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Triazolo-Peptidomimetics: Novel Radiolabeled Minigastrin Analogs for Improved Tumor Targeting
Journal
Journal of Medicinal Chemistry
Volume
63
Number
9
Pages / Article-Number
4484-4495
Mesh terms
Animals; Antineoplastic Agents, chemical synthesis, metabolism, pharmacokinetics, pharmacology; Cell Line, Tumor; Female; Gastrins, chemical synthesis, metabolism, pharmacokinetics, pharmacology; Humans; Lutetium, chemistry; Mice; Neoplasms, metabolism; Peptidomimetics, chemical synthesis, metabolism, pharmacokinetics, pharmacology; Protein Binding; Protein Conformation; Radioisotopes, chemistry; Radiopharmaceuticals, chemical synthesis, metabolism, pharmacokinetics, pharmacology; Receptor, Cholecystokinin B, metabolism; Triazoles, chemical synthesis, metabolism, pharmacokinetics, pharmacology
Abstract
MG11 is a truncated analog of minigastrin, a peptide with high affinity and specificity toward the cholecystokinin-2 receptor (CCK2R), which is overexpressed by different tumors. Thus, radiolabeled MG11 derivatives have great potential for use in cancer diagnosis and therapy. A drawback of MG11 is its fast degradation by proteases, leading to moderate tumor uptake; in vivo; . We introduced 1,4-disubstituted 1,2,3-triazoles as metabolically stable bioisosteres to replace labile amide bonds of the peptide. The "triazole scan" yielded peptidomimetics with improved resistance to enzymatic degradation and/or enhanced affinity toward the CCK2R. Remarkably, our lead compound achieved a 10-fold increase in receptor affinity, resulting in a 2.6-fold improved tumor uptake; in vivo; . Modeling of the ligand-CCK2R complex suggests that an additional cation-π interaction of the aromatic triazole moiety with the Arg; 356; residue of the receptor is accountable for these observations. We show for the first time that the amide-to-triazole substitution strategy offers new opportunities in drug development that go beyond the metabolic stabilization of bioactive peptides.
