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.