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

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Highlights

  • MT-3014 is a potent, selective and orally bioactive PDE10A inhibitor.

  • MT-3014 was effective for positive-like symptoms in rat models of schizophrenia.

  • MT-3014 also showed cognitive improvement in the novel object recognition test.

  • MT-3014 did not cause side effects such as catalepsy caused by current antipsychotics.

  • A PET study of MT-3014 suggested that the effect of MT-3014 would be predicted using plasma MT-3014 concentration.

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.

Introduction

Schizophrenia is a complex psychiatric disorder primarily characterized by positive symptoms, negative symptoms, and cognitive impairment (Owen et al., 2016). Typical antipsychotics with dopamine D2 receptor antagonism as a primary mechanism of action are highly effective against positive symptoms but less so against negative symptoms and cognitive impairment and are accompanied by side effects such as extrapyramidal symptoms (EPS) and hyperprolactinemia (De Hert et al., 2016; Kane, 2001). Atypical antipsychotics have partial effects on negative symptoms and cognitive impairment through a broader mechanism of actions, such as partial agonism of the dopamine D2 receptor, dual dopamine/serotonin blockage, and multiple receptor blockade. Atypical antipsychotics have achieved success in reducing side effects caused by typical antipsychotics but have been reported to cause other side effects such as weight gain and an increased risk of diabetes (Leucht et al., 2009; Serretti et al., 2004; Tschoner et al., 2007). New classes of drugs that show a greater effect against symptoms for which current antipsychotics lack potency, or that have better side effect profiles, are desired (Citrome, 2014; Forray and Buller, 2017; Krebs et al., 2006). Phosphodiesterase (PDE) 10A inhibitors are one of the candidates for novel antipsychotics (Kehler and Nielsen, 2011; Krogmann et al., 2019; Swierczek et al., 2019).

PDE10A is highly expressed in medium spiny neurons (MSNs) of the striatum (Fujishige et al., 1999; Seeger et al., 2003; Soderling et al., 1999) and hydrolyzes both cAMP and cGMP. The striatum is a region in which a large amount information is integrated, including glutamatergic input from the cortex and dopaminergic input from the ventral tegmental area or the substantia nigra (Graybiel, 1990, Graybiel, 2000). Outputs from the striatum are mainly divided into the direct pathway from D1-expressing neurons and the indirect pathway from D2-expressing neurons and then reintegrated (Surmeier et al., 2007). Inhibition of PDE10A activates both direct and indirect pathways via the upregulation of cAMP and cGMP in both types of neurons, indicating that PDE10A inhibitors could have a dual D1 agonist and D2 antagonist-like effect (Siuciak et al., 2006b). It is likely that PDE10A inhibitors may provide a new therapeutic approach for schizophrenia by rescuing the weakened cortical glutamatergic input, which seems to be associated with negative symptoms and cognitive symptoms in addition to the antipsychotic effect of D2 blockade (Siuciak et al., 2006a; Siuciak et al., 2006b; Snyder and Vanover, 2014, Snyder and Vanover, 2017). Moreover, PDE10A inhibitors may avoid side effects caused by current antipsychotics via excess activation of the indirect pathway, as well as activating the direct pathway. Indeed, several PDE10A inhibitors have been developed for the treatment of schizophrenia in the last decade (Arakawa et al., 2016; Geerts et al., 2017; Grauer et al., 2009; Kehler, 2013; Suzuki et al., 2015; Takakuwa et al., 2019; Zagorska et al., 2018).

In this study, we investigated the antipsychotic-like profiles 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, Koizumi et al., 2019), in rats. Furthermore, we examined the receptor occupancy of PDE10A in the brain after intravenous injection of MT-3014 using positron emission tomography (PET) in rats.

Section snippets

Animals

Male Wistar rats (5–9 weeks old, Japan Charles River Inc., Yokohama, Japan) were used for the measurement of striatal cAMP and cGMP levels, measurement of cAMP response element-binding protein (CREB) phosphorylation levels and the conditioned avoidance response (CAR) test. Male Wistar rats (7–10 weeks old, Japan SLC, Inc., Hamamatsu, Japan) were used for the locomotor activity tests, prepulse inhibition (PPI) test, catalepsy test and measurement of plasma prolactin levels. Male Long-Evans rats

In vitro profiling of MT-3014

MT-3014 showed a potent inhibitory effect against PDE10A with an IC50 value (95% CI) of 0.357 (0.131–0.976) nmol/L (Table 1). MT-3014 showed good selectivity over other PDE families with IC50 values over 500-fold (Table 1) and over the other 52 primary target proteins (enzymes, ion channels, receptors and transporters related to central nervous systems) with IC50 values over 1000-fold (Supplemental Table 1).

Oral bioactivity of MT-3014 in rats

The oral bioactivity of MT-3014 was investigated. Oral administration of MT-3014

Discussion

Here, we demonstrated the antipsychotic-like effect of MT-3014 (Koizumi et al., 2019) in rats. MT-3014 showed a potent inhibitory effect against PDE10A with high selectivity over other PDE families and other primary off-targets. Oral administration of MT-3014 increased striatal cAMP, cGMP and CREB phosphorylation at doses of 1.0 mg/kg or higher doses, indicating good biological activity of MT-3014. For assessment of antipsychotic-like effects, MK-801-induced rat models have been widely used (

Acknowledgments

We sincerely thank Ms. Fumiko Eguchi, Ms. Itsuko Nakamura, Ms. Kumiko Hikida, Mr. Masayuki Suzuki, Mr. Youta Goto, Dr. Koji Teshima and MTPC colleagues for their support in conducting the experiments and writing the manuscript.

Declaration of competing interest

Dr. Hashimoto has received research support or consultant fees from Dainippon-Sumitomo, Otsuka, and Taisho. Other authors are employees of MTPC.

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