⁶⁸Ga-DOTA-GGNle-CycMSH_hex targets the melanocortin-1 receptor for melanoma imaging

Melanocortin-1 receptor (MC1R) is a molecular target for melanoma imaging and therapy because of its overex-pression on rodent and human melanoma cells. Here, we evaluated the MC1R targeting and specificity of ⁶⁸Ga-DOTA-GGNle-CycMSH_hex and Cy5.5-GGNle-CycMSH_hex using murine and human melanoma cells, and murine and xenografted tumors. ⁶⁸Ga-DOTA-GGNle-CycMSH_hex 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-CycMSH_hex and Cy5.5-GGNle-CycMSH_hex 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-CycMSH_hex. 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-CycMSH_hex as an MC1R-targeting melanoma imaging probe and underscoring the need to develop MC1R-targeting therapeutic agents for treating patients with metastatic melanoma.