Tritium and deuterium labelling of a kainate receptor antagonist and evaluation as a radioligand

0583406 - ÚOCHB 2025 RIV US eng J - Článek v odborném periodiku
Chalupnik, P. - Marek, Aleš - Hovah, M. E. L. - Pickering, D. S. - Temperini, P. - Donbosco, S. - Szymanska, E. - Johansen, T. N.
Tritium and deuterium labelling of a kainate receptor antagonist and evaluation as a radioligand.
Journal of Labelled Compounds and Radiopharmaceuticals. Roč. 67, č. 4 (2024), s. 120-130. ISSN 0362-4803. E-ISSN 1099-1344
Institucionální podpora: RVO:61388963
Klíčová slova: ionotropic glutamate receptors * quinoxaline-2,3-diones * tritium labelling
Impakt faktor: 1.8, rok: 2022
Způsob publikování: Open access
https://doi.org/10.1002/jlcr.4087

Kainate receptors play a crucial role in mediating synaptic transmission within the central nervous system. However, the lack of selective pharmacological tool compounds for the GluK3 subunit represents a significant challenge in studying these receptors. Recently presented compound 1 stands out as a potent antagonist of GluK3 receptors, exhibiting nanomolar affinity at GluK3 receptors and strongly inhibiting glutamate-induced currents at homomeric GluK1 and GluK3 receptors in HEK293 cells with Kb values of 65 and 39 nM, respectively. This study presents the synthesis of two potent GluK3-preferring iodine derivatives of compound 1, serving as precursors for radiolabelling. Furthermore, we demonstrate the optimisation of dehalogenation conditions using hydrogen and deuterium, resulting in [2H]-1, and demonstrate the efficient synthesis of the radioligand [3H]-1 with a specific activity of 1.48 TBq/mmol (40.1 Ci/mmol). Radioligand binding studies conducted with [3H]-1 as a radiotracer at GluK1, GluK2, and GluK3 receptors expressed in Sf9 and rat P2 membranes demonstrated its potential applicability for selectively studying native GluK3 receptors in the presence of GluK1 and 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-blocking ligands.
Trvalý link: https://hdl.handle.net/11104/0351364