Akina Harada1, Kazunori Suzuki1, Shotaro Miura1, Tomoaki Hasui1, Naomi Kamiguchi2, Tsuyoshi Ishii3, Takahiko Taniguchi1, Takanobu Kuroita1, Akihiro Takano4, Vladimir Stepanov4, Christer Halldin4, Haruhide Kimura5. 1. CNS Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan. 2. Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan. 3. Biomolecular Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan. 4. Center for Psychiatric Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. 5. CNS Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan. Electronic address: haruhide.kimura@takeda.com.
Abstract
INTRODUCTION: 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. CONCLUSION: These results suggest that [(11)C]T-773 is a potential PET radioligand for PDE10A.
INTRODUCTION: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. CONCLUSION: These results suggest that [(11)C]T-773 is a potential PET radioligand for PDE10A.
Authors: Mohammed K Hankir; Mathias Kranz; Thorsten Gnad; Juliane Weiner; Sally Wagner; Winnie Deuther-Conrad; Felix Bronisch; Karen Steinhoff; Julia Luthardt; Nora Klöting; Swen Hesse; John P Seibyl; Osama Sabri; John T Heiker; Matthias Blüher; Alexander Pfeifer; Peter Brust; Wiebke K Fenske Journal: EMBO Mol Med Date: 2016-07-01 Impact factor: 12.137
Authors: Akina Harada; Nidhi Kaushal; Kazunori Suzuki; Atsushi Nakatani; Konstantin Bobkov; John A Vekich; Joseph P Doyle; Haruhide Kimura Journal: Int J Neuropsychopharmacol Date: 2020-02-01 Impact factor: 5.176