Abstract
BackgroundEfforts to develop suitable positron emission tomography (PET) tracers for the ion channel site of human N-methyl-d-aspartate (NMDA) receptors have had limited success. [18F]PK-209 is a GMOM derivative that binds to the intrachannel phencyclidine site with high affinity and selectivity. Primate PET studies have shown that the volume of distribution in the brain was reduced by administration of the NMDA receptor antagonist MK-801, consistent with substantial specific binding. The purpose of the present study was to evaluate [18F]PK-209 in 10 healthy humans by assessing test–retest reproducibility and binding specificity following intravenous S-ketamine administration (0.5 mg ∙ kg−1). Five healthy subjects underwent a test–retest protocol, and five others a baseline-ketamine protocol. In all cases dynamic, 120-min PET scans were acquired together with metabolite-corrected arterial plasma input functions. Additional input functions were tested based on within-subject and population-average parent fractions.ResultsBest fits of the brain time-activity curves were obtained using an irreversible two-tissue compartment model with additional blood volume parameter. Mean test–retest variability of the net rate of influx Ki varied between 7 and 24% depending on the input function. There were no consistent changes in [18F]PK-209 PET parameters following ketamine administration, which may be a consequence of the complex endogenous ligand processes that affect channel gating.ConclusionsThe molecular interaction between [18F]PK-209 and the binding site within the NMDA receptor ion channel is insufficiently reproducible and specific to be a reliable imaging agent for its quantification.Trial registrationEudraCT 2014-001735-36. Registered 28 April 2014
Highlights
Efforts to develop suitable positron emission tomography (PET) tracers for the ion channel site of human N-methyl-D-aspartate (NMDA) receptors have had limited success. [18F]PK-209 is a GMOM derivative that binds to the intrachannel phencyclidine site with high affinity and selectivity
The Areas under the curve (AUC) (0–180 s) for both TRT and ketamine groups did not differ between PET1 and PET2. [18F]PK-209 was rapidly metabolized (Fig. 4)
The divergent clinical and preclinical behavior of [18F]PK-209 could be due to multiple differences in interactions between exogenous and endogenous glutamatergic ligands
Summary
Efforts to develop suitable positron emission tomography (PET) tracers for the ion channel site of human N-methyl-D-aspartate (NMDA) receptors have had limited success. [18F]PK-209 is a GMOM derivative that binds to the intrachannel phencyclidine site with high affinity and selectivity. Primate PET studies have shown that the volume of distribution in the brain was reduced by administration of the NMDA receptor antagonist MK-801, consistent with substantial specific binding. The purpose of the present study was to evaluate [18F]PK-209 in 10 healthy humans by assessing test–retest reproducibility and binding specificity following intravenous S-ketamine administration Positron emission tomography (PET) studies of radiolabelled NMDA-R antagonists in humans have been hampered by poor radiotracer selectivity and affinity, low brain entrance, rapid radioligand metabolism, and/or inability to establish specific NMDA-R targeting [6,7,8,9]. Recent studies using [11C]GMOM in humans demonstrated that intravenous administration of ketamine 0.3 mg · kg−1 reduced the radiotracer net influx rate (Ki) in whole brain gray matter by, on average, 66% [10].
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