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".
Duncan, John S
Howes, Oliver D
Jones, Paul A
Koepp, Matthias J
Riaño Barros, Daniela A
ACS chemical neuroscience
American Chemical Society (ACS)
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McGinnity, C. J., Årstad, E., Beck, K., Brooks, D. J., Coles, J., Duncan, J. S., Galovic, M., et al. (2019). 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".. ACS chemical neuroscience, 10 (1), 768-772. https://doi.org/10.1021/acschemneuro.8b00246
Schoenberger and colleagues (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 (B_max^'). Schoenberger and colleagues anaesthetised rats and rhesus monkeys using isoflurane, which has an inhibitory effect on NMDA receptor function and thus would be expected to further reduce the B_max^'. 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 anaesthesia. Prior data suggest that the uptake of di-substituted 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 anaesthesia, e.g. with GE-179’s antecedent, CNS 5161 (Biegon et al., 2007), and with GMOM (van der Toef et al., 2016). However, the extent of non-specific uptake remains uncertain.
Brain, Animals, Macaca mulatta, Rodentia, Rats, N-Methylaspartate, Radiopharmaceuticals, Positron-Emission Tomography
UNIVERSITY COLLEGE LONDON (FB MRC) (MR/L013215/1)
External DOI: https://doi.org/10.1021/acschemneuro.8b00246
This record's URL: https://www.repository.cam.ac.uk/handle/1810/283060