Classics in Neuroimaging: Development of Positron Emission Tomography Tracers for Imaging the GABAergic Pathway

Murrell, Emily; Pham, Jonathan; Sowa, Alexandra; Brooks, Allen F.; Kilbourn, Michael R.; Scott, Peter; Vasdev, Neil

doi:10.1021/acschemneuro.0c00343

Cited by 9 publications

(7 citation statements)

References 5 publications

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“…To accurately measure GABA release, PET tracers with enhanced sensitivity to GABA are necessary, which could be widely used to evaluate GABA transmission in vivo across various disorders and enable assessment of region-specific changes . This capability to separately image each GABA A subtype, GABA B , and other components (such as GABA transporters and glutamate decarboxylases) in vivo would significantly advance our understanding of the neurobiology of GABA in both healthy and diseased states …”

Section: Pet Tracers For Anesthesia-related Receptorsmentioning

confidence: 99%

A Molecular Toolbox of Positron Emission Tomography Tracers for General Anesthesia Mechanism Research

Wang

Fan

et al. 2023

J. Med. Chem.

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With appropriate radiotracers, positron emission tomography (PET) allows direct or indirect monitoring of the spatial and temporal distribution of anesthetics, neurotransmitters, and biomarkers, making it an indispensable tool for studying the general anesthesia mechanism. In this Perspective, PET tracers that have been recruited in general anesthesia research are introduced in the following order: 1) 11 C/ 18 F-labeled anesthetics, i.e., PET tracers made from inhaled and intravenous anesthetics; 2) PET tracers targeting anesthesia-related receptors, e.g., neurotransmitters and voltage-gated ion channels; and 3) PET tracers for studying anesthesia-related neurophysiological effects and neurotoxicity. The radiosynthesis, pharmacodynamics, and pharmacokinetics of the above PET tracers are mainly discussed to provide a practical molecular toolbox for radiochemists, anesthesiologists, and those who are interested in general anesthesia.

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Section: Pet Tracers For Anesthesia-related Receptorsmentioning

confidence: 99%

A Molecular Toolbox of Positron Emission Tomography Tracers for General Anesthesia Mechanism Research

Wang

Fan

et al. 2023

J. Med. Chem.

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“…Hence, disruptions in the GABAergic system could lead to an imbalance between the two neurotransmission systems and are associated with the pathogenesis of various CNS diseases, such as epilepsy, schizophrenia, Parkinson’s disease, and Alzheimer’s disease [ 4 ]. The GABAergic system is therefore a prime target of several CNS-targeted drugs [ 5 ], even though the exact role of GABA in these disorders is not fully understood. Non-invasive imaging of the GABAergic system could aid to understand this role.…”

Section: Introductionmentioning

confidence: 99%

“…Several imaging methods have been developed for GABA receptors, with the benzodiazepine derivatives [ 11 C]flumazenil ( [ 11 C]2 ), [ 18 F]flumazenil ( [ 18 F]2 ), and [ 11 C]Ro15-4513 ( [ 11 C]3 ) frequently being used as positron emission tomography (PET) tracers for the GABA A receptor (Fig. 2 ) [ 5 , 6 ]. For example, clinical studies using these radioligands include applications in schizophrenia, major depressive disorder, Alzheimer’s disease, and autism spectrum disorder [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Visualizing GABA transporters in vivo: an overview of reported radioligands and future directions

et al. 2023

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By clearing GABA from the synaptic cleft, GABA transporters (GATs) play an essential role in inhibitory neurotransmission. Consequently, in vivo visualization of GATs can be a valuable diagnostic tool and biomarker for various psychiatric and neurological disorders. Not surprisingly, in recent years several research attempts to develop a radioligand have been conducted, but so far none have led to suitable radioligands that allow imaging of GATs. Here, we provide an overview of the radioligands that were developed with a focus on GAT1, since this is the most abundant transporter and most of the research concerns this GAT subtype. Initially, we focus on the field of GAT1 inhibitors, after which we discuss the development of GAT1 radioligands based on these inhibitors. We hypothesize that the radioligands developed so far have been unsuccessful due to the zwitterionic nature of their nipecotic acid moiety. To overcome this problem, the use of non-classical GAT inhibitors as basis for GAT1 radioligands or the use of carboxylic acid bioisosteres may be considered. As the latter structural modification has already been used in the field of GAT1 inhibitors, this option seems particularly viable and could lead to the development of more successful GAT1 radioligands in the future.

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“…Here, we sought to address this issue by using state-of-the-art imaging transcriptomics to (1) uncover patterns of co-expression between genes encoding GABA A R subunits and inhibitory interneuron markers in the human brain, and to (2) decode their links to the binding distribution patterns of two gold-standard GABA PET radiotracers, [ 11 C]Ro15-4513 and [ 11 C]flumazenil 28 . We found that distinct GABAergic inhibitory interneuron marker genes co-expressed with specific GABA A R subunit-encoding genes.…”

Section: Introductionmentioning

confidence: 99%

Cellular and molecular signatures of in vivo imaging measures of GABAergic neurotransmission in the human brain

et al. 2022

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Diverse GABAergic interneuron networks orchestrate information processing in the brain. Understanding the principles underlying the organisation of this system in the human brain, and whether these principles are reflected by available non-invasive in vivo neuroimaging methods, is crucial for the study of GABAergic neurotransmission. Here, we use human gene expression data and state-of-the-art imaging transcriptomics to uncover co-expression patterns between genes encoding GABAA receptor subunits and inhibitory interneuron subtype-specific markers, and their association with binding patterns of the gold-standard GABA PET radiotracers [11C]Ro15-4513 and [11C]flumazenil. We found that the inhibitory interneuron marker somatostatin covaries with GABAA receptor-subunit genes GABRA5 and GABRA2, and that their distribution followed [11C]Ro15-4513 binding. In contrast, the inhibitory interneuron marker parvalbumin covaried with GABAA receptor-subunit genes GABRA1, GABRB2 and GABRG2, and their distribution tracked [11C]flumazenil binding. Our findings indicate that existing PET radiotracers may provide complementary information about key components of the GABAergic system.

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Classics in Neuroimaging: Development of Positron Emission Tomography Tracers for Imaging the GABAergic Pathway

Cited by 9 publications

References 5 publications

A Molecular Toolbox of Positron Emission Tomography Tracers for General Anesthesia Mechanism Research

A Molecular Toolbox of Positron Emission Tomography Tracers for General Anesthesia Mechanism Research

Visualizing GABA transporters in vivo: an overview of reported radioligands and future directions

Cellular and molecular signatures of in vivo imaging measures of GABAergic neurotransmission in the human brain

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