Journal of Medicinal Chemistry p. 3980 - 3990 (2016)
Update date:2022-08-28
Topics:
Shimoda, Yoko
Yamasaki, Tomoteru
Fujinaga, Masayuki
Ogawa, Masanao
Kurihara, Yusuke
Nengaki, Nobuki
Kumata, Katsushi
Yui, Joji
Hatori, Akiko
Xie, Lin
Zhang, Yiding
Kawamura, Kazunori
Zhang, Ming-Rong
We found out 3-[5-(pyridin-2-yl)-2H-tetrazol-2-yl]benzonitrile analogues as the candidate for positron emission tomography (PET) imaging agents of metabotropic glutamate receptor subtype 5 (mGluR5). Among these compounds, 3-methyl-5-(5-(pyridin-2-yl)-2H-tetrazol-2-yl)benzonitrile (10) exhibited high binding affinity (Ki = 9.4 nM) and moderate lipophilicity (cLogD, 2.4). Subsequently, [11C]10 was radiosynthesized at 25 ± 14% radiochemical yield (n = 11) via C-[11C]methylation of the arylstannyl precursor 15 with [11C]methyl iodide. In vitro autoradiography and PET assessments using [11C]10 showed high specific binding in the striatum and hippocampus, two brain regions enriched with mGluR5. Moreover, test-retest PET studies with [11C]10 indicated high reliability to quantify mGluR5 density, such as the intraclass correlation coefficient (0.90) and Pearson r (0.91) in the striatum of rat brain. We demonstrated that [11C]10 is a useful PET ligand for imaging and quantitative analysis of mGluR5. Furthermore, [11C]10 might be modified using its skeleton as a lead compound.
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Doi:10.1002/chem.201500716
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