title: Synthesis, characterization, and first successful monkey imaging studies of metabotropic glutamate receptor subtype 5 (mGluR5) PET radiotracers.
abstract: Three metabotropic glutamate receptor subtype 5 (mGluR5) PET tracers have been labeled with either carbon-11 or fluorine-18 and their in vitro and in vivo behavior in rhesus monkey has been characterized. Each of these tracers share the common features of high affinity for mGluR5 (0.08-0.23 nM vs. rat mGluR5) and moderate lipophilicity (log P 2.8-3.4). Compound 1b was synthesized using a Suzuki or Stille coupling reaction with [11C]MeI. Compounds 2b and 3b were synthesized by a SNAr reaction using a 3-chlorobenzonitrile precursor. Autoradiographic studies in rhesus monkey brain slices using 2b and 3b showed specific binding in cortex, caudate, putamen, amygdala, hippocampus, most thalamic nuclei, and lower binding in the cerebellum. PET imaging studies in monkey showed that all three tracers readily enter the brain and provide an mGluR5-specific signal in all gray matter regions, including the cerebellum. The specific signal observed in the cerebellum was confirmed by the autoradiographic studies and saturation binding experiments that showed tracer binding in the cerebellum of rhesus monkeys. In vitro metabolism studies using the unlabeled compounds showed that 1a, 2a, and 3a are metabolized slower by human liver microsomes than by monkey liver microsomes. In vivo metabolism studies showed 3b to be long-lived in rhesus plasma with only one other more polar metabolite observed.
authors.affiliation: Merck Research Laboratories, Imaging Research Department, West Point, PA 19486, USA. terence_hamill@merck.com
authors.forename: Terence G
authors.initials: TG
authors.lastname: Hamill
authors.forename: Stephen
authors.initials: S
authors.lastname: Krause
authors.forename: Christine
authors.initials: C
authors.lastname: Ryan
authors.forename: Celine
authors.initials: C
authors.lastname: Bonnefous
authors.forename: Steve
authors.initials: S
authors.lastname: Govek
authors.forename: T Jon
authors.initials: TJ
authors.lastname: Seiders
authors.forename: Nicholas D P
authors.initials: ND
authors.lastname: Cosford
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Roppe
authors.forename: Ted
authors.initials: T
authors.lastname: Kamenecka
authors.forename: Shil
authors.initials: S
authors.lastname: Patel
authors.forename: Raymond E
authors.initials: RE
authors.lastname: Gibson
authors.forename: Sandra
authors.initials: S
authors.lastname: Sanabria
authors.forename: Kerry
authors.initials: K
authors.lastname: Riffel
authors.forename: Waisi
authors.initials: W
authors.lastname: Eng
authors.forename: Christopher
authors.initials: C
authors.lastname: King
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Yang
authors.forename: Mitchell D
authors.initials: MD
authors.lastname: Green
authors.forename: Stacey S
authors.initials: SS
authors.lastname: O'Malley
authors.forename: Richard
authors.initials: R
authors.lastname: Hargreaves
authors.forename: H Donald
authors.initials: HD
authors.lastname: Burns
mesh_terms: D000818:Animals; D001345:Autoradiography / Q000379:methods; D001665:Binding Sites / Q000187:drug effects; D001921:Brain / Q000033:anatomy & histology / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D001923:Brain Chemistry; D001931:Brain Mapping; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis* / Q000145:classification / Q000493:pharmacokinetics; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics; D006801:Humans; D066298:In Vitro Techniques; D008253:Macaca mulatta; D008279:Magnetic Resonance Imaging; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D049268:Positron-Emission Tomography; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013223:Statistics as Topic; D013997:Time Factors
chemical_list: D002250:Carbon Radioisotopes; D018691:Excitatory Amino Acid Antagonists; D005462:Fluorine Radioisotopes; C578935:GRM5 protein, human; C578937:Grm5 protein, rat; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate