Response to Comment on “In Vivo [<sup>18</sup>F]GE-179 Brain Signal Does Not Show NMDA-Specific Modulation with Drug Challenges in Rodents and Nonhuman Primates”

Sander, Christin Y.; Schoenberger, Matthias; Hooker, Jacob M.

doi:10.1021/acschemneuro.8b00423

Cited by 5 publications

(4 citation statements)

References 16 publications

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“…A recent study by Schoenberger et al 40 and the related commentary letters by McGinnity et al 41 and Sander et al 42 23 We believe that the combination of 60 Hz electrical stimulation to open and activate the NMDAR-ICs so allowing [ 18 F]GE-179 to enter and access the PCP site and blockade with S-ketamine during and after electrical stimulation effectively blocked these sites to [ 18 F] GE-179.…”

Section: Discussionmentioning

confidence: 86%

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NMDA receptor ion channel activation detected in vivo with [¹⁸F]GE-179 PET after electrical stimulation of rat hippocampus

Vibholm

Landau

Møller

et al. 2020

J Cereb Blood Flow Metab

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The positron emission tomography (PET) tracer [18F]GE-179 binds to the phencyclidine (PCP) site in the open N-methyl-D-aspartate receptor ion channel (NMDAR-IC). To demonstrate that PET can visualise increased [18F]GE-179 uptake by active NMDAR-ICs and that this can be blocked by the PCP antagonist S-ketamine, 15 rats had an electrode unilaterally implanted in their ventral hippocampus. Seven rats had no stimulation, five received pulsed 400 µA supra-threshold 60 Hz stimulation alone, and three received intravenous S-ketamine injection prior to stimulation. Six other rats were not implanted. Each rat had a 90 min [18F]GE-179 PET scan. Stimulated rats had simultaneous depth-EEG recordings of induced seizure activity. [18F]GE-179 uptake (volume of distribution, VT) was compared between hemispheres and between groups. Electrical stimulation induced a significant increase in [18F]GE-179 uptake at the electrode site compared to the contralateral hippocampus (mean 22% increase in VT, p = 0.0014) and to non-stimulated comparator groups. Rats injected with S-ketamine prior to stimulation maintained non-stimulated levels of [18F]GE-179 uptake during stimulation. In conclusion, PET visualisation of focal [18F]GE-179 uptake during electrically activated NMDAR-ICs and the demonstration of specificity for PCP sites by blockade with S-ketamine support the in vivo utility of [18F]GE-179 PET as a use-dependent marker of NMDAR-IC activation.

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Section: Discussionmentioning

confidence: 86%

“…41 and Sander et al. 42 have discussed the difficulties of determining the in vivo specificity of [ 18 F]GE-179 to the NMDAR using pharmacological challenges. Schoenberger et al.…”

Section: Discussionmentioning

confidence: 99%

NMDA receptor ion channel activation detected in vivo with [¹⁸F]GE-179 PET after electrical stimulation of rat hippocampus

Vibholm

Landau

Møller

et al. 2020

J Cereb Blood Flow Metab

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“…A study that used a blocking agent to investigate the specific binding of [ 18 F]GE-179 in rodents and primates did not find evidence of specificity to NMDAR [ 41 ]. However, this study co-administered anaesthetic agents which may also alter the availability of the target sites, complicating interpretation of the findings as tracer binding could have been altered by anaesthetic agents used in the control group [ 41 – 43 ]. Notwithstanding this, a recent study found that electrical stimulation designed to activate NMDAR induced significant increases in the uptake of [ 18 F]GE-179, and also that the NMDAR antagonist, ketamine, blocked this increase in uptake, indicating [ 18 F]GE-179 binds to NMDAR and is sensitive to changes in NMDAR activity [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

N-methyl-D-aspartate receptor availability in first-episode psychosis: a PET-MR brain imaging study

et al. 2021

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N-methyl-D-aspartate receptor (NMDAR) hypofunction is hypothesised to underlie psychosis but this has not been tested early in illness. To address this, we studied 40 volunteers (21 patients with first-episode psychosis and 19 matched healthy controls) using PET imaging with an NMDAR selective ligand, [18F]GE-179, that binds to the ketamine binding site to index its distribution volume ratio (DVR) and volume of distribution (VT). Hippocampal DVR, but not VT, was significantly lower in patients relative to controls (p = 0.02, Cohen’s d = 0.81; p = 0.15, Cohen’s d = 0.49), and negatively associated with total (rho = −0.47, p = 0.04), depressive (rho = −0.67, p = 0.002), and general symptom severity (rho = −0.74, p < 0.001). Exploratory analyses found no significant differences in other brain regions (anterior cingulate cortex, thalamus, striatum and temporal cortex). These findings are consistent with the NMDAR hypofunction hypothesis and identify the hippocampus as a key locus for relative NMDAR hypofunction, although further studies should test specificity and causality.

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“…However, there are also studies in rodents and primates which have not used this stimulation method and do not find that NMDAR antagonists such as ketamine were able to block [ 18 F] GE-179 binding (Schoenberger et al, 2018). However, these studies co-administered anaesthetic agents which may interact with the NMDAR and, consequently, alter the sensitivity of these approaches to detect changes (McGinnity et al, 2018; Sander et al, 2018). Thus, while the in vitro evidence shows the tracer is specific to the NMDAR, there is some inconsistency in the in vivo evidence, potentially due to the use of anaesthetic agents that interact with NMDAR.…”

Section: Strengths and Limitationsmentioning

confidence: 99%

The association between N-methyl-d-aspartate receptor availability and glutamate levels: A multi-modal PET-MR brain imaging study in first-episode psychosis and healthy controls

et al. 2022

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Background: Evidence from post-mortem studies and in vivo imaging studies suggests there may be reduced N-methyl-d-aspartate receptor (NMDAR) levels in the hippocampus in patients with schizophrenia. Other studies have reported increased glutamate in striatum in schizophrenia patients. It has been hypothesised that NMDAR hypofunction leads to the disinhibition of glutamatergic signalling; however, this has not been tested in vivo. Methods: In this study, we investigated the relationship between hippocampal NMDAR and striatal glutamate using simultaneous positron emission tomography-magnetic resonance (PET-MR) imaging. We recruited 40 volunteers to this cross-sectional study; 21 patients with schizophrenia, all in their first episode of illness, and 19 healthy controls. We measured hippocampal NMDAR availability using the PET ligand [18F]GE179. This was indexed relative to whole brain as the distribution volume ratio (DVR). Striatal glutamatergic indices (glutamate and Glx) were acquired simultaneously, using combined PET-MR proton magnetic resonance spectroscopy (1H-MRS). Results: A total of 33 individuals (15 healthy controls, 18 patients) were included in the analyses (mean (SD) age of controls, 27.31 (4.68) years; mean (SD) age of patients, 24.75 (4.33), 27 male and 6 female). We found an inverse relationship between hippocampal DVR and striatal glutamate levels in people with first-episode psychosis (rho = −0.74, p < 0.001) but not in healthy controls (rho = −0.22, p = 0.44). Conclusion: This study show that lower relative NMDAR availability in the hippocampus may drive increased striatal glutamate levels in patients with schizophrenia. Further work is required to determine whether these findings may yield new targets for drug development in schizophrenia.

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Response to Comment on “In Vivo [¹⁸F]GE-179 Brain Signal Does Not Show NMDA-Specific Modulation with Drug Challenges in Rodents and Nonhuman Primates”

Cited by 5 publications

References 16 publications

NMDA receptor ion channel activation detected in vivo with [¹⁸F]GE-179 PET after electrical stimulation of rat hippocampus

NMDA receptor ion channel activation detected in vivo with [¹⁸F]GE-179 PET after electrical stimulation of rat hippocampus

N-methyl-D-aspartate receptor availability in first-episode psychosis: a PET-MR brain imaging study

The association between N-methyl-d-aspartate receptor availability and glutamate levels: A multi-modal PET-MR brain imaging study in first-episode psychosis and healthy controls

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Response to Comment on “In Vivo [18F]GE-179 Brain Signal Does Not Show NMDA-Specific Modulation with Drug Challenges in Rodents and Nonhuman Primates”

Cited by 5 publications

References 16 publications

NMDA receptor ion channel activation detected in vivo with [18F]GE-179 PET after electrical stimulation of rat hippocampus

NMDA receptor ion channel activation detected in vivo with [18F]GE-179 PET after electrical stimulation of rat hippocampus

N-methyl-D-aspartate receptor availability in first-episode psychosis: a PET-MR brain imaging study

The association between N-methyl-d-aspartate receptor availability and glutamate levels: A multi-modal PET-MR brain imaging study in first-episode psychosis and healthy controls

Contact Info

Product

Resources

About

Response to Comment on “In Vivo [¹⁸F]GE-179 Brain Signal Does Not Show NMDA-Specific Modulation with Drug Challenges in Rodents and Nonhuman Primates”

NMDA receptor ion channel activation detected in vivo with [¹⁸F]GE-179 PET after electrical stimulation of rat hippocampus

NMDA receptor ion channel activation detected in vivo with [¹⁸F]GE-179 PET after electrical stimulation of rat hippocampus