Positron Emission Tomography (PET) Ligand Development for Ionotropic Glutamate Receptors: Challenges and Opportunities for Radiotracer Targeting <i>N</i>-Methyl-<scp>d</scp>-aspartate (NMDA), α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA), and Kainate Receptors

Fu, Hualong; Chen, Zhen; Josephson, Lee; Li, Zijing; Liang, Steven H.

doi:10.1021/acs.jmedchem.8b00714

Cited by 38 publications

(33 citation statements)

References 190 publications

(387 reference statements)

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“…A recent study using a tracer for the metabotropic glutamate receptor 5 found no patient‐control differences. New tracers are under development, but lack of specificity remains an ongoing problem when attempting to image glutamate receptors.…”

Section: Glutamatementioning

confidence: 99%

Dopamine and glutamate in schizophrenia: biology, symptoms and treatment

2020

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Glutamate and dopamine systems play distinct roles in terms of neuronal signalling, yet both have been proposed to contribute significantly to the pathophysiology of schizophrenia. In this paper we assess research that has implicated both systems in the aetiology of this disorder. We examine evidence from post‐mortem, preclinical, pharmacological and in vivo neuroimaging studies. Pharmacological and preclinical studies implicate both systems, and in vivo imaging of the dopamine system has consistently identified elevated striatal dopamine synthesis and release capacity in schizophrenia. Imaging of the glutamate system and other aspects of research on the dopamine system have produced less consistent findings, potentially due to methodological limitations and the heterogeneity of the disorder. Converging evidence indicates that genetic and environmental risk factors for schizophrenia underlie disruption of glutamatergic and dopaminergic function. However, while genetic influences may directly underlie glutamatergic dysfunction, few genetic risk variants directly implicate the dopamine system, indicating that aberrant dopamine signalling is likely to be predominantly due to other factors. We discuss the neural circuits through which the two systems interact, and how their disruption may cause psychotic symptoms. We also discuss mechanisms through which existing treatments operate, and how recent research has highlighted opportunities for the development of novel pharmacological therapies. Finally, we consider outstanding questions for the field, including what remains unknown regarding the nature of glutamate and dopamine function in schizophrenia, and what needs to be achieved to make progress in developing new treatments.

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Section: Glutamatementioning

confidence: 99%

Dopamine and glutamate in schizophrenia: biology, symptoms and treatment

2020

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“…As such, the glutamate receptors present a diverse range of important targets for molecular brain imaging by single photon emission computed tomography (SPECT) and positron emission tomography (PET). While there have been several reviews of this topic in recent years [ 20 , 21 , 22 , 23 ], we now present a systematic review of the state of development of glutamate receptor imaging, placing our emphasis on the findings of clinical studies, and on the lacunae remaining in the literature due to lack of specific tracers for many of these molecular targets. In selected cases, we give an account of the procedures for radiopharmaceutical synthesis.…”

Section: Introductionmentioning

confidence: 99%

A Review of Molecular Imaging of Glutamate Receptors

et al. 2020

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Molecular imaging with positron emission tomography (PET) and single photon emission computed tomography (SPECT) is a well-established and important in vivo technique to evaluate fundamental biological processes and unravel the role of neurotransmitter receptors in various neuropsychiatric disorders. Specific ligands are available for PET/SPECT studies of dopamine, serotonin, and opiate receptors, but corresponding development of radiotracers for receptors of glutamate, the main excitatory neurotransmitter in mammalian brain, has lagged behind. This state of affairs has persisted despite the central importance of glutamate neurotransmission in brain physiology and in disorders such as stroke, epilepsy, schizophrenia, and neurodegenerative diseases. Recent years have seen extensive efforts to develop useful ligands for molecular imaging of subtypes of the ionotropic (N-methyl-D-aspartate (NMDA), kainate, and AMPA/quisqualate receptors) and metabotropic glutamate receptors (types I, II, and III mGluRs). We now review the state of development of radioligands for glutamate receptor imaging, placing main emphasis on the suitability of available ligands for reliable in vivo applications. We give a brief account of the radiosynthetic approach for selected molecules. In general, with the exception of ligands for the GluN2B subunit of NMDA receptors, there has been little success in developing radiotracers for imaging ionotropic glutamate receptors; failure of ligands for the PCP/MK801 binding site in vivo doubtless relates their dependence on the open, unblocked state of the ion channel. Many AMPA and kainite receptor ligands with good binding properties in vitro have failed to give measurable specific binding in the living brain. This may reflect the challenge of developing brain-penetrating ligands for amino acid receptors, compounded by conformational differences in vivo. The situation is better with respect to mGluR imaging, particularly for the mGluR5 subtype. Several successful PET ligands serve for investigations of mGluRs in conditions such as schizophrenia, depression, substance abuse and aging. Considering the centrality and diversity of glutamatergic signaling in brain function, we have relatively few selective and sensitive tools for molecular imaging of ionotropic and metabotropic glutamate receptors. Further radiopharmaceutical research targeting specific subtypes and subunits of the glutamate receptors may yet open up new investigational vistas with broad applications in basic and clinical research.

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“…Subtype‐selective allosteric modulators of the NMDA receptor bind to allosteric sites, which are distinct from the competitive binding sites and allow pharmacological and therapeutic interventions . Triggered by the discovery of traxoprodil, a noncompetitive antagonist for the GluN2B‐containing NMDA receptors with rapid antidepressant‐like effects, enormous effort has been put into the development of GluN2B selective ligands including radioligands for positron emission tomography (PET) imaging over the last decades . However, there is a striking lack in comprehending and monitoring subunit‐selective modulations other than of GluN2B.…”

Section: Introductionmentioning

confidence: 99%

Recent progress in allosteric modulators for GluN2A subunit and development of GluN2A‐selective nuclear imaging probes

Ametamey

et al. 2019

Labelled Comp Radiopharmac

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N-methyl-D-aspartate (NMDA) receptors play key roles in physiology by regulating the synaptic plasticity and the cellular mechanism involved in learning and memory. The GluN2A subunit is the most abundant expression of NMDA receptors in mature brain, and its dysfunction has been implicated in various neurological disorders. However, the function of GluN2A subunit in physiological and pathological conditions is not yet completely unveil due to the lack of subunit-selective ligands, including specific positron emission tomography (PET)/single photon emission computed tomography (SPECT) imaging probes.In this review, recent progresses in understanding its pathophysiological role, the structure-activity relationship, and the postulated mechanisms of novel GluN2A ligands as well as status of molecular imaging probes for PET are summarized.

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Positron Emission Tomography (PET) Ligand Development for Ionotropic Glutamate Receptors: Challenges and Opportunities for Radiotracer Targeting N-Methyl-d-aspartate (NMDA), α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA), and Kainate Receptors

Cited by 38 publications

References 190 publications

Dopamine and glutamate in schizophrenia: biology, symptoms and treatment

Dopamine and glutamate in schizophrenia: biology, symptoms and treatment

A Review of Molecular Imaging of Glutamate Receptors

Recent progress in allosteric modulators for GluN2A subunit and development of GluN2A‐selective nuclear imaging probes

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