Triazolo-Peptidomimetics: Novel Radiolabeled Minigastrin Analogs for Improved Tumor Targeting

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 Arg356 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.