Melanocortin-1 receptor (MC1R) is a molecular target for melanoma imaging and therapy because of its overexpression on rodent and human melanoma cells. Here, we evaluated the MC1R targeting and specificity of 68Ga-DOTA-GGNle-CycMSHhex and Cy5.5-GGNle-CycMSHhex using murine and human melanoma cells, and murine and xenografted tumors. 68Ga-DOTA-GGNle-CycMSHhex was used first in human as an imaging probe to evaluate the possibility of radionuclide therapy in patients with advanced-stage melanoma. 68Ga-DOTA-GGNle-CycMSHhex and Cy5.5-GGNle-CycMSHhex displayed MC1R-specific targeting properties in murine and human melanoma cells, as well as in murine melanoma and human melanoma-xenografted tumors. Both B16/F10 and M21 melanoma lesions could be easily imaged by positron emission tomography using 68Ga-DOTA-GGNle-CycMSHhex The first-in-human images of melanoma brain metastases in patients demonstrated the clinical relevance of MC1R as a molecular target for melanoma imaging, highlighting the potential of 68Ga-DOTA-GGNle-CycMSHhex as an MC1R-targeting melanoma imaging probe and underscoring the need to develop MC1R-targeting therapeutic agents for treating patients with metastatic melanoma.
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