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

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• 作者：Yoko Shimoda ; Tomoteru Yamasaki ; Masayuki Fujinaga ; Masanao Ogawa ; Yusuke Kurihara ; Nobuki Nengaki ; Katsushi Kumata ; Joji Yui ; Akiko Hatori ; Lin Xie ; Yiding Zhang ; Kazunori Kawamura ; Ming-Rong Zhang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：April 28, 2016
• 年：2016
• 卷：59
• 期：8
• 页码：3980-3990
• 全文大小：526K
• 年卷期：0
• ISSN：1520-4804

文摘

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.