title: Molecular Imaging of PDE10A Knockout Mice with a Novel PET Radiotracer: [(11)C]T-773.
abstract: OBJECTIVE
  [(11)C]T-773 is a new radioligand for positron emission tomography (PET) targeting the phosphodiesterase 10A enzyme (PDE10A). PDE10A is highly expressed in the striatum by medium spiny neurons, and it has been demonstrated to be involved in the regulation of striatal signaling through the reduction of medium spiny neuronal sensitivity towards glutamatergic excitation. PDE10A is associated with Parkinson's disease and different neuropsychiatric disorders such as Huntington's disease, obsessive-compulsive disorders (OCD) and schizophrenia. Studies have indicated that the inhibition of PDE10A may represent a novel therapeutic approach to the treatment of the aforementioned diseases characterized by the reduced activity of medium spiny neurons. An appropriate PET radioligand for PDE10A would help to facilitate drug development and drug evaluation.
  
  
  METHODS
  We have evaluated the [(11)C]T-773 ligand in PDE10A knockout mice (heterozygous [HET] and homozygous [HOM]) as well as in normal control animals (WILD) with PET.
  
  
  RESULTS
  The regional percent standardized uptake values (%SUV; mean ± SD) in the striatum were 48.2 ± 1.0 (HOM), 63.6 ± 5.3 (HET) and 85.1 ± 6.3 (WILD). Between each animal group the striatal %SUV values were significantly different (p < 0.0001). The striatal BPND values (mean ± SD) were 0.0 ± 0.0 (HOM), 0.14 ± 0.07 (HET) and 0.56 ± 0.15 (WILD). The BPND values were significantly lower in homozygous and heterozygous animals compared to wild type (p < 0.0001).
  
  
  CONCLUSIONS
  The novel PDE10A radioligand [(11)C]T-773 shows increased signals with higher levels of PDE10A and acceptable binding in the striatum in control animals compared to knockout mice.
authors.affiliation: Center for Psychiatric Research, Department of Clinical Neuroscience, Karolinska Institutet, SE-171 76, Stockholm, Sweden, miklos.toth@ki.se.
authors.forename: Miklós
authors.initials: M
authors.lastname: Tóth
authors.forename: Jenny
authors.initials: J
authors.lastname: Häggkvist
authors.forename: Vladimir
authors.initials: V
authors.lastname: Stepanov
authors.forename: Akihiro
authors.initials: A
authors.lastname: Takano
authors.forename: Ryuji
authors.initials: R
authors.lastname: Nakao
authors.forename: Nahid
authors.initials: N
authors.lastname: Amini
authors.forename: Shotaro
authors.initials: S
authors.lastname: Miura
authors.forename: Haruhide
authors.initials: H
authors.lastname: Kimura
authors.forename: Takahiko
authors.initials: T
authors.lastname: Taniguchi
authors.forename: Balázs
authors.initials: B
authors.lastname: Gulyás
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D001923:Brain Chemistry; D002250:Carbon Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D057054:Molecular Imaging / Q000379:methods*; D059906:Neuroimaging / Q000379:methods*; D010727:Phosphoric Diester Hydrolases / Q000235:genetics*; D049268:Positron-Emission Tomography / Q000379:methods*; D011849:Radioactive Tracers
chemical_list: D002250:Carbon Radioisotopes; D011849:Radioactive Tracers; C492284:Pde10a protein, mouse; D010727:Phosphoric Diester Hydrolases