Binding of the D3-preferring antipsychotic candidate F17464 to dopamine D3 and D2 receptors: a PET study in healthy subjects with [11C]-(+)-PHNO

Slifstein, Mark; Abi‐Dargham, Anissa; Girgis, Ragy R.; Suckow, Raymond F.; Cooper, Thomas B.; Divgi, Chaitanya; Sokoloff, Pierre; Leriche, Ludovic; Carberry, Patrick; Oya, Shunichi; Joseph, Simon; Guiraud, Marlène; Montagne, Agnès; Brunner, Valérie; Gaudoux, Florence; Tonner, Françoise

doi:10.1007/s00213-019-05387-w

Cited by 14 publications

(8 citation statements)

References 23 publications

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“…Similarly, the D3R selective antagonist F17141 reverses subacute MK-801-induced social interaction deficits in mice [192]. The D3R full antagonist F17464 counteracted the social deficit in an animal model of autism caused by prenatal valproate exposure [140,237]. The D3R partial agonist cariprazine is also able to facilitate social interactions in animal models of schizophrenia [205,209,210].…”

Section: Role In Social Behaviormentioning

confidence: 98%

“…F17464 is a recently published high affinity, selective and potent D3R antagonist (Ki: 0.16 nM) with similar affinity but partial agonist activity at serotonin 5-HT 1A receptors (Ki: 0.16 nM) and 71-fold lower affinity for D2Rs (Ki: 12.5 nM). It demonstrated promising antipsychotic profile [139], occupied D3Rs in the human brain [140] and improved acute exacerbation of schizophrenia [141].…”

Section: High Affinity Selective D3r Antagonistsmentioning

confidence: 99%

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Neuronal Dopamine D3 Receptors: Translational Implications for Preclinical Research and CNS Disorders

et al. 2021

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Dopamine (DA), as one of the major neurotransmitters in the central nervous system (CNS) and periphery, exerts its actions through five types of receptors which belong to two major subfamilies such as D1-like (i.e., D1 and D5 receptors) and D2-like (i.e., D2, D3 and D4) receptors. Dopamine D3 receptor (D3R) was cloned 30 years ago, and its distribution in the CNS and in the periphery, molecular structure, cellular signaling mechanisms have been largely explored. Involvement of D3Rs has been recognized in several CNS functions such as movement control, cognition, learning, reward, emotional regulation and social behavior. D3Rs have become a promising target of drug research and great efforts have been made to obtain high affinity ligands (selective agonists, partial agonists and antagonists) in order to elucidate D3R functions. There has been a strong drive behind the efforts to find drug-like compounds with high affinity and selectivity and various functionality for D3Rs in the hope that they would have potential treatment options in CNS diseases such as schizophrenia, drug abuse, Parkinson’s disease, depression, and restless leg syndrome. In this review, we provide an overview and update of the major aspects of research related to D3Rs: distribution in the CNS and periphery, signaling and molecular properties, the status of ligands available for D3R research (agonists, antagonists and partial agonists), behavioral functions of D3Rs, the role in neural networks, and we provide a summary on how the D3R-related drug research has been translated to human therapy.

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Section: Role In Social Behaviormentioning

confidence: 98%

Section: High Affinity Selective D3r Antagonistsmentioning

confidence: 99%

Neuronal Dopamine D3 Receptors: Translational Implications for Preclinical Research and CNS Disorders

et al. 2021

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“…Clinical observation keep suggesting some involvement of ventral striatum in the control of motivation, emotions and social behavior as relevant for negative symptoms in SCZ with regular debates on the matter ( Fareri et al., 2017 ; Stepien et al., 2018 ; Waltz et al., 2018 ). Interestingly, D3 receptor expression is enriched in midbrain ventral striatum (including nAcc) ( Slifstein et al., 2020 ) where the receptor is present on pre- and postsynaptic locations and can also work in cooperation with the receptor D1 (in MSN - AKT signal) ( Castrellon et al., 2019 ; Guitart et al., 2019 ). The D3 receptor has been linked to control of DA firing in VTA, emotion and reward control in animal models ( Takeuchi et al., 2019 ), but the lack of selective D3 ligands has so far hampered specific research on the subject ( Correll and Schooler, 2020 ).…”

Section: Section 2: Dr Alterations In Schizophreniamentioning

confidence: 99%

“…Subtype-selective compounds have been sought for more than two decades with difficulties achieving sufficient selectivity and central exposure. Clinical PET data have recently provided encouraging results with cariprazine and F17464 ( Slifstein et al., 2020 ). More recent D3 over D2 new ligands have been obtained exploiting the presence of a secondary allosteric D3 pocket to generate bitopic ligands with long molecular bridges.…”

Section: Section 3 Dr Ligands and Scz Therapies The New Wave Of Ligmentioning

confidence: 99%

Dopamine Receptor Subtypes, Physiology and Pharmacology: New Ligands and Concepts in Schizophrenia

Martel¹,

McArthur²

2020

Front. Pharmacol.

169

125

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Dopamine receptors are widely distributed within the brain where they play critical modulator roles on motor functions, motivation and drive, as well as cognition. The identification of five genes coding for different dopamine receptor subtypes, pharmacologically grouped as D1- (D1 and D5) or D2-like (D2S, D2L, D3, and D4) has allowed the demonstration of differential receptor function in specific neurocircuits. Recent observation on dopamine receptor signaling point at dopamine—glutamate-NMDA neurobiology as the most relevant in schizophrenia and for the development of new therapies. Progress in the chemistry of D1- and D2-like receptor ligands (agonists, antagonists, and partial agonists) has provided more selective compounds possibly able to target the dopamine receptors homo and heterodimers and address different schizophrenia symptoms. Moreover, an extensive evaluation of the functional effect of these agents on dopamine receptor coupling and intracellular signaling highlights important differences that could also result in highly differentiated clinical pharmacology. The review summarizes the recent advances in the field, addressing the relevance of emerging new targets in schizophrenia in particular in relation to the dopamine – glutamate NMDA systems interactions.

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“…It was reported that in a double blind, multicenter Phase II study, F17464 (20 mg/bd) improved schizophrenia symptoms ( 122 ). In a phase I study, F17464 resulted in 69–95% occupancy of D 3 Rs whereas only a 20% occupancy of D 2 Rs were noted ( 145 ).…”

Section: Imaging the D 3 Rs In Vivomentioning

confidence: 99%

Potential Mechanisms for Why Not All Antipsychotics Are Able to Occupy Dopamine D3 Receptors in the Brain in vivo

2022

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Dysfunctions of the dopaminergic system are believed to play a major role in the core symptoms of schizophrenia such as positive, negative, and cognitive symptoms. The first line of treatment of schizophrenia are antipsychotics, a class of medications that targets several neurotransmitter receptors in the brain, including dopaminergic, serotonergic, adrenergic and/or muscarinic receptors, depending on the given agent. Although the currently used antipsychotics display in vitro activity at several receptors, majority of them share the common property of having high/moderate in vitro affinity for dopamine D2 receptors (D2Rs) and D3 receptors (D3Rs). In terms of mode of action, these antipsychotics are either antagonist or partial agonist at the above-mentioned receptors. Although D2Rs and D3Rs possess high degree of homology in their molecular structure, have common signaling pathways and similar in vitro pharmacology, they have different in vivo pharmacology and therefore behavioral roles. The aim of this review, with summarizing preclinical and clinical evidence is to demonstrate that while currently used antipsychotics display substantial in vitro affinity for both D3Rs and D2Rs, only very few can significantly occupy D3Rs in vivo. The relative importance of the level of endogenous extracellular dopamine in the brain and the degree of in vitro D3Rs receptor affinity and selectivity as determinant factors for in vivo D3Rs occupancy by antipsychotics, are also discussed.

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Binding of the D3-preferring antipsychotic candidate F17464 to dopamine D3 and D2 receptors: a PET study in healthy subjects with [11C]-(+)-PHNO

Cited by 14 publications

References 23 publications

Neuronal Dopamine D3 Receptors: Translational Implications for Preclinical Research and CNS Disorders

Neuronal Dopamine D3 Receptors: Translational Implications for Preclinical Research and CNS Disorders

Dopamine Receptor Subtypes, Physiology and Pharmacology: New Ligands and Concepts in Schizophrenia

Potential Mechanisms for Why Not All Antipsychotics Are Able to Occupy Dopamine D3 Receptors in the Brain in vivo

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