Delving into the Latest Updates on Carbon-11-T-773 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug, Diagnostic radiopharmaceuticals

Synonyms

11C-T-773, C-11-T-773, Carbon-11-T 773

+ [4]

Target

PDE10A

Action

inhibitors, enhancers

Mechanism

PDE10A inhibitors(Phosphodiesterase 10A inhibitors), PET imaging(Positron-emission tomography enhancers)

Therapeutic Areas

Other DiseasesNervous System DiseasesCongenital Disorders

Active Indication-

Inactive Indication

Huntington DiseaseSchizophrenia

Originator Organization

Takeda Pharmaceutical Co., Ltd.

Active Organization-

Inactive Organization

Takeda Pharmaceutical Co., Ltd.

Karolinska Institutet

License Organization-

Drug Highest PhasePendingPhase 1

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC25H23FN4O3

InChIKeyPFQQSVKFDVADLG-BJUDXGSMSA-N

CAS Registry1425937-06-9

Phosphodiesterase 10 (PDE10) inhibitors have received much attention as promising therapeutic agents for central nervous system (CNS) disorders such as schizophrenia and Huntington's disease.Recently, a hit compound 1 with a novel chromone scaffold has shown moderate inhibitory activity against PDE10A (IC₅₀ = 500 nM).Hit-to-lead optimization has resulted in compound 3e with an improved inhibitory activity (IC₅₀ = 6.5 nM), remarkable selectivity (>95-fold over other PDEs), and good metabolic stability (RLM t_1/2 = 105 min) by using an integrated strategy (mol. modeling, chem. synthesis, bioassay, and cocrystal structure).The cocrystal structural information provides insights into the binding pattern of 3e in the PDE10A catalytic domain to highlight the key role of the halogen and hydrogen bonds toward Tyr524 and Tyr693, resp., thereby resulting in high selectivity against other PDEs.These new observations are of benefit for the rational design of the next generation PDE10 inhibitors for CNS disorders.

25 Mar 2020·The 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 ; Doyle, Joseph P ; Nakatani, Atsushi ; Bobkov, Konstantin ; Harada, Akina ; Kaushal, Nidhi ; Vekich, John A

Abstract:

Background:

Faster 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.

Methods:

Phosphodiesterase 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.

Results:

Compared 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.

Conclusions:

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

INTRODUCTION:

Phosphodiesterase 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.

RESULTS:

Both [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.

100 Deals associated with Carbon-11-T-773

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R&D Status

10 top R&D records.

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

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Clinical Result

Indication

Phase

Evaluation

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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)	tvfjcxaaub(yypauewfmn) = bgoxbgwhev zxsunagfdd (jtskfvspsb, 16.4049) View more	-	20 Mar 2015
				TAK-063 (TAK-063 10 mg)	tvfjcxaaub(yypauewfmn) = ydyedoefsq zxsunagfdd (jtskfvspsb, 2.4749)