Synthesis and Evaluation of Novel Radioligands Based on 3-[5(Pyridin-2-y1)-2H-tetrazol-2-yl]benzonitrile for Positron Emission Tomography Imaging of Metabotropic Glutamate Receptor Subtype 5

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, [C-11]10 was radiosynthesized at 25 +/- 14% radiochemical yield (n = 11) via C-[C-11]methylation of the arylstannyl precursor 15 with [11C]methyl iodide. In vitro autoradiography and PET assessments using [C-11]10 showed high specific binding in the striatum and hippocampus, two brain regions enriched with mGluR5. Moreover, testretest PET studies with [C-11]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 [C-11]10 is a useful PET ligand for imaging and quantitative analysis of mGluR5. Furthermore, [C-11]10 might be modified using its skeleton as a lead compound.