부산대학교 도서관

Early detection of primary melanoma tumors is essential because there is no effective treatment for metastatic melanoma. Several linear and cyclic radiolabeled [alpha]-melanocyte stimulating hormone ([alpha]-MSH) analogs have been proposed to target the melanocortin type 1 receptor (MC1R) overexpressed in melanoma. The compact structure of a rhenium-cyclized [alpha]-MSH analog (Re-CCMSH) significantly enhanced its in vivo tumor uptake and retention. Melanotan II (MT-II), a cyclic lactam analog of [alpha]-MSH (Ac-Nle-cyclo[Asp-His-dPhe-Arg-Trp-Lys]-NH.sub.2]), is a very potent and stable agonist peptide largely used in the characterization of melanocortin receptors. Taking advantage of the superior biological features associated with the MT-II cyclic peptide, we assessed the effect of lactam-based cyclization on the tumor-seeking properties of [alpha]-MSH analogs by comparing the pharmacokinetics profile of the 99m.sup.Tc-labeled cyclic peptide [beta]Ala-Nle-cyclo[Asp-His-d-Phe-Arg-Trp-Lys]-NH.sub.2 with that of the linear analog [beta]Ala-Nle-Asp-His-dPhe-Arg-Trp-Lys-NH.sub.2 in melanoma-bearing mice. We have synthesized and coupled the linear and cyclic peptides to a bifunctional chelator containing a pyrazolyl-diamine backbone (pz) through the amino group of [beta]Ala, and the resulting pz--peptide conjugates were reacted with the fac[-[.sup.99m]Tc(CO).sub.3].sup.+ moiety. The 99m.sup.Tc(CO).sub.3-labeled conjugates were obtained in high yield, high specific activity, and high radiochemical purity. The cyclic 99m.sup.Tc(CO).sub.3-labeled conjugate presents a remarkable internalization (87.1% of receptor-bound tracer and 50.5% of total applied activity, after 6 h at 37 degC) and cellular retention (only 24.7% released from the cells after 5 h) in murine melanoma B16F1 cells. A significant tumor uptake and retention was obtained in melanoma-bearing C57BL6 mice for the cyclic radioconjugate [9.26 +- 0.83 and 11.31 +- 1.83% ID/g at 1 and 4 h after injection, respectively]. The linear 99m.sup.Tc(CO).sub.3-pz--peptide presented lower values for both cellular internalization and tumor uptake. Receptor blocking studies with the potent (Nle.sup.4,dPhe.sup.7)-[alpha]MSH agonist demonstrated the specificity of the radioconjugates to MC1R (74.8 and 44.5% reduction of tumor uptake at 4 h after injection for cyclic and linear radioconjugates, respectively).