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

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.
AuthorsAlba Mascarin, Ibai E Valverde, Sandra Vomstein, Thomas L Mindt
JournalBioconjugate chemistry (Bioconjug Chem) Vol. 26 Issue 10 Pg. 2143-52 (Oct 21 2015) ISSN: 1520-4812 [Electronic] United States
PMID26347939 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • Peptide Fragments
  • Peptidomimetics
  • Radioisotopes
  • Receptors, Neurotensin
  • Triazoles
  • neurotensin type 1 receptor
  • Neurotensin
  • Lutetium
  • neurotensin (8-13)
Topics
  • Animals
  • Antineoplastic Agents (chemistry, pharmacokinetics)
  • Chemistry Techniques, Synthetic
  • Cycloaddition Reaction
  • Female
  • HT29 Cells
  • Half-Life
  • Humans
  • Isotope Labeling (methods)
  • Lutetium (chemistry)
  • Mice, Nude
  • Molecular Targeted Therapy (methods)
  • Neurotensin (chemistry)
  • Peptide Fragments (chemistry)
  • Peptidomimetics (chemistry, pharmacokinetics)
  • Radioisotopes (chemistry)
  • Receptors, Neurotensin (metabolism)
  • Structure-Activity Relationship
  • Tissue Distribution
  • Triazoles (chemistry)
  • Xenograft Model Antitumor Assays

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