Antipsychotic-like effects of a novel phosphodiesterase 10A inhibitor MT-3014 in rats.

Abstract

Phosphodiesterase (PDE) 10A is an attractive therapeutic target for schizophrenia. Here, we investigated the antipsychotic-like effects of a novel PDE10A inhibitor, 1-({2-(7-fluoro-3-methylquinoxalin-2-yl)-5-[(3R)-3-fluoropyrrolidin-1-yl]pyrazolo[1,5-α]pyrimidin-7-yl}amino)-2-methylpropan-2-ol hydrochloride (MT-3014) in rats. MT-3014 showed a potent and selective inhibitory effect against PDE10A (IC50 = 0.357 nmol/L). Oral administration of MT-3014 (1.0-10 mg/kg) significantly increased the levels of cAMP, cGMP and cAMP response element-binding protein (CREB) phosphorylation in the rat striatum. MT-3014 decreased MK-801 (0.075 mg/kg)-induced hyperactivity (ED50 = 0.30 mg/kg) in a dose-dependent manner, although it decreased spontaneous locomotion in control rats (ED50 = 0.48 mg/kg); its effects were equivalent to those of risperidone. MT-3014 (0.3-3.0 mg/kg and 0.2 mg/kg) attenuated MK-801-induced prepulse inhibition deficits and cognitive deficits in rats, respectively, whereas risperidone attenuated MK-801-induced prepulse inhibition at only a high dose and failed to improve MK-801-induced cognitive deficits. Similar to risperidone (ID50 = 0.63 mg/kg), MT-3014 suppressed the conditioned avoidance response (ID50 = 0.32 mg/kg). Interestingly, MT-3014 did not elicit catalepsy and plasma prolactin increases at high doses. Furthermore, it also did not affect body weight. A positron emission tomography study using [11C]IMA107 showed a plasma concentration-dependent increase in brain PDE10A occupancy after oral administration of MT-3014 within the pharmacological dose range in rats. Brain PDE10A occupancy corresponding to the ID50 value in the conditioned avoidance response was approximately 60%, predicting the target occupancy in patients with schizophrenia. These results suggest that MT-3014 may be a novel antipsychotic drug, which is expected to have additional effects on cognitive impairment, without the prominent side effects associated with current atypical antipsychotics.

• Authors: Misae Takakuwa, Yumi Watanabe, Takeaki Saijo, Meguru Murata, Jun Anabuki, Tomoaki Tezuka, Saori Sato, Koki Kojima, Kenji Hashimoto
• Journal: Pharmacology, biochemistry, and behavior (Pharmacol Biochem Behav) Vol. 196 Pg. 172972 (09 2020) ISSN: 1873-5177 [Electronic] United States
• PMID: 32562717 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Antipsychotic Agents
• MT-3014
• Phosphodiesterase Inhibitors
• Pyrazoles
• Pyrimidines
• Pyrrolidines
• PDE10A protein, rat
• Phosphoric Diester Hydrolases

Topics

• Animals
• Antipsychotic Agents (pharmacology)
• Cognition (drug effects)
• Male
• Phosphodiesterase Inhibitors (pharmacology)
• Phosphoric Diester Hydrolases (metabolism)
• Positron-Emission Tomography
• Pyrazoles (pharmacology)
• Pyrimidines (pharmacology)
• Pyrrolidines (pharmacology)
• Rats
• Rats, Wistar