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.

磷酸二酯酶（PDE）10A是精神分裂症的有吸引力的治疗靶标。在这里，我们研究了新型PDE10A抑制剂1-（{2-（7-氟-3-甲基喹喔啉-2-基）-5-[（3 R）-3-氟吡咯烷-1-基大鼠]吡唑并[1,5-α]嘧啶-7-基}氨基）-2-甲基丙烷-2-醇盐酸盐（MT-3014）。MT-3014对PDE10A表现出有效的选择性抑制作用（IC ₅₀  = 0.357 nmol / L）。口服MT-3014（1.0-10 mg / kg）可以显着增加大鼠纹状体中cAMP，cGMP和cAMP反应元件结合蛋白（CREB）的磷酸化水平。MT-3014降低了MK-801（0.075 mg / kg）诱导的机能亢进（ED ₅₀ = 0.30 mg / kg），尽管它降低了对照组大鼠的自发运动（ED ₅₀  = 0.48 mg / kg）；其作用与利培酮相当。MT-3014（0.3–3.0 mg / kg和0.2 mg / kg）分别减轻了MK-801诱导的大鼠前冲抑制功能障碍和认知功能障碍，而利培酮仅以高剂量减弱了MK-801诱导的前脉冲抑制功能，但失败了。改善MK-801引起的认知缺陷。与利培酮（ID ₅₀  = 0.63 mg / kg）相似，MT-3014抑制条件回避反应（ID ₅₀  = 0.32 mg / kg）。有趣的是，MT-3014不会引起僵直，大剂量时血浆催乳激素会增加。此外，它也没有影响体重。使用[^图11C] IMA107显示在大鼠药理剂量范围内口服MT-3014后，脑PDE10A占有率的血浆浓度依赖性增加。与条件回避反应中的ID ₅₀值相对应的大脑PDE10A占用率约为60％，预示着精神分裂症患者的目标占用率。这些结果表明，MT-3014可能是一种新型的抗精神病药，有望对认知障碍产生其他作用，而不会出现与当前非典型抗精神病药有关的显着副作用。