| Autor: |
Grob NM; Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zürich, Switzerland., Schmid S; Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zürich, Switzerland., Schibli R; Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zürich, Switzerland.; Center for Radiopharmaceutical Sciences, Division of Biology and Chemistry, Paul Scherrer Institute, 5232 Villigen, Switzerland., Behe M; Center for Radiopharmaceutical Sciences, Division of Biology and Chemistry, Paul Scherrer Institute, 5232 Villigen, Switzerland., Mindt TL; Ludwig Boltzmann Institute Applied Diagnostics, General Hospital of Vienna, 1090 Vienna, Austria.; Department of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, 1090 Vienna, Austria.; Department of Biomedical Imaging and Image Guided Therapy, Medical University of Vienna, 1090 Vienna, Austria. |
| Abstrakt: |
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 177 Lu-labeled tumor-targeting analog of minigastrin, [Nle 15 ]MG11. The reported novel mono-triazolo-peptidomimetics of [Nle 15 ]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 [Nle 15 ]MG11. In addition, we report here for the first time a linear peptidomimetic with three triazole insertions in its backbone and maintained biological activity. |
