Characterization of the binding properties of T-773 as a PET radioligand for phosphodiesterase 10A

Harada

et al. 2016

Neuropsychopharmacol

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Phosphodiesterase 10A (PDE10A) inhibitors are expected to be novel drugs for schizophrenia through activation of both direct and indirect pathway medium spiny neurons. However, excess activation of the direct pathway by a dopamine D 1 receptor agonist SKF82958 canceled antipsychotic-like effects of a dopamine D 2 receptor antagonist haloperidol in methamphetamine (METH)-induced hyperactivity in rats. Thus, balanced activation of these pathways may be critical for PDE10A inhibitors. Current antipsychotics and the novel PDE10A inhibitor TAK-063, but not the selective PDE10A inhibitor MP-10, produced dose-dependent antipsychotic-like effects in METH-induced hyperactivity and prepulse inhibition in rodents. TAK-063 and MP-10 activated the indirect pathway to a similar extent; however, MP-10 caused greater activation of the direct pathway than did TAK-063. Interestingly, the off-rate of TAK-063 from PDE10A in rat brain sections was faster than that of MP-10, and a slower off-rate PDE10A inhibitor with TAK-063-like chemical structure showed an MP-10-like pharmacological profile. In general, faster off-rate enzyme inhibitors are more sensitive than slower off-rate inhibitors to binding inhibition by enzyme substrates. As expected, TAK-063 was more sensitive than MP-10 to binding inhibition by cyclic nucleotides. Moreover, an immunohistochemistry study suggested that cyclic adenosine monophosphate levels in the direct pathway were higher than those in the indirect pathway. These data can explain why TAK-063 showed partial activation of the direct pathway compared with MP-10. The findings presented here suggest that TAK-063's antipsychotic-like efficacy may be attributable to its unique pharmacological properties, resulting in balanced activation of the direct and indirect striatal pathways.

Section: Mp-10 But Not Tak-063 Markedly Induced Dopamine Release Inmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Section: Mp-10 But Not Tak-063 Markedly Induced Dopamine Release Inmentioning

confidence: 99%

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

Harada

et al. 2016

Neuropsychopharmacol

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“…Pharmacological Property of a Novel PDE10A Inhibitor TAK-063 in rats (Harada et al, 2014; Harada A, Suzuki K, Kamiguchi N, Miyamoto M, Tohyama K, Nakashima K, Taniguchi T, and Kimura H, manuscript in preparation). Combined with the results of the present study, investigation of the doseoccupancy relationship in humans will provide further characterization of the preclinical and clinical aspects of the pharmacological profile of TAK-063.…”

Section: Discussionmentioning

confidence: 99%

In Vivo Pharmacological Characterization of TAK-063, a Potent and Selective Phosphodiesterase 10A Inhibitor with Antipsychotic-Like Activity in Rodents

Harada

Shiraishi

et al. 2014

J Pharmacol Exp Ther

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Phosphodiesterase 10A (PDE10A) is a cAMP/cGMP phosphodiesterase highly expressed in medium spiny neurons (MSNs) in the striatum. We evaluated the in vivo pharmacological profile of a potent and selective 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). TAK-063 at 0.3 and 1 mg/kg p.o., increased cAMP and cGMP levels in the rodent striatum and upregulated phosphorylation levels of key substrates of cAMP-and cGMPdependent protein kinases. TAK-063 at 0.3 and 1 mg/kg p.o.,-imine]-induced hyperlocomotion, which is often used as a predictive model for antipsychotic-like activity in rodents. Upregulation of striatal cAMP/cGMP levels and the antipsychotic-like effect of TAK-063 were not attenuated after 15 days of pretreatment with TAK-063 in mice. The potential side effect profile of TAK-063 was assessed in rats using the clinical antipsychotics haloperidol, olanzapine, and aripiprazole as controls. TAK-063 did not affect plasma prolactin or glucose levels at doses up to 3 mg/kg p.o. At 3 mg/kg p.o., TAK-063 elicited a weak cataleptic response compared with haloperidol and olanzapine. Evaluation of pathway-specific markers (substance P mRNA for the direct pathway and enkephalin mRNA for the indirect pathway) revealed that TAK-063 activated both the direct and indirect pathways of MSNs. These findings suggest that TAK-063 represents a promising drug for the treatment of schizophrenia with potential for superior safety and tolerability profiles.

“…Recently, several potent radiotracers targeting PDE10A have been developed and validated in vivo by different groups (Barret et al, 2014; Barret, 2012; Celen et al, 2010; Celen et al, 2013; Harada et al, 2015; Hwang et al, 2014; Kehler et al, 2014; Van Laere et al, 2013a; Van Laere et al, 2013b), including another radiolabeled MP-10 analogue, [ 18 F]JNJ42259152. However, as found with MP-10, the possible influence of a brain-penetrating radioactive metabolite of [ 18 F]JNJ42259152 was reported (Celen et al, 2013; Van Laere et al, 2013b).…”

Section: Discussionmentioning

confidence: 99%

Preclinical evaluation of a promising C-11 labeled PET tracer for imaging phosphodiesterase 10A in the brain of living subject

et al. 2015

Phosphodiesterase 10A (PDE10A) plays a key role in the regulation of brain striatal signaling. A PET tracer for PDE10A may serve as a tool to evaluate PDE10A expression in vivo in central nervous system disorders with striatal pathology. Here, we further characterized the binding properties of a previously reported radioligand we developed for PDE10A, [11C]TZ1964B, in rodents and nonhuman primates (NHPs). The tritiated counterpart [3H]TZ1964B was used for in vitro binding characterizations in rat striatum homogenates and in vitro autoradiographic studies in rat brain slices. The carbon-11 labeled [11C]TZ1964B was utilized in the ex vivo autoradiography studies for the brain of rats and microPET imaging studies for the brain of NHPs. MicroPET scans of [11C]TZ1964B in NHPs were conducted at baseline, as well as with using a selective PDE10A inhibitor MP-10 for either pretreatment or displacement. The in vivo regional target occupancy (Occ) was obtained by pretreating with different doses of MP-10 (0.05 - 2.00 mg/kg). Both in vitro binding assays and in vitro autoradiographic studies revealed a nanomolar binding affinity of [3H]TZ1964B to the rat striatum. The striatal binding of [3H]TZ1964B and [11C]TZ1964B was either displaced or blocked by MP-10 in rats and NHPs. Autoradiography and microPET imaging confirmed that the specific binding of the radioligand was found in the striatum but not in the cerebellum. Blocking studies also confirmed the suitability of the cerebellum as an appropriate reference region. The binding potentials (BPND) of [11C]TZ1964B in the NHP striatum that were calculated using either the Logan reference model (LoganREF, 3.96 ± 0.17) or the simplified reference tissue model (SRTM, 4.64 ± 0.47), with the cerebellum as the reference region, was high and had good reproducibility. The occupancy studies indicated a MP-10 dose of 0.31 ± 0.09 mg/kg (LoganREF) / 0.45 ± 0.17 mg/kg (SRTM) occupies 50% striatal PDE10A binding sites. Studies in rats and NHPs demonstrated radiolabelled TZ1964B has a high binding affinity and good specificity for PDE10A, as well as favorable in vivo pharmacokinetic properties and binding profiles. Our data suggests that [11C]TZ1964B is a promising radioligand for in vivo imaging PDE10A in the brain of living subject.