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

• Published in: Biological psychiatry (1969) Vol. 77; no. 3; pp. 266 - 275
• Main Authors: DeLorenzo, Christine, DellaGioia, Nicole, Bloch, Michael, Sanacora, Gerard, Nabulsi, Nabeel, Abdallah, Chadi, Yang, Jie, Wen, Ruofeng, Mann, J. John, Krystal, John H., Parsey, Ramin V., Carson, Richard E., Esterlis, Irina
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2015
• Subjects: [11C]ABP688; Adult; Blood Pressure - drug effects; Brain; Brain - diagnostic imaging; Brain - metabolism; Brain Mapping; Carbon Radioisotopes; Excitatory Amino Acid Antagonists - blood; Excitatory Amino Acid Antagonists - pharmacology; Glutamate; Heart Rate - drug effects; Humans; Ketamine; Ketamine - blood; Ketamine - pharmacology; Mental Processes - drug effects; mGluR5; Neuropsychological Tests; Oximes; PET; Positron-Emission Tomography; Psychiatric/Mental Health; Pyridines; Radiopharmaceuticals; Receptor, Metabotropic Glutamate 5 - metabolism; Brain; Ketamine; [11C]ABP688; Glutamate; mGluR5; PET; [ 11C]ABP688; [C]ABP688
• ISSN: 0006-3223; 1873-2402
• DOI: 10.1016/j.biopsych.2014.06.024

At 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. Two [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. A 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. This 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.