Ex Vivo Tracing of NMDA and GABA-A Receptors in Rat Brain After Traumatic Brain Injury Using <sup>18</sup>F-GE-179 and <sup>18</sup>F-GE-194 Autoradiography

López-Picón, Francisco R.; Snellman, Anniina; Shatillo, Olena; Lehtiniemi, Paula; Grönroos, Tove J.; Marjamäki, Päivi; Trigg, William; Jones, Paul A.; Solin, Olof; Pitkänen, Asla; Haaparanta‐Solin, Merja

doi:10.2967/jnumed.115.167403

Cited by 18 publications

(22 citation statements)

References 23 publications

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“…The microdialysis assay showed that extracellular glutamate levels were significantly elevated in WT brains, while the increases were diminished in the HIF‐1α −/− brains (Figure B). To observe the glutamate receptor activation, a radiotracer, 18 F‐labelled alkylthiophenyl guanidine ( 18 F‐FSAG or 18 F‐GE‐179), which binds to the phencyclidine (PCP) site of the N ‐methyl‐ d ‐aspartate (NMDA) channel , was synthesized for observing the activation of NMDA receptor (NMDAR) in vitro and in vivo . Positron emission tomography (PET) imaging and magnetic resonance imaging (MRI) studies showed a high accumulation of 18 F‐FSAG in infraction area, and 18 F‐FSAG uptake reached a steady state at 30 min after injection in WT mice with or without CIR (see supplementary material, Figure S1A, B).…”

Section: Resultsmentioning

confidence: 99%

HIF-1α triggers long-lasting glutamate excitotoxicity via system x_c⁻in cerebral ischaemia-reperfusion

et al. 2016

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Hypoxia-inducible factor 1α (HIF-1α) controls many genes involved in physiological and pathological processes. However, its roles in glutamatergic transmission and excitotoxicity are unclear. Here, we proposed that HIF-1α might contribute to glutamate-mediated excitotoxicity during cerebral ischaemia-reperfusion (CIR) and investigated its molecular mechanism. We showed that an HIF-1α conditional knockout mouse displayed an inhibition in CIR-induced elevation of extracellular glutamate and N-methyl-d-aspartate receptor (NMDAR) activation. By gene screening for glutamate transporters in cortical cells, we found that HIF-1α mainly regulates the cystine-glutamate transporter (system x ) subunit xCT by directly binding to its promoter; xCT and its function are up-regulated in the ischaemic brains of rodents and humans, and the effects lasted for several days. Genetic deletion of xCT in cortical cells of mice inhibits either oxygen glucose deprivation/reoxygenation (OGDR) or CIR-mediated glutamate excitotoxicity in vitro and in vivo. Pharmaceutical inhibition of system x by a clinically approved anti-cancer drug, sorafenib, improves infarct volume and functional outcome in rodents with CIR and its therapeutic window is at least 3 days. Taken together, these findings reveal that HIF-1α plays a role in CIR-induced glutamate excitotoxicity via the long-lasting activation of system x -dependent glutamate outflow and suggest that system x is a promising therapeutic target with an extended therapeutic window in stroke. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Section: Resultsmentioning

confidence: 99%

HIF-1α triggers long-lasting glutamate excitotoxicity via system x_c⁻in cerebral ischaemia-reperfusion

et al. 2016

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“…The stimulation apparently provoked an increase in the grey matter V T from about 3.5 mL g −1 to 5 mL g −1 , in the absence of any effect on perfusion as measured by [ 15 O]-water PET in the same session. Autoradiographic studies ex vivo with [ 18 F]GE-179 ( 38 ) showed persistent increases in binding in rat cerebral cortex after traumatic brain injury, which were interpreted to indicate activation of NMDA receptors in the injured tissue [ 63 ].…”

Section: Glutamate Receptorsmentioning

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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“…The diarylguanidine analog, [123I]-CNS-1261 exhibited limited success in a clinical study of patients with schizophrenia (207). In PET imaging, despite encouraging results (208), a recent preclinical study using [18F]GE-179 was unable to demonstrate displaceable in vivo binding that would have been evidence of an in vivo activity-dependent NMDA signal in rats and primates (209–211). Recently, a new [18F]-labeled derivative of memantine, [18F]-fluoroethylnormemantine ([18F]-FNM), was synthesized.…”

Section: Glutamate Receptorsmentioning

confidence: 99%

Innovative Molecular Imaging for Clinical Research, Therapeutic Stratification, and Nosography in Neuroscience

Beaurain

et al. 2019

Front. Med.

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Over the past few decades, several radiotracers have been developed for neuroimaging applications, especially in PET. Because of their low steric hindrance, PET radionuclides can be used to label molecules that are small enough to cross the blood brain barrier, without modifying their biological properties. As the use of 11C is limited by its short physical half-life (20 min), there has been an increasing focus on developing tracers labeled with 18F for clinical use. The first such tracers allowed cerebral blood flow and glucose metabolism to be measured, and the development of molecular imaging has since enabled to focus more closely on specific targets such as receptors, neurotransmitter transporters, and other proteins. Hence, PET and SPECT biomarkers have become indispensable for innovative clinical research. Currently, the treatment options for a number of pathologies, notably neurodegenerative diseases, remain only supportive and symptomatic. Treatments that slow down or reverse disease progression are therefore the subject of numerous studies, in which molecular imaging is proving to be a powerful tool. PET and SPECT biomarkers already make it possible to diagnose several neurological diseases in vivo and at preclinical stages, yielding topographic, and quantitative data about the target. As a result, they can be used for assessing patients' eligibility for new treatments, or for treatment follow-up. The aim of the present review was to map major innovative radiotracers used in neuroscience, and explain their contribution to clinical research. We categorized them according to their target: dopaminergic, cholinergic or serotoninergic systems, β-amyloid plaques, tau protein, neuroinflammation, glutamate or GABA receptors, or α-synuclein. Most neurological disorders, and indeed mental disorders, involve the dysfunction of one or more of these targets. Combinations of molecular imaging biomarkers can afford us a better understanding of the mechanisms underlying disease development over time, and contribute to early detection/screening, diagnosis, therapy delivery/monitoring, and treatment follow-up in both research and clinical settings.

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Ex Vivo Tracing of NMDA and GABA-A Receptors in Rat Brain After Traumatic Brain Injury Using ¹⁸F-GE-179 and ¹⁸F-GE-194 Autoradiography

Cited by 18 publications

References 23 publications

HIF-1α triggers long-lasting glutamate excitotoxicity via system x_c⁻in cerebral ischaemia-reperfusion

HIF-1α triggers long-lasting glutamate excitotoxicity via system x_c⁻in cerebral ischaemia-reperfusion

A Review of Molecular Imaging of Glutamate Receptors

Innovative Molecular Imaging for Clinical Research, Therapeutic Stratification, and Nosography in Neuroscience

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Ex Vivo Tracing of NMDA and GABA-A Receptors in Rat Brain After Traumatic Brain Injury Using 18F-GE-179 and 18F-GE-194 Autoradiography

Cited by 18 publications

References 23 publications

HIF-1α triggers long-lasting glutamate excitotoxicity via system xc−in cerebral ischaemia-reperfusion

HIF-1α triggers long-lasting glutamate excitotoxicity via system xc−in cerebral ischaemia-reperfusion

A Review of Molecular Imaging of Glutamate Receptors

Innovative Molecular Imaging for Clinical Research, Therapeutic Stratification, and Nosography in Neuroscience

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Product

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Ex Vivo Tracing of NMDA and GABA-A Receptors in Rat Brain After Traumatic Brain Injury Using ¹⁸F-GE-179 and ¹⁸F-GE-194 Autoradiography

HIF-1α triggers long-lasting glutamate excitotoxicity via system x_c⁻in cerebral ischaemia-reperfusion

HIF-1α triggers long-lasting glutamate excitotoxicity via system x_c⁻in cerebral ischaemia-reperfusion