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

Lookup NU author(s): Professor David BrooksORCiD

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Abstract

© 2018 American Chemical Society. Schoenberger and colleagues (Schoenberger et al.. (2018) ACS Chem. Neurosci. 9, 298-305) recently reported attempts to demonstrate specific binding of the positron emission tomography (PET) radiotracer, [18F]GE-179, to NMDA receptors in both rats and Rhesus macaques. GE-179 did not work as expected in animal models; however, we disagree with the authors' conclusion that "the [18F]GE-179 signal seems to be largely nonspecific". It is extremely challenging to demonstrate specific binding for the use-dependent NMDA receptor intrachannel ligands such as [18F]GE-179 in animals via traditional blocking, due to its low availability of target sites (Bmax′). Schoenberger and colleagues anesthetized rats and Rhesus monkeys using isoflurane, which has an inhibitory effect on NMDA receptor function and thus would be expected to further reduce the Bmax′. The extent of glutamate release achieved in the provocation experiments is uncertain, as is whether a significant increase in NMDA receptor channel opening can be expected under anesthesia. Prior data suggest that the uptake of disubstituted arylguanidine-based ligands such as GE-179 can be reduced by phencyclidine binding site antagonists, if injection is performed in the absence of ketamine and isoflurane anesthesia, e.g., with GE-179's antecedent, CNS 5161 (Biegon et al.. (2007) Synapse 61, 577-586), and with GMOM (van der Doef et al.. (2016) J. Cereb. Blood Flow Metab. 36, 1111-1121). However, the extent of nonspecific uptake remains uncertain.


Publication metadata

Author(s): McGinnity CJ, Arstad E, Beck K, Brooks DJ, Coles JP, Duncan JS, Galovic M, Hinz R, Hirani E, Howes OD, Jones PA, Koepp MJ, Luo F, Riano Barros DA, Singh N, Trigg W, Hammers A

Publication type: Article

Publication status: Published

Journal: ACS Chemical Neuroscience

Year: 2019

Volume: 10

Issue: 1

Pages: 768-772

Print publication date: 16/01/2019

Online publication date: 11/10/2018

Acceptance date: 02/04/2018

ISSN (electronic): 1948-7193

Publisher: American Chemical Society

URL: https://doi.org/10.1021/acschemneuro.8b00246

DOI: 10.1021/acschemneuro.8b00246


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