Preclinical profile of ITI-214, an inhibitor of phosphodiesterase 1, for enhancement of memory performance in rats

Gretchen L. Snyder*, Jos Prickaerts, Marie-Louise Wadenberg, Lei Zhang, Hailin Zheng, Wei Yao, Sven Akkerman, Hongwen Zhu, Joseph P. Hendrick, Kimberly E. Vanover, Robert Davis, Peng Li, Sharon Mates, Lawrence P. Wennogle

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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.
Original languageEnglish
Pages (from-to)3113-3124
JournalPsychopharmacology
Volume233
Issue number17
DOIs
Publication statusPublished - Sep 2016

Keywords

  • Novel object recognition
  • Phosphodiesterase-1
  • Cyclic GMP
  • Cyclic AMP
  • Memory
  • Conditioned avoidance response

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