1,2,3-Triazole Stabilized Neurotensin-Based Radiopeptidomimetics for Improved Tumor Targeting

Bioconjugate Chemistry
Alba MascarinThomas L Mindt

Abstract

Neurotensin (NT) is a regulatory peptide with nanomolar affinity toward NT receptors, which are overexpressed by different clinically relevant tumors. Its binding sequence, NT(8-13), represents a promising vector for the development of peptidic radiotracers for tumor imaging and therapy. The main drawback of the peptide is its short biological half-life due to rapid proteolysis in vivo. Herein, we present an innovative strategy for the stabilization of peptides using nonhydrolizable 1,4-disubstituted, 1,2,3-triazoles as amide bond surrogates. A "triazole scan" of the peptide sequence yielded novel NT(8-13) analogues with enhanced stability, retained receptor affinity, and improved tumor targeting properties in vivo. The synthesis of libraries of triazole-based peptidomimetics was achieved efficiently on solid support by a combination of Fmoc-peptide chemistry, diazo transfer reactions, and the Cu(I)-catalyzed alkyne azide cycloaddition (CuAAC) employing methods that are fully compatible with standard solid phase peptide synthesis (SPPS) chemistry. Thus, the amide-to-triazole substitution strategy may represent a general methodology for the metabolic stabilization of biologically active peptides.

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Citations

Apr 8, 2016·Journal of Medicinal Chemistry·Ibai E ValverdeThomas L Mindt
Jun 24, 2016·Journal of Medicinal Chemistry·Simone MaschauerOlaf Prante
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Apr 18, 2020·Journal of Medicinal Chemistry·Nathalie M GrobThomas L Mindt
Apr 18, 2020·Journal of Medicinal Chemistry·Nathalie M GrobThomas L Mindt

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