title: Evaluation of novel 99mTc(I)-labeled homobivalent α-melanocyte-stimulating hormone analogs for melanocortin-1 receptor targeting.
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 α-melanocyte-stimulating hormone (α-MSH) analog [Ac-Nle(4), Asp(5), D-Phe(7), Lys(11)]α-MSH4-11 separated by linkers of different length (L(2) nine atoms and L(3) 14 atoms). The MC1R-binding affinity of L(2) and L(3) is significantly higher than that of the monovalent conjugate L(1). Metallation of these conjugates yielded the complexes fac-[M(CO)(3)(k(3)-L)](+) (M is (99m)Tc/Re; 1/1a, L is L(1); 2/2a, L is L(2); 3/3a, L is L(3)), with IC(50) 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 melanoma-bearing mice have shown low nonspecific accumulation with a tumor uptake that correlates with IC(50) 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.
authors.affiliation: Unidade de Ciências Químicas e Radiofarmacêuticas, ITN, Estrada Nacional 10, 2686-953 Sacavém, Portugal.
authors.forename: Maurício
authors.initials: M
authors.lastname: Morais
authors.forename: Paula D
authors.initials: PD
authors.lastname: Raposinho
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Oliveira
authors.forename: João D G
authors.initials: JD
authors.lastname: Correia
authors.forename: Isabel
authors.initials: I
authors.lastname: Santos
mesh_terms: D000818:Animals; D005260:Female; D006801:Humans; D008546:Melanoma, Experimental / Q000175:diagnosis* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D057054:Molecular Imaging; D015609:Organotechnetium Compounds / Q000737:chemistry / Q000493:pharmacokinetics; D010455:Peptides / Q000737:chemistry / Q000493:pharmacokinetics; D044102:Receptor, Melanocortin, Type 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D000521:alpha-MSH / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D015609:Organotechnetium Compounds; D010455:Peptides; D044102:Receptor, Melanocortin, Type 1; D000521:alpha-MSH