Evaluation of novel ~(99m)Tc(I)-labeled homobivalent α-melanocyte-stimulating hormone analogs for melanocortin-1 receptor targeting

摘要

Abstract Aiming to apply the multivalency concept to melanoma imaging, we have assessed the in vivo melanocortin type 1 receptor (MC1R)-targeting properties of ~(99m)Tc(I)-labeled homobivalent peptide conjugates which contain copies of the a-melanocyte-stimulating hormone (a-MSH) analog [Ac-Nle4, Asp5, D-Phe7, Lys11]a-MSH4-11 separated by linkers of different length (L2 nine atoms and L3 14 atoms). The MC1R-binding affinity of L2 and L3 is significantly higher than that of the monovalent conjugate L1. Metallation of these conjugates yielded the complexes fac-[M(CO)3(k3-L)]? (M is ~(99m)Tc/Re; 1/1a, L is L1; 2/2a, L is L2; 3/3a, L is L3), with IC50 values in the subnanomolar and nanomolar range. The MC1R-mediated internalization of 2 and 3 is higher than that of 1 in B16F1 melanoma cells. Biodistribution studies in melanomabearing mice have shown low nonspecific accumulation with a tumor uptake that correlates with IC50 values. However, no correlation between tumor uptake and valency was found. Nevertheless, 2 displayed the highest tumor retention, and the best tumor to nontarget organ ratios.