title: Radiosynthesis and in vivo evaluation of [(11)C]MP-10 as a positron emission tomography radioligand for phosphodiesterase 10A.
abstract: BACKGROUND
  The aim of this study was to evaluate a newly reported positron emission tomography (PET) radioligand [(11)C]MP-10, a potent and selective inhibitor of the central phosphodiesterase 10A enzyme (PDE10A) in vivo, using PET.
  
  
  METHODS
  A procedure was developed for labeling MP-10 with carbon-11. [(11)C]MP-10 was evaluated in vivo both in the pig and baboon brain.
  
  
  RESULTS
  Alkylation of the corresponding desmethyl compound with [(11)C]methyl iodide produced [(11)C]MP-10 with good radiochemical yield and specific activity. PET studies in the pig showed that [(11)C]MP-10 rapidly entered the brain reaching peak tissue concentration at 1-2 min postadministration, followed by washout from the tissue. Administration of a selective PDE10A inhibitor reduced the binding in all brain regions to the levels of the cerebellum, demonstrating the saturability and selectivity of [(11)C]MP-10 binding. In the nonhuman primate, the brain tissue kinetics of [(11)C]MP-10 were slower, reaching peak tissue concentrations at 30-60 min postadministration. In both species, the observed rank order of regional brain signal was striatum>diencephalon>cortical regions=cerebellum, consistent with the known distribution and concentration of PDE10A. [(11)C]MP-10 brain kinetics were well described by a two-tissue compartment model, and estimates of total volume of distribution (V(T)) were obtained. Blocking studies with unlabeled MP-10 revealed the suitability of the cerebellum as a reference tissue and enabled the estimation of regional binding potential (BP(ND)) as the outcome measure of specific binding. Quantification of [(11)C]MP-10 binding using the simplified reference tissue model with cerebellar input function produced BP(ND) estimates consistent with those obtained by the two-tissue compartment model.
  
  
  CONCLUSIONS
  We demonstrated that [(11)C]MP-10 possesses good characteristics for the in vivo quantification of the PDE10A in the brain by PET.
authors.affiliation: GlaxoSmithKline, Clinical Imaging Centre Hammersmith Hospital, London, W12 0NN, UK. Christophe.2.plisson@gsk.com
authors.forename: Christophe
authors.initials: C
authors.lastname: Plisson
authors.forename: Cristian
authors.initials: C
authors.lastname: Salinas
authors.forename: David
authors.initials: D
authors.lastname: Weinzimmer
authors.forename: David
authors.initials: D
authors.lastname: Labaree
authors.forename: Shu-Fei
authors.initials: SF
authors.lastname: Lin
authors.forename: Yu-Shin
authors.initials: YS
authors.lastname: Ding
authors.forename: Steen
authors.initials: S
authors.lastname: Jakobsen
authors.forename: Paul W
authors.initials: PW
authors.lastname: Smith
authors.forename: Kawanishi
authors.initials: K
authors.lastname: Eiji
authors.forename: Richard E
authors.initials: RE
authors.lastname: Carson
authors.forename: Roger N
authors.initials: RN
authors.lastname: Gunn
authors.forename: Eugenii A
authors.initials: EA
authors.lastname: Rabiner
mesh_terms: D000818:Animals; D002250:Carbon Radioisotopes; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism*; D005260:Female; D006801:Humans; D007700:Kinetics; D008024:Ligands; D010215:Papio; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods*; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000378:metabolism*; D011804:Quinolines / Q000138:chemical synthesis* / Q000378:metabolism*; D011854:Radiochemistry / Q000379:methods*; D013379:Substrate Specificity; D013552:Swine
chemical_list: C545121:2-((4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)phenoxy)methyl)quinoline; D002250:Carbon Radioisotopes; D004791:Enzyme Inhibitors; D008024:Ligands; D011720:Pyrazoles; D011804:Quinolines; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases