Radiosynthesis and characterisation of a potent and selective GPR139 agonist radioligand
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Radiosynthesis and characterisation of a potent and selective GPR139 agonist radioligand. / Kuhne, Sebastiaan; Nøhr, Anne Cathrine; Marek, AleŠ; Elbert, TomáŠ; Klein, Anders Bue; Bräuner-Osborne, Hans; Wellendorph, Petrine; Pedersen, Daniel Sejer.
In: RSC Advances, Vol. 6, No. 2, 2016, p. 947-952.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - Radiosynthesis and characterisation of a potent and selective GPR139 agonist radioligand
AU - Kuhne, Sebastiaan
AU - Nøhr, Anne Cathrine
AU - Marek, AleŠ
AU - Elbert, TomáŠ
AU - Klein, Anders Bue
AU - Bräuner-Osborne, Hans
AU - Wellendorph, Petrine
AU - Pedersen, Daniel Sejer
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
U2 - 10.1039/c5ra21326f
DO - 10.1039/c5ra21326f
M3 - Journal article
AN - SCOPUS:84953896371
VL - 6
SP - 947
EP - 952
JO - RSC Advances
JF - RSC Advances
SN - 2046-2069
IS - 2
ER -
ID: 154039339