title: In vivo evaluation of carbon-11-labelled non-sarcosine-based glycine transporter 1 inhibitors in mice and conscious monkeys.
abstract: BACKGROUND
  Glycine transporter 1 (GlyT-1) is an attractive target in positron emission tomography (PET) studies. Here, we report the in vivo evaluation of three carbon-11-labelled non-sarcosine-type GlyT-1 inhibitors--[(11)C]SA1, [(11)C]SA2 and [(11)C]SA3--as novel PET tracers for GlyT-1.
  
  
  METHODS
  The regional brain distributions of the three compounds in mice were studied at baseline and under receptor-blockade conditions with co-injection of carrier loading or pretreatment with an excess of selective GlyT-1 inhibitors (ALX-5407 and SSR504734). Metabolic stability was investigated by radio high-performance liquid chromatography. Dynamic PET scans in conscious monkeys were performed with/without selective GlyT-1 inhibitors.
  
  
  RESULTS
  The IC(50) values of SA1, SA2 and SA3 were 9.0, 6400 and 39.7 nM, respectively. The regional brain uptakes of [(11)C]SA1 and [(11)C]SA3 in mice were heterogeneous and consistent with the known distribution of GlyT-1. [(11)C]SA2 showed low and homogeneous uptake in the brain. Most radioactivity in the brain was detected in unchanged form, although peripherally these compounds were degraded. Carrier loading decreased the uptake of [(11)C]SA1 in GlyT-1-rich regions. However, similar reductions were not observed with [(11)C]SA3. Pretreatment with ALX-5407 decreased the uptake of [(11)C]SA1 in GlyT-1-rich regions. In the monkey at baseline, regional brain uptake of [(11)C]SA1 was heterogeneous and consistent with the known GlyT-1 distribution. Pretreatment with selective GlyT-1 inhibitors significantly decreased the distribution volume ratio of [(11)C] SA1 in GlyT-1-rich regions.
  
  
  CONCLUSIONS
  [(11)C]SA1 has the most suitable profile among the three carbon-11-labelled GlyT-1 inhibitors. Lead optimization of [(11)C]SA1 structure will be required to achieve in vivo selective GlyT-1 imaging.
authors.affiliation: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan 260-8670.
authors.forename: Jun
authors.initials: J
authors.lastname: Toyohara
authors.forename: Kiichi
authors.initials: K
authors.lastname: Ishiwata
authors.forename: Muneyuki
authors.initials: M
authors.lastname: Sakata
authors.forename: Jin
authors.initials: J
authors.lastname: Wu
authors.forename: Shingo
authors.initials: S
authors.lastname: Nishiyama
authors.forename: Hideo
authors.initials: H
authors.lastname: Tsukada
authors.forename: Kenji
authors.initials: K
authors.lastname: Hashimoto
mesh_terms: D000577:Amides / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D002250:Carbon Radioisotopes; D003243:Consciousness; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000882:Haplorhini; D008024:Ligands; D008297:Male; D051379:Mice; D049268:Positron-Emission Tomography; D011854:Radiochemistry; D013379:Substrate Specificity
chemical_list: D000577:Amides; D002250:Carbon Radioisotopes; D050487:Glycine Plasma Membrane Transport Proteins; D008024:Ligands