NMDA receptor ion channel activation detected in vivo with [ <sup>18</sup> F]GE-179 PET after electrical stimulation of rat hippocampus
Ali Khalidan Vibholm, Anne M. Landau, Arne Møller, Jan Jacobsen, Kim Vang, Ole Lajord Munk, Dariusz Orłowski, Jens CH Sørensen, David J. Brooks
Abstract
The positron emission tomography (PET) tracer [ 18 F]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 [ 18 F]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 [ 18 F]GE-179 PET scan. Stimulated rats had simultaneous depth-EEG recordings of induced seizure activity. [ 18 F]GE-179 uptake (volume of distribution, V T ) was compared between hemispheres and between groups. Electrical stimulation induced a significant increase in [ 18 F]GE-179 uptake at the electrode site compared to the contralateral hippocampus (mean 22% increase in V T , p = 0.0014) and to non-stimulated comparator groups. Rats injected with S-ketamine prior to stimulation maintained non-stimulated levels of [ 18 F]GE-179 uptake during stimulation. In conclusion, PET visualisation of focal [ 18 F]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 [ 18 F]GE-179 PET as a use-dependent marker of NMDAR-IC activation.