title: Synthesis and characterization in monkey of [11C]SP203 as a radioligand for imaging brain metabotropic glutamate 5 receptors.
abstract: OBJECTIVE
  [(18)F]SP203 (3-fluoro-5-(2-(2-([(18)F]fluoromethyl)-thiazol-4-yl)ethynyl)benzonitrile) is an effective high-affinity and selective radioligand for imaging metabotropic 5 receptors (mGluR5) in human brain with PET. To provide a radioligand that may be used for more than one scanning session in the same subject in a single day, we set out to label SP203 with shorter-lived (11)C (t (1/2) = 20.4 min) and to characterize its behavior as a radioligand with PET in the monkey.
  
  
  METHODS
  Iodo and bromo precursors were obtained by cross-coupling 2-fluoromethyl-4-((trimethylsilyl)ethynyl)-1,3-thiazole with 3,5-diiodofluorobenzene and 3,5-dibromofluorobenzene, respectively. Treatment of either precursor with [(11)C]cyanide ion rapidly gave [(11)C]SP203, which was purified with high-performance liquid chromatography. PET was used to measure the uptake of radioactivity in brain regions after injecting [(11)C]SP203 intravenously into rhesus monkeys at baseline and under conditions in which mGluR5 were blocked with 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP). The emergence of radiometabolites in monkey blood in vitro and in vivo was assessed with radio-HPLC. The stability of [(11)C]SP203 in human blood in vitro was also measured.
  
  
  RESULTS
  The iodo precursor gave [(11)C]SP203 in higher radiochemical yield (>98 %) than the bromo precursor (20-52 %). After intravenous administration of [(11)C]SP203 into three rhesus monkeys, radioactivity peaked early in brain (average 12.5 min) with a regional distribution in rank order of expected mGluR5 density. Peak uptake was followed by a steady decline. No radioactivity accumulated in the skull. In monkeys pretreated with MTEP before [(11)C]SP203 administration, radioactivity uptake in brain was again high but then declined more rapidly than in the baseline scan to a common low level. [(11)C]SP203 was unstable in monkey blood in vitro and in vivo, and gave predominantly less lipophilic radiometabolites. By contrast, [(11)C]SP203 was stable in human blood in vitro.
  
  
  CONCLUSIONS
  [(11)C]SP203 emulates [(18)F]SP203 with regard to providing a sizeable mGluR5-specific signal in monkey brain, and advantageously avoids troublesome accumulation of radioactivity in bone. Although [(11)C]SP203 is unsuitable for mGluR5 quantification in monkey brain, its evaluation as a PET radioligand for studying human brain mGluR5 is nevertheless warranted.
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Fabrice G
authors.initials: FG
authors.lastname: Siméon
authors.forename: Jeih-San
authors.initials: JS
authors.lastname: Liow
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jinsoo
authors.initials: J
authors.lastname: Hong
authors.forename: Robert L
authors.initials: RL
authors.lastname: Gladding
authors.forename: Sami S
authors.initials: SS
authors.lastname: Zoghbi
authors.forename: Robert B
authors.initials: RB
authors.lastname: Innis
authors.forename: Victor W
authors.initials: VW
authors.lastname: Pike
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging*; D002250:Carbon Radioisotopes / Q000097:blood / Q000737:chemistry; D006801:Humans; D008024:Ligands; D008253:Macaca mulatta; D008297:Male; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry* / Q000493:pharmacokinetics*; D011849:Radioactive Tracers; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000032:analysis*; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry* / Q000493:pharmacokinetics*
chemical_list: C522844:3-fluoro-5-(2-(2-(fluoromethyl)thiazol-4-yl)ethynyl)benzonitrile; D002250:Carbon Radioisotopes; C578935:GRM5 protein, human; D008024:Ligands; D009570:Nitriles; D011849:Radioactive Tracers; D019275:Radiopharmaceuticals; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D013844:Thiazoles