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

Author(s): Xabier Guarrochena, Maximilian Anderla, Philipp Salomon, Irene V.J. Feiner, Berthold A. Nock, Theodosia Maina, Thomas L. Mindt
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.
Organisation(s): Department of Inorganic Chemistry, Joint Applied Medicinal Radiochemistry Facility
External organisation(s): Medizinische Universität Wien, National Centre for Scientific Research Demokritos (NCSR)
Journal: Journal of Peptide Science
Volume: 31
ISSN: 1075-2617
DOI: https://doi.org/10.1002/psc.3654
Publication date: 2024
Peer reviewed: Yes
Austrian Fields of Science 2012: 301303 Medical biochemistry, 301206 Pharmacology, 104015 Organic chemistry
Keywords
ASJC Scopus subject areas: Structural Biology, Biochemistry, Molecular Medicine, Molecular Biology, Pharmacology, Drug Discovery, Organic Chemistry
Sustainable Development Goals: SDG 3 - Good Health and Well-being
Portal url: https://ucrisportal.univie.ac.at/en/publications/1dc75544-9fa2-472f-81e3-1cf115c69d65