose of vehicle or [At]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. [At]NpG-GGN4c showed tumor accumulation comparable to that of [I]NpG-GGN4b and maintained the tumor radioactivity retention from 1 to 3 h postinjection. [At]NpG-GGN4c exhibited a dose-dependent inhibitory effect on B16F10 xenograft growth without apparent body weight loss.

Conclusion: [At]NpG-GGN4c showed dose-dependent efficacy against B16F10 xenografts, suggesting that [At]NpG-GGN4c is a promising TAT agent for treating metastatic melanoma.