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

• Published in: Journal of medicinal chemistry 2016-04, Vol.59 (8), p.3980-3990
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Animals; Autoradiography; Male; Mice; Positron-Emission Tomography; Pyridines - chemical synthesis; Pyridines - pharmacology; Radioligand Assay; Rats; Receptor, Metabotropic Glutamate 5 - metabolism; Tetrazoles - chemical synthesis; Tetrazoles - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.6b00209

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.