title: 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.
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 (Ki = 9.4 nM) and moderate lipophilicity (cLogD, 2.4). Subsequently, [(11)C]10 was radiosynthesized at 25 ± 14% radiochemical yield (n = 11) via C-[(11)C]methylation of the arylstannyl precursor 15 with [(11)C]methyl iodide. In vitro autoradiography and PET assessments using [(11)C]10 showed high specific binding in the striatum and hippocampus, two brain regions enriched with mGluR5. Moreover, test-retest PET studies with [(11)C]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 [(11)C]10 is a useful PET ligand for imaging and quantitative analysis of mGluR5. Furthermore, [(11)C]10 might be modified using its skeleton as a lead compound.
authors.affiliation: Department of Radiopharmaceuticals Development, Radiological Science Research and Development Directorate, National Institutes for Quantum and Radiological Science and Technology , 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Shimoda
authors.affiliation: Department of Radiopharmaceuticals Development, Radiological Science Research and Development Directorate, National Institutes for Quantum and Radiological Science and Technology , 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.
authors.forename: Tomoteru
authors.initials: T
authors.lastname: Yamasaki
authors.affiliation: Department of Radiopharmaceuticals Development, Radiological Science Research and Development Directorate, National Institutes for Quantum and Radiological Science and Technology , 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Fujinaga
authors.affiliation: Department of Radiopharmaceuticals Development, Radiological Science Research and Development Directorate, National Institutes for Quantum and Radiological Science and Technology , 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.|SHI Accelerator Service Co. Ltd., 1-17-6 Osaki, Shinagawa-ku, Tokyo 141-0032, Japan.
authors.forename: Masanao
authors.initials: M
authors.lastname: Ogawa
authors.affiliation: Department of Radiopharmaceuticals Development, Radiological Science Research and Development Directorate, National Institutes for Quantum and Radiological Science and Technology , 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.|SHI Accelerator Service Co. Ltd., 1-17-6 Osaki, Shinagawa-ku, Tokyo 141-0032, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kurihara
authors.affiliation: Department of Radiopharmaceuticals Development, Radiological Science Research and Development Directorate, National Institutes for Quantum and Radiological Science and Technology , 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.|SHI Accelerator Service Co. Ltd., 1-17-6 Osaki, Shinagawa-ku, Tokyo 141-0032, Japan.
authors.forename: Nobuki
authors.initials: N
authors.lastname: Nengaki
authors.affiliation: Department of Radiopharmaceuticals Development, Radiological Science Research and Development Directorate, National Institutes for Quantum and Radiological Science and Technology , 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.
authors.forename: Katsushi
authors.initials: K
authors.lastname: Kumata
authors.affiliation: Department of Radiopharmaceuticals Development, Radiological Science Research and Development Directorate, National Institutes for Quantum and Radiological Science and Technology , 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.
authors.forename: Joji
authors.initials: J
authors.lastname: Yui
authors.affiliation: Department of Radiopharmaceuticals Development, Radiological Science Research and Development Directorate, National Institutes for Quantum and Radiological Science and Technology , 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Hatori
authors.affiliation: Department of Radiopharmaceuticals Development, Radiological Science Research and Development Directorate, National Institutes for Quantum and Radiological Science and Technology , 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.
authors.forename: Lin
authors.initials: L
authors.lastname: Xie
authors.affiliation: Department of Radiopharmaceuticals Development, Radiological Science Research and Development Directorate, National Institutes for Quantum and Radiological Science and Technology , 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.
authors.forename: Yiding
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Radiopharmaceuticals Development, Radiological Science Research and Development Directorate, National Institutes for Quantum and Radiological Science and Technology , 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kawamura
authors.affiliation: Department of Radiopharmaceuticals Development, Radiological Science Research and Development Directorate, National Institutes for Quantum and Radiological Science and Technology , 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.
authors.forename: Ming-Rong
authors.initials: MR
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001345:Autoradiography; D008297:Male; D051379:Mice; D049268:Positron-Emission Tomography; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism*; D013777:Tetrazoles / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: C000621318:3-methyl-5-(5-(pyridin-2-yl)-2H-tetrazol-2-yl)benzonitrile; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D013777:Tetrazoles