High-Affinity and Proteolytically Stable Peptidic Fluorescent NTS1R Ligands

Ertl FJ, Friedel A, Schmid EJ, Höring C, Archipowa N, Koch P, Maschauer S, Kutta RJ, Prante O, Keller M (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Journal of Medicinal Chemistry American Chemical Society

Book Volume: 68

Pages Range: 19482-19502

Journal Issue: 18

DOI: 10.1021/acs.jmedchem.5c01701

Abstract

Labeled ligands for the neurotensin receptor 1 (NTS1R), which is expressed in the CNS, the gastrointestinal tract, and in malignant tumors, are needed to investigate NTS1R-ligand binding and NTS1R expression. Aiming for fluorescence-labeled neurotensin(8–13)-derived NTS1R ligands with high affinity and proteolytic stability, several previous approaches were combined: (1) replacement of Arg8by an amino-functionalized carbamoylated arginine, allowing conjugation to a fluorophore, (2) Nα-methylation of Arg8and replacement of Tyr by β,β-dimethyl-l-Tyr11, conferring proteolytic stability, and (3) replacement of Leu13by trimethylsilyl-Ala, boosting binding affinity. This strategy gave fluorescent NTS1R ligands with unprecedented NTS1R binding affinity (5-TAMRA-labeled ligand 19: Ki0.14 nM, sulfo-Cy5-labeled probe 21: Ki0.094 nM) and high stability in human plasma (t1/2≫ 48 h). Their suitability for competition binding studies (flow cytometry; 19, 21) and the imaging of NTS1R expression in living cells (confocal microscopy, biomolecular imaging; 19, 21) and tumor tissue (biomolecular imaging; 21) is demonstrated.

Authors with CRIS profile

Anna Friedel Department of Nuclear Medicine Simone Maschauer Department of Nuclear Medicine Olaf Prante Medizinische Fakultät

Involved external institutions

Universität Regensburg DE Germany (DE)

How to cite

APA:

Ertl, F.J., Friedel, A., Schmid, E.J., Höring, C., Archipowa, N., Koch, P.,... Keller, M. (2025). High-Affinity and Proteolytically Stable Peptidic Fluorescent NTS1R Ligands. Journal of Medicinal Chemistry, 68(18), 19482-19502. https://doi.org/10.1021/acs.jmedchem.5c01701

MLA:

Ertl, Fabian J., et al. "High-Affinity and Proteolytically Stable Peptidic Fluorescent NTS1R Ligands." Journal of Medicinal Chemistry 68.18 (2025): 19482-19502.

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