title: Methoxyphenylethynyl, methoxypyridylethynyl and phenylethynyl derivatives of pyridine: synthesis, radiolabeling and evaluation of new PET ligands for metabotropic glutamate subtype 5 receptors.
abstract: We have synthesized three different PET ligands to investigate the physiological function of metabotropic glutamate subtype 5 receptors (mGluR5) in vivo: 2-[(11)C]methyl-6-(2-phenylethynyl)pyridine ([(11)C]MPEP), 2-(2-(3-[(11)C]methoxyphenyl)ethynyl)pyridine ([(11)C]M-MPEP) and 2-(2-(5-[(11)C]methoxypyridin-3-yl)ethynyl)pyridine ([(11)C]M-PEPy). [(11)C]Methyl iodide was used to label the compounds under basic conditions, and a Pd(0) catalyst was applied to label [(11)C]MPEP in a Stille coupling reaction. In vivo microPET imaging studies of the functional accumulation of radiolabeled ligands were conducted in 35 rats (Sprague-Dawley, 8 weeks old male, weight of 300 g). Specific binding was tested using pre-administration of unlabeled mGluR5 antagonist 2-methyl-6-(2-phenylethynyl)pyridine (MPEP) (10 mg/kg iv 5 min before radioactivity injection). In the radiolabeling of [(11)C]MPEP, [(11)C]M-MPEP and [(11)C]M-PEPy, a specific radioactivity of 700-1200 mCi/micromol and over 97% radiochemical purity were obtained. The microPET studies showed these three radiolabeled mGluR5 antagonists having the highest binding in the olfactory bulb followed by striatum, hippocampus and cortex. Pre-administration of the mGluR5 antagonist MPEP induced a 45.1% decrease in [(11)C]MPEP binding, a 59.7% decrease in [(11)C]M-MPEP binding and an 84.6% decrease in [(11)C]M-PEPy binding in the olfactory bulb at 5 min. The feasibility of synthesizing high-affinity and high-selectivity ligands for mGluR5 receptors and their suitability as PET imaging ligands for mGluR5 receptors in vivo are demonstrated.
authors: Experimental PET Laboratory, Department of Radiology, Massachusetts General Hospital, Boston, MA 02114, USA. myu@utmck.edu
authors: Meixiang
authors: M
authors: Yu
authors: Werner
authors: W
authors: Tueckmantel
authors: Xukui
authors: X
authors: Wang
authors: Aijun
authors: A
authors: Zhu
authors: Alan P
authors: AP
authors: Kozikowski
authors: Anna-Liisa
authors: AL
authors: Brownell
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000502:physiology; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D002247:Carbon Isotopes / Q000737:chemistry / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D008024:Ligands; D008297:Male; D009830:Olfactory Bulb / Q000378:metabolism; D049268:Positron-Emission Tomography; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000032:analysis*
chemical_list: D002247:Carbon Isotopes; D018691:Excitatory Amino Acid Antagonists; C578937:Grm5 protein, rat; D008024:Ligands; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C121465:6-methyl-2-(phenylethynyl)pyridine