title: Synthesis and preliminary biological evaluation of 3-[(18)F]fluoro-5-(2-pyridinylethynyl)benzonitrile as a PET radiotracer for imaging metabotropic glutamate receptor subtype 5.
abstract: The metabotropic glutamate receptor subtype 5 (mGluR5) has been reported to be implicated in various neurological disorders in the central nervous system. To investigate physiological and pathological functions of mGluR5, noninvasive imaging in a living body with PET technology and an mGluR5-specific radiotracer is urgently needed. Here, we report the synthesis of 3-[(18)F]fluoro-5-(2-pyridinylethynyl)benzonitrile ([(18)F]FPEB) through a convenient thermal reaction as a highly specific PET radiotracer for mGluR5. The precursor and standard compounds were prepared by a coupling reaction catalyzed by palladium. Radiosynthesis of [(18)F]FPEB was performed using nitro as a leaving group replaced by [(18)F]fluoride under conventional heating condition. Biodistribution, metabolite, and microPET studies were performed using Sprague-Dawley rats. Upto 30 mCi of [(18)F]FPEB was obtained with a radiochemical yield of 5% and a specific activity of 1900 +/- 200 mCi/mumol at the end of syntheses. Biodistribution showed rapid clearance from the blood pool and fast and steady accumulation of radioactivity into the brain. Metabolite studies indicated that only 22% of [(18)F]FPEB remained in the blood system 10 min after administration, and that a metabolite existed which was much more polar than the parent tracer. MicroPET studies demonstrated that [(18)F]FPEB accumulated specifically in mGluR5-rich regions of the brain such as striatum and hippocampus, and that blockade with 2-methyl-6-(2-phenylethynyl)pyridine (MPEP) and 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) substantially reduced the activity uptake in these regions. Selectivity was investigated by blockage with 6-amino-N-cyclohexyl-N,3-dimethylthiazolo[3,2-a]benzimidazole-2-caroxamide (YM-298198), a specific antagonist for mGluR1. [(18)F]FPEB was prepared conveniently and showed high specificity and selectivity toward mGluR5. It possesses the potential to be used in human studies to evaluate mGluR5 functions in various neurological disorders.
authors.affiliation: Experimental PET Laboratory, Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors.forename: Ji-Quan
authors.initials: JQ
authors.lastname: Wang
authors.forename: Werner
authors.initials: W
authors.lastname: Tueckmantel
authors.forename: Aijun
authors.initials: A
authors.lastname: Zhu
authors.forename: Daniela
authors.initials: D
authors.lastname: Pellegrino
authors.forename: Anna-Liisa
authors.initials: AL
authors.lastname: Brownell
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D005069:Evaluation Studies as Topic; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D008297:Male; D009570:Nitriles / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D010880:Piperidines / Q000494:pharmacology; D049268:Positron-Emission Tomography / Q000379:methods; D011725:Pyridines / Q000494:pharmacology; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000032:analysis*; D013844:Thiazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000494:pharmacology; D014018:Tissue Distribution / Q000187:drug effects; D051598:Whole Body Imaging / Q000379:methods