1,2,3-Triazole Stabilized Neurotensin-Based Radiopeptidomimetics for Improved Tumor Targeting.
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.
Division of Radiopharmaceutical Chemistry, University of Basel Hospital , Petersgraben 4, 4031 Basel, Switzerland.
Alba
A
Mascarin
Division of Radiopharmaceutical Chemistry, University of Basel Hospital , Petersgraben 4, 4031 Basel, Switzerland.
Ibai E
IE
Valverde
Division of Radiopharmaceutical Chemistry, University of Basel Hospital , Petersgraben 4, 4031 Basel, Switzerland.
Sandra
S
Vomstein
Division of Radiopharmaceutical Chemistry, University of Basel Hospital , Petersgraben 4, 4031 Basel, Switzerland.
Thomas L
TL
Mindt
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D060326:Chemistry Techniques, Synthetic; D061565:Cycloaddition Reaction; D005260:Female; D019073:HT29 Cells; D006207:Half-Life; D006801:Humans; D007553:Isotope Labeling / Q000379:methods; D008187:Lutetium / Q000737:chemistry; D008819:Mice, Nude; D058990:Molecular Targeted Therapy / Q000379:methods; D009496:Neurotensin / Q000737:chemistry*; D010446:Peptide Fragments / Q000737:chemistry*; D057786:Peptidomimetics / Q000737:chemistry* / Q000493:pharmacokinetics; D011868:Radioisotopes / Q000737:chemistry*; D018028:Receptors, Neurotensin / Q000378:metabolism; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D014230:Triazoles / Q000737:chemistry*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D010446:Peptide Fragments; D057786:Peptidomimetics; D011868:Radioisotopes; D018028:Receptors, Neurotensin; D014230:Triazoles; C114036:neurotensin type 1 receptor; D009496:Neurotensin; D008187:Lutetium; C054381:neurotensin (8-13)