Targeted melanoma imaging and therapy with radiolabeled alpha-melanocyte stimulating hormone peptide analogues.

Radiolabeled alpha-melanocyte stimulating hormone (a-MSH) analogues have been used to define the expression, affinity and function of the melanocortin-1 receptor (MC1-R). The MC1-R is one of a family of five G-protein linker receptors, which is primarily involved in regulation of skin pigmentation. Over-expression of the MC1-R on melanoma tumor cells has made it an attractive target for the development of a-MSH peptide based imaging and therapeutic agents. Initially, the native a-MSH peptide was radiolabeled directly, but it suffered from low specific activity and poor stability. The addition of non-natural amino acids yielded a-MSH analogues with greater MC-1R affinity and stability. Furthermore, peptide cyclization via disulfide and lactam bond formation as well as site-specific metal coordination resulted in additional gains in receptor affinity and peptide stability in vitro and in vivo. Radiochemical stability of the a-MSH analogues was improved through the conjugation of metal chelators to the peptide's N-terminus or lysine residues for radionuclide coordination. In vitro cell binding studies demonstrated that the radiolabeled a-MSH analogues had low to subnanomolar affinities for the MC1-R. Biodistribution and imaging studies in the B16 mouse melanoma modeled showed rapid tumor uptake of the radiolabeled peptides, with the cyclic peptides demonstrating prolonged tumor retention. Cyclic a-MSH analogues labeled with beta and alpha emitting radionuclides demonstrated melanoma therapeutic efficacy in the B16 melanoma mouse model. Strong pre-clinical imaging and therapy data highlight the clinical potential use of radiolabeled a-MSH peptides for melanoma imaging and treatment of disseminated disease.