title: Characterization of the binding properties of T-773 as a PET radioligand for phosphodiesterase 10A.
abstract: BACKGROUND
  Phosphodiesterase 10A (PDE10A) is a dual-substrate PDE that hydrolyzes both cAMP and cGMP and is selectively expressed in striatal medium spiny neurons. Recent studies have suggested that PDE10A inhibition is a novel approach for the treatment of disorders such as schizophrenia and Huntington's disease. A positron emission tomography (PET) occupancy study can provide useful information for the development of PDE10A inhibitors. We discovered T-773 as a candidate PET radioligand for PDE10A and investigated its properties by in vitro autoradiography and a PET study in a monkey.
  
  
  METHODS
  Profiling of T-773 as a PET radioligand for PDE10A was conducted by in vitro enzyme inhibitory assay, in vitro autoradiography, and PET study in a monkey.
  
  
  RESULTS
  T-773 showed a high binding affinity and selectivity for human recombinant PDE10A2 in vitro; the IC50 value in an enzyme inhibitory assay was 0.77nmol/L, and selectivity over other PDEs was more than 2500-fold. In autoradiography studies using mouse, rat, monkey, or human brain sections, radiolabeled T-773 selectively accumulated in the striatum. This selective accumulation was not observed in the brain sections of Pde10a-KO mice. The binding of [(3)H]T-773 to PDE10A in rat brain sections was competitively inhibited by MP-10, a selective PDE10A inhibitor. In rat brain sections, [(3)H]T-773 bound to a single high affinity site of PDE10A with Kd values of 12.2±2.2 and 4.7±1.2nmol/L in the caudate-putamen and nucleus accumbens, respectively. In a monkey PET study, [(11)C]T-773 showed good brain penetration and striatum-selective accumulation.
  
  
  CONCLUSIONS
  These results suggest that [(11)C]T-773 is a potential PET radioligand for PDE10A.
authors.affiliation: CNS Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: Akina
authors.initials: A
authors.lastname: Harada
authors.affiliation: CNS Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: CNS Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: Shotaro
authors.initials: S
authors.lastname: Miura
authors.affiliation: CNS Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Hasui
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: Naomi
authors.initials: N
authors.lastname: Kamiguchi
authors.affiliation: Biomolecular Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Ishii
authors.affiliation: CNS Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Taniguchi
authors.affiliation: CNS Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: Takanobu
authors.initials: T
authors.lastname: Kuroita
authors.affiliation: Center for Psychiatric Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Takano
authors.affiliation: Center for Psychiatric Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Stepanov
authors.affiliation: Center for Psychiatric Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
authors.affiliation: CNS Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan. Electronic address: haruhide.kimura@takeda.com.
authors.forename: Haruhide
authors.initials: H
authors.lastname: Kimura
mesh_terms: D000818:Animals; D001345:Autoradiography; D001667:Binding, Competitive; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D002250:Carbon Radioisotopes; D015971:Gene Expression Regulation, Enzymologic; D055786:Gene Knockout Techniques; D006801:Humans; D008024:Ligands; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D049268:Positron-Emission Tomography; D011485:Protein Binding; D011720:Pyrazoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011724:Pyridazines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats
chemical_list: D002250:Carbon Radioisotopes; D008024:Ligands; D010726:Phosphodiesterase Inhibitors; D011720:Pyrazoles; D011724:Pyridazines; C000601031:T-773 compound; C492284:Pde10a protein, mouse; D010727:Phosphoric Diester Hydrolases
keywords: Autoradiography; C-11; PDE10A; PET; T-773