1,2,3-Triazole Stabilized Neurotensin-Based Radiopeptidomimetics for Improved Tumor Targeting.
Bioconjug Chem
; 26(10): 2143-52, 2015 Oct 21.
Article
en En
| MEDLINE
| ID: mdl-26347939
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.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Fragmentos de Péptidos
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Radioisótopos
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Triazoles
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Neurotensina
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Peptidomiméticos
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Antineoplásicos
Límite:
Animals
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Female
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Humans
Idioma:
En
Año:
2015
Tipo del documento:
Article