title: Radiosynthesis and evaluation of [11C]YM-202074 as a PET ligand for imaging the metabotropic glutamate receptor type 1.
abstract: BACKGROUND
  Developing positron emission tomography (PET) ligands for imaging metabotropic glutamate receptor type 1 (mGluR1) is important for studying its role in the central nervous system. N-cyclohexyl-6-{[N-(2-methoxyethyl)-N-methylamino]methyl}-N-methylthiazolo[3,2-a]benzimidazole-2-carboxamide (YM-202074) exhibited high binding affinity for mGluR1 (K(i)=4.8 nM), and selectivity over other mGluRs in vitro. The purpose of this study was to label YM-202074 with carbon-11 and to evaluate in vitro and in vivo characteristics of [(11)C]YM-202074 as a PET ligand for mGluR1 in rodents.
  
  
  METHODS
  [(11)C]YM-202074 was synthesized by N-[(11)C]methylation of its desmethyl precursor with [(11)C]methyl iodide. The in vitro and in vivo brain regional distributions were determined in rats using autoradiography and PET, respectively.
  
  
  RESULTS
  [(11)C]YM-202074 (262-630 MBq, n=5) was obtained with radiochemical purity of >98% and specific activity of 27-52 GBq/mumol at the end of synthesis, starting from [(11)C]CO(2) of 19.3-21.5 GBq. In vitro autoradiographic results showed that the high specific binding of [(11)C]YM-202074 for mGluR1 was presented in the cerebellum, thalamus and hippocampus, which are known as mGluR1-rich regions. In ex vivo autoradiography and PET studies, the radioligand was specifically distributed in the cerebellum, although the uptake was low. Furthermore, the regional distribution was fairly uniform in the whole brain by pretreatment with JNJ16259685 (a mGluR1 antagonist). However, radiometabolite(s) was detected in the brain.
  
  
  CONCLUSIONS
  From these results, especially considering the low brain uptake and the influx of radiometabolite(s) into brain, [(11)C]YM-202074 may not be a useful PET ligand for in vivo imaging of mGluR1 in the brain.
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Inage-ku, Chiba 263-8555, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yanamoto
authors.forename: Fujiko
authors.initials: F
authors.lastname: Konno
authors.forename: Chika
authors.initials: C
authors.lastname: Odawara
authors.forename: Tomoteru
authors.initials: T
authors.lastname: Yamasaki
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kawamura
authors.forename: Akiko
authors.initials: A
authors.lastname: Hatori
authors.forename: Joji
authors.initials: J
authors.lastname: Yui
authors.forename: Hidekatsu
authors.initials: H
authors.lastname: Wakizaka
authors.forename: Nobuki
authors.initials: N
authors.lastname: Nengaki
authors.forename: Makoto
authors.initials: M
authors.lastname: Takei
authors.forename: Ming-Rong
authors.initials: MR
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D008024:Ligands; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D049268:Positron-Emission Tomography / Q000379:methods*; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D013379:Substrate Specificity; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*
chemical_list: D001562:Benzimidazoles; D008024:Ligands; C528872:N-cyclohexyl-6-(((2-methoxyethyl)(methyl)amino)methyl)-N-methylthiazolo(3,2-a)benzimidazole-2-carboxamide; D018094:Receptors, Metabotropic Glutamate; D013844:Thiazoles; C104077:metabotropic glutamate receptor type 1