Issue 2, 2016

Radiosynthesis and characterisation of a potent and selective GPR139 agonist radioligand

Abstract

Compound 1 is a selective and potent agonist of the G protein-coupled receptor GPR139 (EC50 = 39 nM). In this study, we describe the synthesis, radiolabelling and in vitro evaluation of [3H]-1 for the characterisation of GPR139 and its spatial expression in the brain using autoradiography. Two different synthesis routes for the radiolabelling of 1 based on a reductive debromination strategy were investigated using deuterium (D2, g). The route based on reductive debromination of the bromonaphthyl precursor 5 proved superior over arylbromide 4 and was employed for the radiolabelling experiments. Reductive debromination of precursor 5 was accomplished using 3H2, Pd/C and triethylamine in DMF at ambient temperature to give target molecule [3H]-1 with a specific activity of 19.3 Ci mmol−1 and a radiochemical purity of ≥95%. By application of autoradiography and binding studies, it was not possible to discriminate [3H]-1 binding to wildtype mice brains from GPR139 knockout mice brains and total binding from non-specific binding in CHO-k1 cells stably expressing human GPR139 receptor. Based on these experiments we conclude that [3H]-1 is not a suitable radioligand for the characterisation of GPR139.

Graphical abstract: Radiosynthesis and characterisation of a potent and selective GPR139 agonist radioligand

Supplementary files

Article information

Article type
Paper
Submitted
14 Oct 2015
Accepted
10 Dec 2015
First published
17 Dec 2015
This article is Open Access
Creative Commons BY license

RSC Adv., 2016,6, 947-952

Author version available

Radiosynthesis and characterisation of a potent and selective GPR139 agonist radioligand

S. Kuhne, A. C. Nøhr, A. Marek, T. Elbert, A. B. Klein, H. Bräuner-Osborne, P. Wellendorph and D. S. Pedersen, RSC Adv., 2016, 6, 947 DOI: 10.1039/C5RA21326F

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