Design of Radiolabeled Analogs of Minigastrin by Multiple Amide-to-Triazole Substitutions

The insertion of single 1,4-disubstituted
1,2,3-triazoles as metabolically
stable bioisosteres of trans-amide bonds (triazole
scan) was recently applied to the 177Lu-labeled tumor-targeting
analog of minigastrin, [Nle15]­MG11. The reported novel
mono-triazolo-peptidomimetics of [Nle15]­MG11 showed either
improved resistance against enzymatic degradation or a significantly
increased affinity toward the target receptor but never both. To enhance
further the tumor-targeting properties of the minigastrin analogs,
we studied conjugates with multiple amide-to-triazole substitutions
for additive or synergistic effects. Promising candidates were identified
by modification of two or three amide bonds, which yielded both improved
stability and increased receptor affinity of the peptidomimetics in vitro. Biodistribution studies of radiolabeled multi-triazolo-peptidomimetics
in mice bearing receptor-positive tumor xenografts revealed up to
4-fold increased tumor uptake in comparison to the all-amide reference
compound [Nle15]­MG11. In addition, we report here for the
first time a linear peptidomimetic with three triazole insertions
in its backbone and maintained biological activity.