title: Evaluation of a novel PDE10A PET radioligand, [(11) C]T-773, in nonhuman primates: brain and whole body PET and brain autoradiography.
abstract: Phosphodiesterase 10A (PDE10A) is considered to be a key target for the treatment of several neuropsychiatric diseases. The characteristics of [(11) C]T-773, a novel positron emission tomography (PET) radioligand with high binding affinity and selectivity for PDE10A, were evaluated in autoradiography and in nonhuman primate (NHP) PET. Brain PET measurements were performed under baseline conditions and after administration of a selective PDE10A inhibitor, MP-10. Total distribution volume (VT ) and binding potential (BPND ) were calculated using various kinetic models. Whole body PET measurements were performed to calculate the effective dose of [(11) C]T-773. Autoradiography studies in postmortem human and monkey brain sections showed high accumulation of [(11) C]T-773 in the striatum and substantia nigra which was blocked by MP-10. Brain PET showed high accumulation of [(11) C]T-773 in the striatum, and the data could be fitted using a two tissue compartment model. BPND was approximately 1.8 in the putamen when the cerebellum was used as the reference region. Approximately 70% of PDE10A binding was occupied by 1.8 mg/kg of MP-10. Whole body PET showed high accumulation of [(11) C]T-773 in the liver, kidney, heart, and brain in the initial phase. The radioligand was partly excreted via bile and the gastrointestinal tract, and partly excreted through the urinary tract. The calculated effective dose was 0.007 mSv/MBq. In conclusion, [(11) C]T-773 was demonstrated to be a promising PET radioligand for PDE10A with favorable brain kinetics. Dosimetry results support multiple PET measurements per person in human studies. Further research is required with [(11) C]T-773 in order to test the radioligand's potential clinical applications.
authors.affiliation: Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Takano
authors.affiliation: Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Stepanov
authors.affiliation: Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Balázs
authors.initials: B
authors.lastname: Gulyás
authors.affiliation: Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Nakao
authors.affiliation: Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Nahid
authors.initials: N
authors.lastname: Amini
authors.affiliation: Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Stockholm, Sweden.|CNS Drug Discovery Unit, Pharmaceutical Research Division, TAKEDA Pharmaceutical Company, Ltd., Fujisawa, Japan.
authors.forename: Shotaro
authors.initials: S
authors.lastname: Miura
authors.affiliation: CNS Drug Discovery Unit, Pharmaceutical Research Division, TAKEDA Pharmaceutical Company, Ltd., Fujisawa, Japan.
authors.forename: Haruhide
authors.initials: H
authors.lastname: Kimura
authors.affiliation: CNS Drug Discovery Unit, Pharmaceutical Research Division, TAKEDA Pharmaceutical Company, Ltd., Fujisawa, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Taniguchi
authors.affiliation: Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
mesh_terms: D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D008252:Macaca fascicularis; D008253:Macaca mulatta; D049268:Positron-Emission Tomography; D011485:Protein Binding / Q000187:drug effects; D011720:Pyrazoles / Q000493:pharmacokinetics*; D011724:Pyridazines / Q000493:pharmacokinetics*; D013997:Time Factors; D014018:Tissue Distribution / Q000187:drug effects; D051598:Whole Body Imaging / Q000379:methods
chemical_list: D011720:Pyrazoles; D011724:Pyridazines; C000601031:T-773 compound
keywords: dosimetry; imaging; kinetics