title: Preclinical profile of ITI-214, an inhibitor of phosphodiesterase 1, for enhancement of memory performance in rats.
abstract: Therapeutic agents for memory enhancement in psychiatric disorders, such as schizophrenia, are urgently needed.
  
  
  
  The aim of this study is to characterize the preclinical profile of ITI-214, a potent inhibitor of phosphodiesterase 1 (PDE1).
  
  
  
  ITI-214 was assayed for inhibition of PDE1 versus other PDE enzyme families using recombinant human PDE enzymes and for off-target binding to 70 substrates (General SEP II diversity panel; Caliper Life Sciences). Effects of ITI-214 (0.1-10 mg/kg, po) on memory performance were assayed in rats using the novel object recognition (NOR) paradigm, with drug given at specified time points prior to or following exposure to objects in an open field. ITI-214 was evaluated for potential drug-drug interaction with risperidone in rats using conditioned avoidance response (CAR) and pharmacokinetic assessments.
  
  
  
  ITI-214 inhibited PDE1A (K i = 33 pmol) with >1000-fold selectivity for the nearest other PDE family (PDE4D) and displayed minimal off-target binding interactions in a 70-substrate selectivity profile. By using specific timing of oral ITI-214 administration, it was demonstrated in the NOR that ITI-214 is able to enhance acquisition, consolidation, and retrieval memory processes. All memory effects were in the absence of effects on exploratory behavior. ITI-214 did not disrupt the risperidone pharmacokinetic profile or effects in CAR.
  
  
  
  ITI-214 improved the memory processes of acquisition, consolidation, and retrieval across a broad dose range (0.1-10 mg/kg, po) without disrupting the antipsychotic-like activity of a clinical antipsychotic medication, specifically risperidone. Clinical development of ITI-214 is currently in progress.
authors.affiliation: Intra-Cellular Therapies Inc., 430 East 29th Street, Suite 900, New York, NY, 10016, USA. gsnyder@intracellulartherapies.com.
authors.forename: Gretchen L
authors.initials: GL
authors.lastname: Snyder
authors.affiliation: Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, P.O. Box 616, NL-6200, Maastricht, MD, The Netherlands.
authors.forename: Jos
authors.initials: J
authors.lastname: Prickaerts
authors.affiliation: School of Natural Sciences, Linnaeus University, Kalmar, Sweden.
authors.forename: Marie-Louise
authors.initials: ML
authors.lastname: Wadenberg
authors.affiliation: Intra-Cellular Therapies Inc., 430 East 29th Street, Suite 900, New York, NY, 10016, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Intra-Cellular Therapies Inc., 430 East 29th Street, Suite 900, New York, NY, 10016, USA.
authors.forename: Hailin
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Intra-Cellular Therapies Inc., 430 East 29th Street, Suite 900, New York, NY, 10016, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Yao
authors.affiliation: Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, P.O. Box 616, NL-6200, Maastricht, MD, The Netherlands.
authors.forename: Sven
authors.initials: S
authors.lastname: Akkerman
authors.affiliation: Tianjin Hospital, Tianjin, 300211, People's Republic of China.
authors.forename: Hongwen
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Intra-Cellular Therapies Inc., 430 East 29th Street, Suite 900, New York, NY, 10016, USA.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Hendrick
authors.affiliation: Intra-Cellular Therapies Inc., 430 East 29th Street, Suite 900, New York, NY, 10016, USA.
authors.forename: Kimberly E
authors.initials: KE
authors.lastname: Vanover
authors.affiliation: Intra-Cellular Therapies Inc., 430 East 29th Street, Suite 900, New York, NY, 10016, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Davis
authors.affiliation: Intra-Cellular Therapies Inc., 430 East 29th Street, Suite 900, New York, NY, 10016, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.affiliation: Intra-Cellular Therapies Inc., 430 East 29th Street, Suite 900, New York, NY, 10016, USA.
authors.forename: Sharon
authors.initials: S
authors.lastname: Mates
authors.affiliation: Intra-Cellular Therapies Inc., 430 East 29th Street, Suite 900, New York, NY, 10016, USA.
authors.forename: Lawrence P
authors.initials: LP
authors.lastname: Wennogle
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1 / Q000037:antagonists & inhibitors*; D004347:Drug Interactions; D005106:Exploratory Behavior / Q000187:drug effects; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D008297:Male; D008568:Memory / Q000187:drug effects*; D018697:Nootropic Agents / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D051381:Rats; D021641:Recognition, Psychology / Q000187:drug effects*; D018967:Risperidone / Q000494:pharmacology; D012559:Schizophrenia; D012565:Schizophrenic Psychology
chemical_list: D014150:Antipsychotic Agents; D006576:Heterocyclic Compounds, 4 or More Rings; C000625407:ITI-214; D018697:Nootropic Agents; D010726:Phosphodiesterase Inhibitors; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; C517263:Pde1a protein, rat; D018967:Risperidone
keywords: Conditioned avoidance response; Cyclic AMP; Cyclic GMP; Memory; Novel object recognition; Phosphodiesterase-1