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

• Published in: Journal of cerebral blood flow and metabolism 2021-06, Vol.41 (6), p.1301-1312
• Main Authors: Vibholm, Ali K, Landau, Anne M, Møller, Arne, Jacobsen, Jan, Vang, Kim, Munk, Ole L, Orlowski, Dariusz, Sørensen, Jens CH, Brooks, David J
• Format: Article
• Language: English
• Subjects: Original
• ISSN: 0271-678X; 1559-7016
• DOI: 10.1177/0271678X20954928

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.