title: Synthesis, radiolabeling, in vitro and in vivo evaluation of [18F]-FPECMO as a positron emission tomography radioligand for imaging the metabotropic glutamate receptor subtype 5.
abstract: BACKGROUND
  [18F]-(E)-3-((6-Fluoropyridin-2-yl)ethynyl)cyclohex-2-enone O-methyl oxime ([18F]-FPECMO) is a novel derivative of [11C]-ABP688. [18F]-FPECMO was characterized as a PET imaging agent for the metabotropic glutamate receptor subtype 5 (mGluR5).
  
  
  METHODS
  [18F]-FPECMO was synthesized in a one-step reaction sequence by reacting [(18)F]-KF-K(222) complex with (E)-3-((6-bromopyridin-2-yl)ethynyl)cyclohex-2-enone O-methyl oxime in dry DMSO. The in vitro affinity of FPECMO was determined by displacement assays using rat whole brain homogenates (without cerebellum) and the mGluR5-specific radioligand [(3)H]-M-MPEP. Further in vitro characterization involved metabolite studies, lipophilicity determination and autoradiographical analyses of brain slices. In vivo evaluation was performed by postmortem biodistribution studies and PET experiments using Sprague-Dawley rats.
  
  
  RESULTS
  The radiochemical yield after semipreparative HPLC was 35+/-7% and specific activity was >240 GBq/micromol. [(18)F]-FPECMO exhibited optimal lipophilicity (logD=2.1) and high metabolic stability in vitro. Displacement studies revealed a K(i) value of 3.6+/-0.7 nM for FPECMO. Biodistribution studies and ex vivo autoradiography showed highest radioactivity accumulation in mGluR5-rich brain regions such as the striatum and hippocampus. Co-injection of [18F]-FPECMO and ABP688 (1 mg/kg body weight), an mGluR5 antagonist, showed 40% specific binding in the striatum, hippocampus and cortex, regions known to contain high densities of the mGluR5. PET imaging, however, did not allow the visualization of mGluR5-rich brain regions in the rat brain due to a fast washout of [18F]-FPECMO from mGluR5-expressing tissues and rapid defluorination.
  
  
  CONCLUSIONS
  [18F]-FPECMO showed significant potential for the detection of mGluR5 in vitro; however, its in vivo characteristics are not optimal for a clear-cut visualization of the mGluR5 in rats.
authors: Center for Radiopharmaceutical Science of ETH, PSI and USZ, 8093 Zurich, Switzerland; Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland.
authors: Christophe
authors: C
authors: Lucatelli
authors: Michael
authors: M
authors: Honer
authors: Jean-Frédéric
authors: JF
authors: Salazar
authors: Tobias L
authors: TL
authors: Ross
authors: P August
authors: PA
authors: Schubiger
authors: Simon M
authors: SM
authors: Ametamey
mesh_terms: D000818:Animals; D001345:Autoradiography; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007553:Isotope Labeling; D008024:Ligands; D008297:Male; D010091:Oximes / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D049268:Positron-Emission Tomography; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: C545083:3-((6-Fluoropyridin-2-yl)ethynyl)cyclohex-2-enone O-methyl oxime; C510950:3-(6-methylpyridin-2-ylethynyl)cyclohex-2-enone-O-methyloxime; C578935:GRM5 protein, human; C578937:Grm5 protein, rat; D008024:Ligands; D010091:Oximes; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate