title: Biochemical and behavioral effects of PDE10A inhibitors: Relationship to target site occupancy.
abstract: Phosphodiesterase 10A (PDE10A) inhibitors increase the functionality of striatal medium spiny neurons and produce antipsychotic-like effects in rodents by blocking PDE10A mediated hydrolysis of cAMP and/or cGMP. In the current study, we characterized a radiolabeled PDE10A inhibitor, [(3)H]BMS-843496, and developed an ex vivo PDE10 binding autoradiographic assay to explore the relationship between PDE10 binding site occupancy and the observed biochemical and behavioral effects of PDE10 inhibitors in mice. [(3)H]BMS-843496 is a potent PDE10A inhibitor with a binding affinity (KD) of 0.15 nM and a functional selectivity of >100-fold over other PDE subtypes tested. Specific [(3)H]BMS-843496 binding sites were dominant in the basal ganglia, especially the striatum, with low to moderate binding in the cortical and hippocampal areas, of the mouse and monkey brain. Systemic administration of PDE10 inhibitors produced a dose- and plasma/brain concentration-dependent increase in PDE10A occupancy measured in the striatum. PDE10A occupancy was positively correlated with striatal pCREB expression levels. PDE10A occupancy was also correlated with antipsychotic-like effects measured using the conditioned avoidance response model; a minimum of ∼40% occupancy was typically required to achieve efficacy. In contrast, a clear relationship between PDE10A occupancy and catalepsy scores, a potential extrapyramidal symptom readout in rodent, was not evident.
authors.affiliation: Neuroscience Biology, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492-7660, USA. Electronic address: yu-wen.li@bms.com.
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Li
authors.affiliation: Neuroscience Biology, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Seager
authors.affiliation: Neuroscience Biology, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Trevor
authors.initials: T
authors.lastname: Wojcik
authors.affiliation: Neuroscience Biology, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Heman
authors.affiliation: Neuroscience Biology, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Thaddeus F
authors.initials: TF
authors.lastname: Molski
authors.affiliation: Neuroscience Biology, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Alda
authors.initials: A
authors.lastname: Fernandes
authors.affiliation: Neuroscience Biology, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Shaun
authors.initials: S
authors.lastname: Langdon
authors.affiliation: Neuroscience Chemistry, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Annapurna
authors.initials: A
authors.lastname: Pendri
authors.affiliation: Neuroscience Chemistry, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Gerritz
authors.affiliation: Radiosynthesis, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Radiosynthesis, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Hong
authors.affiliation: Lead Evaluation, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Lizbeth
authors.initials: L
authors.lastname: Gallagher
authors.affiliation: Pharmacopeia Inc, 3000 Eastpark Boulevard, Cranbury, NJ 08512, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Merritt
authors.affiliation: Pharmacopeia Inc, 3000 Eastpark Boulevard, Cranbury, NJ 08512, USA.
authors.forename: Chongwu
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Neuroscience Biology, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Westphal
authors.affiliation: Neuroscience Biology, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Zaczek
authors.affiliation: Neuroscience Chemistry, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Macor
authors.affiliation: Neuroscience Chemistry, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Joanne J
authors.initials: JJ
authors.lastname: Bronson
authors.affiliation: Neuroscience Biology, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Lodge
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D001665:Binding Sites; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D010726:Phosphodiesterase Inhibitors; C492284:Pde10a protein, mouse; D010727:Phosphoric Diester Hydrolases
keywords: Antipsychotic; Catalepsy; Conditioned avoidance response; Occupancy; PDE10A; Radioligand