In Vivo Ketamine-Induced Changes in [11C]ABP688 Binding to Metabotropic Glutamate Receptor Subtype 5

Abstract

BackgroundAt subanesthetic doses, ketamine, an N-methyl-D-aspartate glutamate receptor antagonist, increases glutamate release. We imaged the acute effect of ketamine on brain metabotropic glutamatergic receptor subtype 5 with a high-affinity positron emission tomography (PET) ligand [11C]ABP688 (E)-3-[2-(6-methyl-2-pyridinyl)ethynyl]-2-cyclohexen-1-one-O-(methyl-11C)oxime, a negative allosteric modulator of the metabotropic glutamatergic receptor subtype 5. MethodsTwo [11C]ABP688 PET scans were performed in 10 healthy nonsmoking human volunteers (34 ± 13 years old); the two PET scans were performed on the same day—before (scan 1) and during intravenous ketamine administration (.23 mg/kg over 1 min, then .58 mg/kg over 1 hour; scan 2). The PET data were acquired for 90 min immediately after [11C]ABP688 bolus injection. Input functions were obtained through arterial blood sampling with metabolite analysis. ResultsA significant reduction in [11C]ABP688 volume of distribution was observed in scan 2 relative to scan 1 of 21.3% ± 21.4%, on average, in the anterior cingulate, medial prefrontal cortex, orbital prefrontal cortex, ventral striatum, parietal lobe, dorsal putamen, dorsal caudate, amygdala, and hippocampus. There was a significant increase in measurements of dissociative state after ketamine initiation (p < .05), which resolved after completion of the scan. ConclusionsThis study provides first evidence that ketamine administration decreases [11C]ABP688 binding in vivo in human subjects. The results suggest that [11C]ABP688 binding is sensitive to ketamine-induced effects, although the high individual variation in ketamine response requires further examination.