title: In vitro and in vivo characterization of two C-11-labeled pet tracers for vesicular acetylcholine transporter.
abstract: OBJECTIVE
  The vesicular acetylcholine transporter (VAChT) is a specific biomarker for imaging presynaptic cholinergic neurons. Herein, two potent and selective (11)C-labeled VAChT inhibitors were evaluated in rodents and nonhuman primates for imaging VAChT in vivo.
  
  
  METHODS
  For both (-)-[(11)C]2 and (-)-[(11)C]6, biodistribution, autoradiography, and metabolism studies were performed in male Sprague Dawley rats. Positron emission tomography (PET) brain studies with (-)-[(11)C]2 were performed in adult male cynomolgus macaques; 2 h dynamic data was acquired, and the regions of interest were drawn by co-registration of the PET images with the MRI.
  
  
  RESULTS
  The resolved enantiomers (-)-2 and (-)-6 were very potent and selective for VAChT in vitro (K i  < 5 nM for VAChT with >35-fold selectivity for VAChT vs. σ receptors); both radioligands, (-)-[(11)C]2 and (-)-[(11)C]6, demonstrated high accumulation in the VAChT-enriched striatum of rats. (-)-[(11)C]2 had a higher striatum to cerebellum ratio of 2.4-fold at 60 min; at 30 min, striatal uptake reached 0.550 ± 0.086 %ID/g. Uptake was also specific and selective; following pretreatment with (±)-2, striatal uptake of (-)-[(11)C]2 in rats at 30 min decreased by 50 %, while pretreatment with a potent sigma ligand had no significant effect on striatal uptake in rats. In addition, (-)-[(11)C]2 displayed favorable in vivo stability in rat blood and brain. PET studies of (-)-[(11)C]2 in nonhuman primates indicate that it readily crosses the blood-brain barrier (BBB) and provides clear visualization of the striatum; striatal uptake reaches the maximum at 60 min, at which time the target to nontarget ratio reached ~2-fold.
  
  
  CONCLUSIONS
  The radioligand (-)-[(11)C]2 has high potential to be a suitable PET radioligand for imaging VAChT in the brain of living subjects.
authors.affiliation: Department of Radiology, Washington University School of Medicine, 510 South Kingshighway Blvd., St. Louis, MO, 63110, USA.
authors.forename: Prashanth K
authors.initials: PK
authors.lastname: Padakanti
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhang
authors.forename: Hongjun
authors.initials: H
authors.lastname: Jin
authors.forename: Jinquan
authors.initials: J
authors.lastname: Cui
authors.forename: Ruike
authors.initials: R
authors.lastname: Wang
authors.forename: Junfeng
authors.initials: J
authors.lastname: Li
authors.forename: Hubert P
authors.initials: HP
authors.lastname: Flores
authors.forename: Stanley M
authors.initials: SM
authors.lastname: Parsons
authors.forename: Joel S
authors.initials: JS
authors.lastname: Perlmutter
authors.forename: Zhude
authors.initials: Z
authors.lastname: Tu
mesh_terms: D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000378:metabolism; D001923:Brain Chemistry; D002247:Carbon Isotopes / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D008252:Macaca fascicularis; D008297:Male; D011849:Radioactive Tracers; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D050494:Vesicular Acetylcholine Transport Proteins / Q000378:metabolism*
chemical_list: D002247:Carbon Isotopes; D011849:Radioactive Tracers; D019275:Radiopharmaceuticals; D050494:Vesicular Acetylcholine Transport Proteins