Characterization of Binding and Inhibitory Properties of TAK-063, a Novel Phosphodiesterase 10A Inhibitor

Abstract

Phosphodiesterase 10A (PDE10A) inhibition is a novel and promising approach for the treatment of central nervous system disorders such as schizophrenia and Huntington’s disease. A novel PDE10A inhibitor, TAK-063 [1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)-pyridazin-4(1H)-one] has shown high inhibitory activity and selectivity for human recombinant PDE10A2 in vitro; the half-maximal inhibitory concentration was 0.30 nM, and selectivity over other phosphodiesterases (PDEs) was more than 15000-fold. TAK-063 at 10 µM did not show more than 50% inhibition or stimulation of 91 enzymes or receptors except for PDEs. In vitro autoradiography (ARG) studies using rat brain sections revealed that [3H]TAK-063 selectively accumulated in the caudate putamen (CPu), nucleus accumbens (NAc), globus pallidus, substantia nigra, and striatonigral projection, where PDE10A is highly expressed. This [3H]TAK-063 accumulation was almost entirely blocked by an excess amount of MP-10, a PDE10A selective inhibitor, and the accumulation was not observed in brain slices of Pde10a-knockout mice. In rat brain sections, [3H]TAK-063 bound to a single high-affinity site with mean ± SEM dissociation constants of 7.2 ± 1.2 and 2.6 ± 0.5 nM for the CPu and NAc shell, respectively. Orally administered [14C]TAK-063 selectively accumulated in PDE10A expressing brain regions in an in vivo ARG study in rats. Striatal PDE10A occupancy by TAK-063 in vivo was measured using T-773 as a tracer and a dose of 0.88 mg/kg (p.o.) was calculated to produce 50% occupancy in rats. Translational studies with TAK-063 and other PDE10A inhibitors such as those presented here will help us better understand the pharmacological profile of this class of potential central nervous system drugs.

TAK-063, a PDE10A Inhibitor with Balanced Activation of Direct and Indirect Pathways, Provides Potent Antipsychotic-Like Effects in Multiple Paradigms

“…In rats treated with the N-methyl-D-aspartic acid receptor antagonist MK-801, an animal model of psychosis, both TAK-063 (0.3 mg/kg) and MP-10 (3 mg/kg) produced 470% suppression of MK-801-induced hyperactivity at doses that resulted in 26 and 36% PDE10A occupancy, respectively (Table 1, Figure 1a, and Supplementary Figure S1) (Harada et al, 2015a;Suzuki et al, 2015). The same results were replicated in mice, whereby treatment with either TAK-063 (0.3 mg/kg, 38% occupancy) or MP-10 (3 mg/kg, 68% occupancy) produced 470% reduction in MK-801-induced hyperactivity (Table 1 and Supplementary Figure S1; Suzuki et al, 2015).…”

“…The current antipsychotic risperidone also significantly increased the Figure S1. a Striatal PDE10A occupancy was determined by regression analysis in an in vivo occupancy study using T-773 (Supplementary Figure S1) (Harada et al, 2015a). b The percentage increase in striatal cAMP in mice was measured 1 h after administration of TAK-063 or MP-10 (Supplementary Figure S1).…”

“…Pde10a-knockout mice were used to confirm the role of PDE10A in TAK-063-and MP-10-dependent dopamine release in the striatum. In Pde10a-knockout mice, TAK-063 does not accumulate in the striatum (Harada et al, 2015a) and is not effective in reversing phencyclidine-induced hyperactivity (Kunitomo et al, 2014). The slight dopamine release by TAK-063 at 86% occupancy (3 mg/kg) was absent in Pde10a-knockout mice and the excessive dopamine release by MP-10 at 96% occupancy (30 mg/kg) was also completely abolished in Pde10a-knockout mice; thus, PDE10A inhibition appears to induce dopamine release (Figure 2f).…”

“…PDE10A occupancies by PDE10A inhibitors were measured using non-radiolabeled T-773 as a tracer (Harada et al, 2015a). Methods are described in the Supplementary Information.…”

“…We searched selective PDE10A inhibitors with dosedependent efficacy in both METH-induced hyperactivity in rats and PPI deficits in mice and discovered the novel and highly selective PDE10A inhibitor TAK-063 (Harada et al, 2015a;Kunitomo et al, 2014). TAK-063 has some pharmacological effects in common with MP-10 (Grauer et al, 2009;Suzuki et al, 2015): increased cAMP and cGMP levels in the mouse striatum and reduced potential for induction of cataleptic responses compared with current antipsychotics.…”