European journal of nuclear medicine and molecular imaging · 2025
An 211At-labeled alpha-melanocyte stimulating hormone peptide analog for targeted alpha therapy of metastatic melanoma.
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Suzuki Hiroyuki, Yamashita Saki, Tanaka Shoko, Kannaka Kento, Sasaki Ichiro, Ohshima Yasuhiro, Watanabe Shigeki, Ooe Kazuhiro, Watabe Tadashi, Ishioka Noriko S, Tanaka Hiroshi, Uehara Tomoya
Аннотация
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.
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.