A human [ 11 C]T-773 PET study of PDE10A binding after oral administration of TAK-063, a PDE10A inhibitor

Takano, Akihiro; Stenkrona, Per; Степанов, В. А.; Amini, Nahid; Martinsson, Stefan; Tsai, Max; Goldsmith, Paul; Xie, Jiaheng; Wu, Jingtao; Uz, Tolga; Halldin, Christer; Macek, Thomas A.

doi:10.1016/j.neuroimage.2016.06.047

Cited by 26 publications

(28 citation statements)

References 23 publications

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“…Clinical results were generally consistent with those of the preclinical studies. The main findings in humans included confirmation of target engagement in the PET study, the pharmacological effects of TAK‐063 on fMRI BOLD (ketamine‐challenge), and pharmacodynamic effects on EEG and cognition in subjects with schizophrenia (Macek et al, presented at the 5 th Biennial Schizophrenia International Research Society Conference 2016). A recent phase 2 study evaluated the efficacy and safety of 20‐mg daily TAK‐063 vs placebo in subjects with acutely exacerbated symptoms of schizophrenia (ClinicalTrials.gov Identifier: NCT02477020).…”

Section: Pharmacological Profiles Of Tak‐063 In Clinical Studiesmentioning

confidence: 96%

TAK‐063, a novel PDE10A inhibitor with balanced activation of direct and indirect pathways, provides a unique opportunity for the treatment of schizophrenia

Suzuki

Kimura

2018

CNS Neurosci Ther

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The basal ganglia regulates motor, cognitive, and emotional behaviors. Dysfunction of dopamine system in this area is implicated in the pathophysiology of schizophrenia characterized by positive symptoms, negative symptoms, and cognitive deficits. Medium spiny neurons (MSNs) are principal output neurons of striatum in the basal ganglia. Similar to current antipsychotics with dopamine D receptor antagonism or partial agonism, phosphodiesterase 10A (PDE10A) inhibitors activate indirect pathway MSNs, leading to the expectation of therapeutic potential for the treatment of psychosis. PDE10A inhibitors also activate direct pathway MSNs which may be associated with cognitive functions. These pathways have competing effects on antipsychotic-like activities and extrapyramidal symptoms in rodents. Therefore, careful consideration of activation pattern of these pathways by a PDE10A inhibitor is critical to produce potent efficacy and superior safety profiles. In this review, we outline the pharmacological profile of TAK-063, a novel PDE10A selective inhibitor. Our study revealed that off-rates of PDE10A inhibitors may characterize their pharmacological profiles via regulation of each MSN pathway. TAK-063, with a faster off-rate property, could provide a unique opportunity as a novel therapeutic approach to treatment of psychosis and cognitive deficits in schizophrenia. TAK-063 also has a therapeutic potential in other basal ganglia disorders.

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Section: Pharmacological Profiles Of Tak‐063 In Clinical Studiesmentioning

confidence: 96%

TAK‐063, a novel PDE10A inhibitor with balanced activation of direct and indirect pathways, provides a unique opportunity for the treatment of schizophrenia

Suzuki

Kimura

2018

CNS Neurosci Ther

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“…Several of these radiotracers already have been transferred into clinical settings, including 18F-JNJ42259152, 14,15 11C-IMA107, 16–19 11 C-Lu AE92686, 20,21 18 F-MNI-659, 22–25 and 11C-T-773. 26 MP-10 is the first generation of PDE10A compounds for treating schizophrenia, and was successfully radiolabeled with C-11 for in vivo evaluation. However, nonpolar radio-metabolites hampered its further application.…”

Section: Introductionmentioning

confidence: 99%

In Vivo Characterization of Two ¹⁸F-Labeled PDE10A PET Radioligands in Nonhuman Primate Brains

Liu

Jin

Luo

et al. 2018

ACS Chem. Neurosci.

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Positron emission tomography (PET) with phosphodiesterase 10A (PDE10A) specific radioligands provides a noninvasive and quantitative imaging tool to access the expression of this enzyme in vivo under normal and diseased conditions. We recently reported two potent F-labeled PDE10A radioligands (F-TZ19106B and F-TZ8110); initial evaluation in rats and nonhuman primates indicated stable metabolic profiles and excellent target-to-nontarget ratio (striatum/cerebellum) for both tracers. Herein, we focused on in vivo characterization ofF-TZ19106B and F-TZ8110 to identify a suitable radioligand for imaging PDE10A in vivo. We directly compared microPET studies of these two radiotracers in adult male Macaca fascicularis nonhuman primates (NHPs).F-TZ19106B had higher striatal uptake and tracer retention in NHP brains than F-TZ8110, quantified by either standardized uptake values (SUVs) or nondisplaceable binding potential (BP) estimated using reference-based modeling analysis. Blocking and displacement studies using the PDE10A inhibitor MP-10 indicated the binding of F-TZ19106B to PDE10A was specific and reversible. We also demonstrated sensitivity ofF-TZ19106B binding to varying number of specific binding sites using escalating doses of MP-10 blockade (0.3, 0.5, 1.0, 1.5, and 2.0 mg/kg). Pretreatment with a dopamine D2-like receptor antagonist enhanced the striatal uptake of F-TZ19106B. Our results indicate thatF-TZ19106B is a promising radioligand candidate for imaging PDE10A in vivo and it may be used to determine target engagement of PDE10A inhibitors and serve as a tool to evaluate the effect of novel antipsychotic therapies.

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“…The ratio of brain-to-plasma TAK-063 was approximately 1 at 3 hr after dosing. In a human [ 11 C]T-773 PET study of PDE10A binding after TAK-063 oral administration, TAK-063 bound PDE10A in a plasma concentrationdependent manner [15]. These data demonstrate that TAK-063 was well distributed in the brains of animal models and human beings.…”

Section: Discussionmentioning

confidence: 68%

Pre‐clinical Characterization of Absorption, Distribution, Metabolism and Excretion Properties of TAK‐063

Tohyama

Sudo

Morohashi

et al. 2018

Basic Clin Pharma Tox

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TAK-063 is currently being developed to treat schizophrenia. In this study, we investigated the absorption, distribution, metabolism and excretion (ADME) properties of TAK-063 using several paradigms. Following oral administration of TAK-063 at 0.3 mg/kg, bioavailability of TAK-063 was 27.4% in rats and 49.5% in dogs with elimination half-lives of 3.1 hr in rats and 3.7 hr in dogs. TAK-063 is a highly permeable compound without P-glycoprotein (P-gp) or breast cancer resistance protein substrate liability and can be readily absorbed into systemic circulation via the intestine. TAK-063 can also cross the blood-brain barrier. TAK-063 was metabolized mainly by CYP2C8 and CYP3A4/5, while incubation with human liver microsomes produced the major human metabolite, M-I as well as several unknown minor metabolites. Metabolism of TAK-063 to M-I occurs through hydroxylation of the mono-substituted pyrazole moiety. In vitro, TAK-063 was observed to inhibit CYP2C8, CYP2C19 and Pgp with IC 50 values of 8.4, 12 and 7.13 lM, respectively. TAK-063 was primarily excreted in the faeces in rats and dogs with M-I as a predominant component. The pre-clinical data from these ADME studies demonstrate a favourable pharmacokinetic profile for TAK-063 with good brain distribution supporting the feasibility of targeting central nervous system regions involved in schizophrenia pathophysiology. TAK-063 has recently been investigated in a phase 2 clinical trial (NCT02477020).Phosphodiesterase 10A (PDE10A) acts as an important regulator of signal transduction by degrading the second messengers cyclic adenosine monophosphate and cyclic guanosine monophosphate [1,2]. PDE10A is preferentially expressed in the medium spiny neurons of the striatum, a region of critical importance for domains that are disrupted in patients with schizophrenia [3][4][5].Current treatments often do not adequately address the multifaceted clinical symptomatology of schizophrenia [6]. In addition, antipsychotics are associated with cardiometabolic disturbances and cardiovascular morbidity that worsen longterm outcomes [7]. Because of the shortcomings in current treatment options for schizophrenia, PDE10A inhibition by TAK-063 is being evaluated as a new therapeutic strategy.TAK-063 is a potent and highly selective PDE10A inhibitor [8,9]. Furthermore, TAK-063 has demonstrated pre-clinical efficacy in animal models of schizophrenia. TAK-063 produced dose-dependent antipsychotic-like effects in rodent models of induced psychosis [10]. In rodents, PDE10A inhibition by TAK-063 also improved cognitive functions impaired in schizophrenia [11]. TAK-063 exhibits a favourable safety profile in a rodent study [12]. To understand the mechanism of these efficacy and safety profiles of TAK-063, the absorption, distribution, metabolism and excretion (ADME) properties of TAK-063 were investigated.In general, ADME properties using radiolabelled materials in animals and human beings are required for inclusion in the New Drug Application for new molecular entities. This report he...

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A human [ 11 C]T-773 PET study of PDE10A binding after oral administration of TAK-063, a PDE10A inhibitor

Cited by 26 publications

References 23 publications

TAK‐063, a novel PDE10A inhibitor with balanced activation of direct and indirect pathways, provides a unique opportunity for the treatment of schizophrenia

TAK‐063, a novel PDE10A inhibitor with balanced activation of direct and indirect pathways, provides a unique opportunity for the treatment of schizophrenia

In Vivo Characterization of Two ¹⁸F-Labeled PDE10A PET Radioligands in Nonhuman Primate Brains

Pre‐clinical Characterization of Absorption, Distribution, Metabolism and Excretion Properties of TAK‐063

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A human [ 11 C]T-773 PET study of PDE10A binding after oral administration of TAK-063, a PDE10A inhibitor

Cited by 26 publications

References 23 publications

TAK‐063, a novel PDE10A inhibitor with balanced activation of direct and indirect pathways, provides a unique opportunity for the treatment of schizophrenia

TAK‐063, a novel PDE10A inhibitor with balanced activation of direct and indirect pathways, provides a unique opportunity for the treatment of schizophrenia

In Vivo Characterization of Two 18F-Labeled PDE10A PET Radioligands in Nonhuman Primate Brains

Pre‐clinical Characterization of Absorption, Distribution, Metabolism and Excretion Properties of TAK‐063

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In Vivo Characterization of Two ¹⁸F-Labeled PDE10A PET Radioligands in Nonhuman Primate Brains