Combination of the amide-to-triazole substitution strategy with alternative structural modifications for the metabolic stabilization of tumor-targeting, radiolabeled peptides

Xabier Guarrochena, Maximilian Anderla, Philipp Salomon, Irene V.J. Feiner, Berthold A. Nock, Theodosia Maina, Thomas L. Mindt (Corresponding author)

Publications: Contribution to journalArticlePeer Reviewed

Abstract

Radiolabeled peptides play a key role in nuclear medicine to selectively deliver radionuclides to malignancies for diagnosis (imaging) and therapy. Yet, their efficiency is often compromised by low metabolic stability. The use of 1,4-disubstituted 1,2,3-triazoles (1,4-Tzs) as stable amide bond bioisosteres can increase the half-life of peptides in vivo while maintaining their biological properties. Previously, the amide-to-triazole substitution strategy was used for the stabilization of the pansomatostatin radioligand [111In]In-AT2S, resulting in the mono-triazolo-peptidomimetic [111In]In-XG1, a radiotracer with moderately enhanced stability in vivo and retained ability to bind multiple somatostatin receptor (SSTR) subtypes. However, inclusion of additional 1,4-Tz led to a loss of affinity towards SST2R, the receptor overexpressed by most SSTR-positive cancers. To enhance further the stability of [111In]In-XG1, alternative modifications at the enzymatically labile position Thr10-Phe11 were employed. Three novel 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-peptide conjugates were synthesized with a 1,4-Tz (Asn5-Ψ[Tz]-Phe6) and either a β-amino acid (β-Phe11), reduced amide bond (Thr10-Ψ[NH]-Phe11), or N-methylated amino acid (N-Me-Phe11). Two of the new peptidomimetics were more stable in blood plasma in vitro than [111In]In-XG1. Yet none of them retained high affinity towards SST2R. We demonstrate for the first time the combination of the amide-to-triazole substitution strategy with alternative stabilization methods to improve the metabolic stability of tumor-targeting peptides.

Original languageEnglish
Article numbere3654
JournalJournal of Peptide Science
Volume31
Issue number1
DOIs
Publication statusPublished - Jan 2025

Austrian Fields of Science 2012

  • 301303 Medical biochemistry
  • 301206 Pharmacology
  • 104015 Organic chemistry

Keywords

  • bioisosteres
  • CuAAC
  • peptide-based radiotracer
  • proteolytic stability
  • somatostatin
  • triazolo-peptidomimetic

Fingerprint

Dive into the research topics of 'Combination of the amide-to-triazole substitution strategy with alternative structural modifications for the metabolic stabilization of tumor-targeting, radiolabeled peptides'. Together they form a unique fingerprint.

Cite this