Effects of the Arg-Pro and Gly-Gly-Nle moieties on melanocortin-1 receptor binding affinities of α-MSH peptides

The purpose of this study was to examine the effects of the -Arg-Pro- (RP) and -Gly-Gly-Nle- (GGNle) moieties on the melanoma targeting and clearance properties of ^99mTc-peptides. We synthesized four new peptides {Ac-GGNle-CCEHdFRWC-NH₂, Ac-GGNle-CCEHdFRWCRP-NH₂, Ac-CCEHdFRWC-NleGG-NH₂, and Ac-CCEHdFRWCRP-NleGG-NH₂} and determined their melanocortin-1 (MC1) receptor binding affinities in B16/F1 melanoma cells. Then we further examined the biodistribution properties of ^99mTc-Ac-GGNle-CCEHdFRWCRP-NH₂ and ^99mTc-Ac- CCEHdFRWCRP-NleGG-NH₂ in B16/F1 melanoma-bearing C57 mice. Overall, the -RP- moiety was critical for retaining low nanomolar MC1 receptor binding affinity. The deletion of the -RP- moiety dramatically reduced the receptor binding affinities of the peptides. The N-terminus was a better position than C-terminus for the -GGNle- moiety in retaining the lower renal and liver uptake. High melanoma uptake coupled with fast urinary clearance of ^99mTc-Ac-GGNle-CCEHdFRWCRP-NH₂ provided a new insight into the design of new α-melanocyte stimulating hormone (α-MSH) peptides.