An Open-Label [^11C]T-773 Positron Emission Tomography Study to Determine Phosphodiesterase10A Occupancy by TAK-063 After a Single Oral Dose in Human Volunteers

The purpose of this study is to estimate phosphodiesterase 10A (PDE10A) occupancy in brain following a single dose of TAK-063.

Start Date01 Oct 2013

Sponsor / Collaborator

Takeda Pharmaceutical Co., Ltd.

100 Clinical Results associated with Carbon-11-T-773

100 Translational Medicine associated with Carbon-11-T-773

100 Patents (Medical) associated with Carbon-11-T-773

Literatures (Medical) associated with Carbon-11-T-773

25 Mar 2020·International Journal of NeuropsychopharmacologyQ2 · MEDICINE

Balanced Activation of Striatal Output Pathways by Faster Off-Rate PDE10A Inhibitors Elicits Not Only Antipsychotic-Like Effects But Also Procognitive Effects in Rodents

Q2 · MEDICINE

ArticleOA

Author: Kimura, Haruhide ; Suzuki, Kazunori ; Vekich, John A ; Bobkov, Konstantin ; Doyle, Joseph P ; Kaushal, Nidhi ; Harada, Akina ; Nakatani, Atsushi

AbstractBackgroundFaster off-rate competitive enzyme inhibitors are generally more sensitive than slower off-rate ones to binding inhibition by enzyme substrates. We previously reported that the cyclic adenosine monophosphate concentration in dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs) may be higher than that in D2-MSNs. Consequently, compared with slower off-rate phosphodiesterase 10A inhibitors, faster off-rate ones comparably activated D2-MSNs but partially activated D1-MSNs. We further investigated the pharmacological profiles of phosphodiesterase 10A inhibitors with different off-rates.MethodsPhosphodiesterase 10A inhibitors with slower (T-609) and faster (T-773) off-rates were used. D1- and D2-MSN activation was assessed by substance P and enkephalin mRNA induction, respectively, in rodents. Antipsychotic-like effects were evaluated by MK-801- and methamphetamine-induced hyperactivity and prepulse inhibition in rodents. Cognition was assessed by novel object recognition task and radial arm maze in rats. Prefrontal cortex activation was evaluated by c-Fos immunohistochemistry in rats. Gene translations in D1- and D2-MSNs were evaluated by translating ribosome affinity purification and RNA sequencing in mice.ResultsCompared with T-609, T-773 comparably activated D2-MSNs but partially activated D1-MSNs. Haloperidol (a D2 antagonist) and T-773, but not T-609, produced antipsychotic-like effects in all paradigms. T-773, but not T-609 or haloperidol, activated the prefrontal cortex and improved cognition. Overall gene translation patterns in D2-MSNs by all drugs and those in D1-MSNs by T-773 and T-609 were qualitatively similar.ConclusionsDifferential pharmacological profiles among those drugs could be attributable to activation balance of D1- and D2-MSNs. The “balanced activation” of MSNs by faster off-rate phosphodiesterase 10A inhibitors may be favorable to treat schizophrenia.

01 Feb 2018·Nuclear Medicine and Biology

Development of two fluorine-18 labeled PET radioligands targeting PDE10A and in vivo PET evaluation in nonhuman primates

Article

Author: Nahid Amini ; Shotaro Miura ; Ryuji Nakao ; Christer Halldin ; Vladimir Stepanov ; Tomoaki Hasui ; Akihiro Takano ; Haruhide Kimura ; Takahiko Taniguchi

INTRODUCTIONPhosphodiesterase 10A (PDE10A) is a member of the PDE enzyme family that degrades cyclic adenosine and guanosine monophosphates (cAMP and cGMP). Based on the successful development of [¹¹C]T-773 as PDE10A positron emission tomography (PET) radioligand, in this study our aim was to develop and evaluate fluorine-18 analogs of [¹¹C]T-773.METHODS[¹⁸F]FM-T-773-d₂ and [¹⁸F]FE-T-773-d₄ were synthesized from the same precursor used for ¹¹C-labeling of T-773 in a two-step approach via ¹⁸F-fluoromethylation and ¹⁸F-fluoroethylation, respectively, using corresponding deuterated synthons. A total of 12 PET measurements were performed in seven non-human primates. First, baseline PET measurements were performed using High Resolution Research Tomograph system with both [¹⁸F]FM-T-773-d₂ and [¹⁸F]FE-T-773-d₄; the uptake in whole brain and separate brain regions, as well as the specific binding and tissue ratio between putamen and cerebellum, was examined. Second, baseline and pretreatment PET measurements using MP-10 as the blocker were performed for [¹⁸F]FM-T-773-d₂ including arterial blood sampling with radiometabolite analysis in four NHPs.RESULTSBoth [¹⁸F]FM-T-773-d₂ and [¹⁸F]FE-T-773-d₄ were successfully radiolabeled with an average molar activity of 293 ± 114 GBq/μmol (n=8) for [¹⁸F]FM-T-773-d₂ and 209 ± 26 GBq/μmol (n=4) for [¹⁸F]FE-T-773-d₄, and a radiochemical yield of 10% (EOB, n=12, range 3%-16%). Both radioligands displayed high brain uptake (~5.5% of injected radioactivity for [¹⁸F]FM-T-773-d₂ and ~3.5% for [¹⁸F]FE-T-773-d₄ at the peak) and a fast washout. Specific binding reached maximum within 30 min for [¹⁸F]FM-T-773-d₂ and after approximately 45 min for [¹⁸F]FE-T-773-d₄. [¹⁸F]FM-T-773-d₂ data fitted well with kinetic compartment models. BP_ND values obtained indirectly through compartment models were correlated well with those obtained by SRTM. BP_ND calculated with SRTM was 1.0-1.7 in the putamen. The occupancy with 1.8 mg/kg of MP-10 was approximately 60%.CONCLUSIONS[¹⁸F]FM-T-773-d₂ and [¹⁸F]FE-T-773-d₄ were developed as fluorine-18 PET radioligands for PDE10A, with the [¹⁸F]FM-T-773-d₂ being the more promising PET radioligand warranting further evaluation.

01 Nov 2016·NeuroImageQ1 · MEDICINE

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

Q1 · MEDICINE

ArticleOA

Author: Tsai, Max ; Takano, Akihiro ; Macek, Thomas A ; Uz, Tolga ; Martinsson, Stefan ; Xie, Jinhui ; Goldsmith, Paul ; Halldin, Christer ; Stepanov, Vladimir ; Stenkrona, Per ; Wu, Jingtao ; Amini, Nahid

Phosphodiesterase 10A (PDE10A) is selectively expressed in the striatal regions in the brain and may play a role in modulating dopaminergic and glutamatergic second messenger pathways. PDE10A inhibitors are expected to be useful in treating neuropsychiatric disorders such as schizophrenia and Huntington's disease. In this study, the brain kinetics of [(11)C]T-773 in the human brain and test-retest reproducibility of the outcome measures were evaluated. Subsequently, the occupancy of a novel PDE10A inhibitor, TAK-063, was measured using [(11)C]T-773. Dynamic PET measurements were conducted three times for 12 healthy male subjects after intravenous bolus injection of [(11)C]T-773: two baseline PETs and one postdose PET (3hours) after oral administration of TAK-063 for four subjects, and one baseline PET and two postdose PET (3hours and 23hours) for eight subjects. Kinetic model analysis was performed with arterial input functions. PDE10A occupancy was calculated as the percent change of the binding specific to PDE10A (Vs) total distribution volume (VT), which was calculated as the VT of the putamen minus the VT of the cerebellum. Regional brain uptake was highest in the putamen. Time-activity curves of the brain regions were described with two tissue-compartment (2TC) models. The mean VT was 5.5±0.7 in the putamen and 2.3±0.5 in the cerebellum in the baseline PET. Absolute VT variability between the two baseline scans was less than 7%. Reproducibility of VT was excellent. PDE10A occupancy in the putamen ranged from 2.8% to 72.1% at 3hours after a single administration of 3 to 1000mg of TAK-063, and increased in a dose- and plasma concentration-dependent manner. At 23hours postdose, PDE10A occupancy in the putamen was 0 to 42.8% following administration of 3 to 100mg of TAK-063. In conclusion, [(11)C]T-773 showed good characteristics as a PET radioligand for PDE10A in the human brain.

100 Deals associated with Carbon-11-T-773

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Indication	Highest Phase	Country/Location	Organization	Date
Huntington Disease	Phase 1	Japan	Takeda Pharmaceutical Co., Ltd.	28 Sep 2014
Schizophrenia	Phase 1	Japan	Takeda Pharmaceutical Co., Ltd.	28 Sep 2014

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02370602 (CTgov)	Phase 1	-	13	TAK-063+[^11C]T-773 (TAK-063 3 mg + [^11C]T-773)	tywqjmisak(oijeyghjos) = hckrittrbs vjkrauornc (osclrjqvrc, syqzlylpkt - bgahljpgbv) View more	-	20 Mar 2015
				TAK-063 (TAK-063 10 mg)	tywqjmisak(oijeyghjos) = lcfxzxepwp vjkrauornc (osclrjqvrc, rrkowfhydl - tlnchvfavr)

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