title: Kinetics modeling and occupancy studies of a novel C-11 PET tracer for VAChT in nonhuman primates.
abstract: BACKGROUND
  Deficits in cholinergic function have been found in the aged brain and in neurodegenerative diseases including Alzheimer's disease (AD) and Parkinson's disease (PD). The vesicular acetylcholine transporter (VAChT) is a reliable biomarker for the cholinergic system. We previously reported the initial in vitro and ex vivo characterization of (-)-[(11)C]TZ659 as a VAChT specific ligand. Here, we report the in vivo specificity, tracer kinetics, and dose-occupancy studies in the nonhuman primate brain.
  
  
  METHODS
  MicroPET brain imaging of (-)-[(11)C]TZ659 was performed under baseline conditions in two male macaques. Tracer kinetic modeling was carried out using a two-tissue compartment model (2TCM) and Logan plot with arterial blood input function and using a simplified reference tissue model (SRTM) and Logan plot (LoganREF) without blood input. Specificity for VAChT was demonstrated by pretreatment with (+)-pentazocine, (-)-vesamicol, or S-(-)-eticlopride. Target occupancy (Occ) was calculated following pretreatment with escalating doses of (-)-vesamicol.
  
  
  RESULTS
  Baseline PET imaging revealed selective retention in the striatum with rapid clearance from the cerebellar hemispheres as a reference region. Total volume of distribution (VT) values derived from both 2TCM and Logan analysis with blood input revealed ~3-fold higher levels of (-)-[(11)C]TZ659 in the striatum than the cerebellar hemispheres. Injection of (-)-vesamicol either as a blocking or displacing agent significantly reduced striatal uptake of (-)-[(11)C]TZ659. In contrast, pretreatment with the sigma-1 ligand (+)-pentazocine had no impact. Pretreatment with the S-(-)-eticlopride, a dopamine D2-like receptor antagonist, increased striatal uptake of (-)-[(11)C]TZ659. Striatal binding potential (BPND, range of 0.33-1.6 with cerebellar hemispheres as the reference region) showed good correlation (r(2)=0.97) between SRTM and LoganREF. Occupancy studies found that ~0.0057 mg/kg of (-)-vesamicol produced 50% VAChT occupancy in the striatum.
  
  
  CONCLUSIONS
  (-)-[(11)C]TZ659 demonstrated specific and reversible VAChT binding and favorable pharmacokinetic properties for assessing the density of VAChT in the living brain.
authors.affiliation: Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Hongjun
authors.initials: H
authors.lastname: Jin
authors.affiliation: Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Xuyi
authors.initials: X
authors.lastname: Yue
authors.affiliation: Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Junfeng
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Hubert
authors.initials: H
authors.lastname: Flores
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Su
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA 93106, USA.
authors.forename: Stanley M
authors.initials: SM
authors.lastname: Parsons
authors.affiliation: Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Joel S
authors.initials: JS
authors.lastname: Perlmutter
authors.affiliation: Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: tuz@mir.wustl.edu.
authors.forename: Zhude
authors.initials: Z
authors.lastname: Tu
mesh_terms: D000814:Aniline Compounds / Q000378:metabolism*; D000818:Animals; D002250:Carbon Radioisotopes; D007700:Kinetics; D008251:Macaca; D008297:Male; D008954:Models, Biological; D010880:Piperidines / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods*; D050494:Vesicular Acetylcholine Transport Proteins / Q000378:metabolism*
chemical_list: D000814:Aniline Compounds; D002250:Carbon Radioisotopes; D010880:Piperidines; C000603497:TZ659 compound; D050494:Vesicular Acetylcholine Transport Proteins
keywords: (−)-[(11)C]TZ659; Binding potential; Occupancy; Tracer kinetics; Vesicular acetylcholine transporter