Abstract

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 (K_i = 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.