title: A human [(11)C]T-773 PET study of PDE10A binding after oral administration of TAK-063, a PDE10A inhibitor.
abstract: Phosphodiesterase 10A (PDE10A) is selectively expressed in the striatal regions in the brain and may play a role in modulating dopaminergic and glutamatergic second messenger pathways. PDE10A inhibitors are expected to be useful in treating neuropsychiatric disorders such as schizophrenia and Huntington's disease. In this study, the brain kinetics of [(11)C]T-773 in the human brain and test-retest reproducibility of the outcome measures were evaluated. Subsequently, the occupancy of a novel PDE10A inhibitor, TAK-063, was measured using [(11)C]T-773. Dynamic PET measurements were conducted three times for 12 healthy male subjects after intravenous bolus injection of [(11)C]T-773: two baseline PETs and one postdose PET (3hours) after oral administration of TAK-063 for four subjects, and one baseline PET and two postdose PET (3hours and 23hours) for eight subjects. Kinetic model analysis was performed with arterial input functions. PDE10A occupancy was calculated as the percent change of the binding specific to PDE10A (Vs) total distribution volume (VT), which was calculated as the VT of the putamen minus the VT of the cerebellum. Regional brain uptake was highest in the putamen. Time-activity curves of the brain regions were described with two tissue-compartment (2TC) models. The mean VT was 5.5±0.7 in the putamen and 2.3±0.5 in the cerebellum in the baseline PET. Absolute VT variability between the two baseline scans was less than 7%. Reproducibility of VT was excellent. PDE10A occupancy in the putamen ranged from 2.8% to 72.1% at 3hours after a single administration of 3 to 1000mg of TAK-063, and increased in a dose- and plasma concentration-dependent manner. At 23hours postdose, PDE10A occupancy in the putamen was 0 to 42.8% following administration of 3 to 100mg of TAK-063. In conclusion, [(11)C]T-773 showed good characteristics as a PET radioligand for PDE10A in the human brain.
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Center for Psychiatric Research, Stockholm, Sweden. Electronic address: akihiro.takano@ki.se.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Takano
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Center for Psychiatric Research, Stockholm, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Stenkrona
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Center for Psychiatric Research, Stockholm, Sweden.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Stepanov
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Center for Psychiatric Research, Stockholm, Sweden.
authors.forename: Nahid
authors.initials: N
authors.lastname: Amini
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Center for Psychiatric Research, Stockholm, Sweden.
authors.forename: Stefan
authors.initials: S
authors.lastname: Martinsson
authors.affiliation: Takeda Development Center Americas, Inc., Deerfield, IL, USA.
authors.forename: Max
authors.initials: M
authors.lastname: Tsai
authors.affiliation: Takeda Development Centre Europe, London, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Goldsmith
authors.affiliation: Takeda Development Center Americas, Inc., Deerfield, IL, USA.
authors.forename: Jinhui
authors.initials: J
authors.lastname: Xie
authors.affiliation: Takeda Development Center Americas, Inc., Deerfield, IL, USA.
authors.forename: Jingtao
authors.initials: J
authors.lastname: Wu
authors.affiliation: Takeda Development Center Americas, Inc., Deerfield, IL, USA.
authors.forename: Tolga
authors.initials: T
authors.lastname: Uz
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Center for Psychiatric Research, Stockholm, Sweden.
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
authors.affiliation: Takeda Development Center Americas, Inc., Deerfield, IL, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Macek
mesh_terms: D000284:Administration, Oral; D000328:Adult; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D008875:Middle Aged; D057054:Molecular Imaging / Q000379:methods*; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods; D011485:Protein Binding; D011720:Pyrazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D011724:Pyridazines / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D014018:Tissue Distribution / Q000187:drug effects
chemical_list: C000594749:1-(2-fluoro-4-(1H-pyrazol-1-yl)phenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one; D010726:Phosphodiesterase Inhibitors; D011720:Pyrazoles; D011724:Pyridazines; D019275:Radiopharmaceuticals; C000601031:T-773 compound; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases