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

Abstract

Background At subanesthetic doses, ketamine, an N-Methyl-D-aspartate (NMDA) glutamate receptor antagonist, increases glutamate release. Here, we imaged the acute effect of ketamine on brain metabotropic glutamatergic receptors subtype 5 (mGluR5) with a high affinity PET ligand [11C]ABP688 ((E)-3-((6-methylpyridin-2-yl)ethynyl)-cyclohex-2-enone-O-11C-methyl-oxime), a negative allosteric modulator of mGluR5. Methods Ten healthy nonsmoking human volunteers (34±13 years old) received two [11C]ABP688 PET scans on the same day – before (scan 1) and during i.v. ketamine administration (0.23mg/kg over 1min, then 0.58mg/kg over 1h; scan 2). PET data were acquired for 90 min immediately following [11C]ABP688 bolus injection. Input functions were obtained through arterial blood sampling with metabolite analysis. Results A significant reduction in [11C]ABP688 volume of distribution (VT) 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<0.05) that resolved after completion of the scan. Discussion This study provides first evidence that ketamine administration decreases [11C]ABP688 binding in vivo in human subjects. Results suggest that [11C]ABP688 binding is sensitive to ketamine-induced effects, although the high individual variation in ketamine response requires further examination.

Ketamine: Promising Path or False Prophecy in the Development of Novel Therapeutics for Mood Disorders?

“…Since there are no readily available ligands for the NMDAR to allow PET imaging studies, alternative measures are needed. A recent paper suggests it may be possible to indirectly monitor ketamine's effects with the use of a PET ligand, [ 11 C]ABP688 (E)-3-[2-(6-methyl-2-pyridinyl)ethynyl]-2-cyclohexen-1-one-O-(methyl-11 C)oxime, that has high affinity for the mGluR5 receptor which is sensitive to changes in endogenous glutamate (DeLorenzo et al, 2014). Preclinical and small clinical studies suggest other imaging methods such as 13 C-MRS measures of glutamate cycling (Chowdhury et al, 2012), or fMRI studies of brain network connectivity could be used to evaluate target engagement, and perhaps may even be more closely related to the critical down stream mechanisms generating the antidepressant response (Dawson et al, 2014;Driesen et al, 2013).…”

Positive Association Between Limbic Metabotropic Glutamate Receptor 5 Availability and Novelty-Seeking Temperament in Humans: An 18F-FPEB PET Study

“…V T values were consistent with the known distribution of mGluR5 in humans, and the reliability of this parameter has been demonstrated (18,21), supporting its validity to quantify mGluR5 availability. Third, as suggested for another allosteric mGluR5 PET tracer (20), variation in extracellular glutamate levels could have affected findings. Here, we found no significant correlations between ACC glutamate/glutamine levels and tracer binding.…”

“…Additionally, given the suggested involvement of ACC glutamate concentrations in personality and their possible influence on mGluR5 availability (20), mGluR5 and temperament measures were related to spectroscopic measures of ACC glutamate-glutamine levels.…”

Effects of anesthetics on vesicular monoamine transporter type 2 binding to 18 F-FP-(+)-DTBZ: a biodistribution study in rat brain

“…Some investigators have reported that ketamine affects several neuronal transmission systems, such as dopamine receptor and transporter [43][44][45][46], serotonin receptor and transporter [47], glutamate receptor [48], etc. However, interference of ketamine with VMAT2, another important target in the central nervous system, which mediating monoaminergic transmission, is still unknown.…”