Design and characterization of α-melanotropin peptide analogs cyclized through rhenium and technetium metal coordination

Abstract

Metal ions often play critical roles in protein structure and function. Engineered metal-binding sites in peptides and proteins have been widely used to enhance structural integrity, stabilize biologically active conformations, and confer novel enzymatic activities (1-3). Biochemical and structural analyses of transition-metal coordination by proteins and peptides have traditionally focused on zinc, copper, manganese, and iron because of their roles in important biological processes (4-7). Other transition metals not found in natural proteins have coordination, isotopic, and chemical properties that make them attractive for peptide and protein engineering. Rhenium (Re) and technetium (Tc) are group VIIB transition metals that share similar coordination geometries and form stable complexes with amine and amide nitrogens, carboxylate oxygens, and thiolate and thioether sulfurs, with a strong preference for thiolate sulfurs (8). Radioactive isotopes of Re and Tc have significant medical applications because of the nature of their associated radiation and physical half-life properties.The synthesis and characterization of radiolabeled antibodies, peptides, and steroid hormones as in vivo tumor-imaging and therapeutic agents is an active area of cancer research today. These molecules specifically target tumor cells by virtue of their high specificities for receptors and antigens present on the surfaces of these cells. In one commonly used approach, metallic radionuclides such as 186 Re, 188

111In-Labeled Lactam Bridge-Cyclized α-Melanocyte Stimulating Hormone Peptide Analogues for Melanoma Imaging

“…Labeling the CCMSH peptides with 99m Tc or 188 Re simultaneously completed the peptide cyclization and the coupling of radionuclides to the peptides for melanoma imaging or therapy. The metal cyclization made α-MSH peptide analogues resistant to chemical and proteolytic degradation in vivo (18,19).…”

“…There is a great need to develop novel imaging probes and treatment approaches for melanoma detection and therapy since early diagnosis and prompt surgical removal are a patient's best hope for a cure. Although 2-[ 18 F]fluoro-2-deoxy-D-glucose ([ 18 F]FDG) is commonly used for positron emission tomography (PET) diagnosis and staging of melanoma, [ 18 F]FDG is not melanoma-specific and some melanoma cells are not detected by [ 18 F]FDG since they use substrates other than glucose as energy sources (2,3). Alternatively, the G protein-coupled melanocortin-1 (MC1) receptors have been used as targets for melanoma imaging peptides due to their over-expression on human and mouse melanoma cells (4)(5)(6)(7)(8).…”

In vivo evaluation of 188Re‐labeled alpha‐melanocyte stimulating hormone peptide analogs for melanoma therapy

“…188 Re labeled ␣-MSH peptides were prepared via a glucoheptonate transchelation reaction as described by Giblin et al 17 Briefly, 200 l of 6 mg/ml SnCl 2 Re generator were added into a reaction vial. The mixture was incubated at 75°C for 30 min.…”

Radioiodination of Rhenium Cyclized α-Melanocyte-Stimulating Hormone Resulting in Enhanced Radioactivity Localization and Retention in Melanoma

“…␣-MSH receptors display nanomolar to subnanomolar affinities for ␣-MSH peptides and are rapidly internalized on ligand binding (21,22). High receptor affinity and specificity make ␣-MSH peptide analogs attractive vehicles for delivering radionuclides to melanoma cells (23)(24)(25). Efforts to develop radiohalogenated ␣-MSH analogs for melanoma targeting have been disappointing for the most part.…”