Dimeric DOTA-α-Melanocyte-Stimulating Hormone Analogs: Synthesis and In Vivo Characteristics of Radiopeptides with High In Vitro Activity

• Published in: Journal of receptors and signal transduction 2007-01, Vol.27 (5-6), p.383-409
• Main Authors: BAPST, JEAN-PHILIPPE, FROIDEVAUX, SYLVIE, CALAME, MARTINE, TANNER, HEIDI, EBERLE, ALEX N.
• Format: Article
• Language: English
• Subjects: alpha-MSH - analogs & derivatives; alpha-MSH - chemistry; alpha-MSH - metabolism; Animals; Cell Line, Tumor; Chelating Agents - chemistry; Chelating Agents - metabolism; Dimeric peptide; Dimerization; DOTA; Heterocyclic Compounds, 1-Ring - chemistry; Heterocyclic Compounds, 1-Ring - metabolism; Humans; Indium Radioisotopes; MC1-R; Melanoma; Melanoma, Experimental - metabolism; Mice; Oligopeptides - chemistry; Oligopeptides - metabolism; Radioligand Assay; Tissue Distribution; Tumor targeting; α-MSH
• ISSN: 1079-9893; 1532-4281
• DOI: 10.1080/10799890701723528

Dimeric analogs of α-melanocyte-stimulating hormone (α-MSH) labeled with radiometals are potential candidates for diagnosis and therapy of melanoma by receptor-mediated tumor targeting. Both melanotic and amelanotic melanomas (over-)express the melanocortin-1 receptor (MC1-R), the target for α-MSH. In the past, dimerized MSH analogs have been shown to display increased receptor affinity compared to monomeric MSH, offering the possibility of improving the ratio between specific uptake of radiolabeled α-MSH by melanoma and nonspecific uptake by the kidneys. We have designed three linear dimeric analogs containing a slightly modified MSH hexapeptide core sequence (Nle-Asp-His-d-Phe-Arg-Trp) in parallel or antiparallel orientation, a short spacer, and the DOTA chelator for incorporation of the radiometal. In vitro, all three peptides were more potent ligands of the mouse B16-F1 melanoma cell melanocortin-1 receptor (MC1-R) than DOTA-NAPamide, which served as standard. The binding activity of DOTA-diHexa(NC-NC)-amide was 1.75-fold higher, that of diHexa(NC-NC)-Gly-Lys(DOTA)-amide was 3.37-fold higher, and that of DOTA-diHexa(CN-NC)-amide was 2.34-fold higher. Using human HBL melanoma cells, the binding activity of diHexa(NC-NC)-Gly-Lys(DOTA)-amide was sixfold higher than that of DOTA-NAPamide. Uptake by cultured B16-F1 cells was rapid and almost quantitative. In vivo, however, the data were less promising: tumor-to-kidney ratios 4 hr postinjection were 0.11 for [111In]DOTA-diHexa(NC-NC)-amide, 0.26 for diHexa(NC-NC)-Gly-Lys([111In]DOTA)-amide, and 0.36 for [111In]DOTA-diHexa(CN-NC)-amide, compared to 1.67 for [111In]DOTA-NAPamide. It appears that despite the higher affinity to the MC1-R of the peptide dimers and their excellent internalization in vitro, the uptake by melanoma tumors in vivo was lower, possibly because of reduced tissue penetration. More striking, however, was the marked increase of kidney uptake of the dimers, explaining the unfavorable ratios. In conclusion, although radiolabeled α-MSH dimer peptides display excellent receptor affinity and internalization, they are no alternative to the monomeric DOTA-NAPamide for in vivo application.