Synthesis and Simple 18F-Labeling of 3-Fluoro-5-(2-(2-(fluoromethyl)thiazol-4-yl)ethynyl)benzonitrile as a High Affinity Radioligand for Imaging Monkey Brain Metabotropic Glutamate Subtype-5 Receptors with Positron Emission Tomography

• Published in: Journal of medicinal chemistry Vol. 50; no. 14; pp. 3256 - 3266
• Main Authors: Siméon, Fabrice G, Brown, Amira K, Zoghbi, Sami S, Patterson, Velvet M, Innis, Robert B, Pike, Victor W
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 12.07.2007
• Subjects: Animals; Brain - diagnostic imaging; Brain - metabolism; Chromatography, High Pressure Liquid; Humans; Macaca mulatta; Nitriles - metabolism; Positron-Emission Tomography; Radioligand Assay; Rats; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate - metabolism; Thiazoles - metabolism
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0701268

2-Fluoromethyl analogs of (3-[(2-methyl-1,3-thiazol-4yl)ethynyl]pyridine) were synthesized as potential ligands for metabotropic glutamate subtype-5 receptors (mGluR5s). One of these, namely, 3-fluoro-5-(2-(2-(fluoromethyl)thiazol-4-yl)ethynyl)benzonitrile (3), was found to have exceptionally high affinity (IC50 = 36 pM) and potency in a phosphoinositol hydrolysis assay (IC50 = 0.714 pM) for mGluR5. Compound 3 was labeled with fluorine-18 (t 1/2 = 109.7 min) in high radiochemical yield (87%) by treatment of its synthesized bromomethyl analog (17) with [18F]fluoride ion and its radioligand behavior was assessed with positron emission tomography (PET). Following intravenous injection of [18F]3 into rhesus monkey, radioactivity was avidly taken up into brain with high uptake in mGluR5 receptor-rich regions such as striata. [18F]3 was stable in monkey plasma and human whole blood in vitro and in monkey and human brain homogenates. In monkey in vivo, a single polar radiometabolite of [18F]3 appeared rapidly in plasma. [18F]3 merits further evaluation as a PET radioligand for mGluR5 in human subjects.