Quantification of the novel N-methyl-d-aspartate receptor ligand [11C]GMOM in man

Abstract

[(11)C]GMOM (carbon-11 labeled N-(2-chloro-5-thiomethylphenyl)-N'-(3-[(11)C]methoxy-phenyl)-N'-methylguanidine) is a PET ligand that binds to the N-methyl-d-aspartate receptor with high specificity and affinity. The purpose of this first in human study was to evaluate kinetics of [(11)C]GMOM in the healthy human brain and to identify the optimal pharmacokinetic model for quantifying these kinetics, both before and after a pharmacological dose of S-ketamine. Dynamic 90 min [(11)C]GMOM PET scans were obtained from 10 subjects. In six of the 10 subjects, a second PET scan was performed following an S-ketamine challenge. Metabolite corrected plasma input functions were obtained for all scans. Regional time activity curves were fitted to various single- and two-tissue compartment models. Best fits were obtained using a two-tissue irreversible model with blood volume parameter. The highest net influx rate (Ki) of [(11)C]GMOM was observed in regions with high N-methyl-d-aspartate receptor density, such as hippocampus and thalamus. A significant reduction in the Ki was observed for the entire brain after administration of ketamine, suggesting specific binding to the N-methyl-d-aspartate receptors. This initial study suggests that the [(11)C]GMOM could be used for quantification of N-methyl-d-aspartate receptors.

Keywords: Glutamate; N-methyl-d-aspartate receptor; [11C]GMOM; kinetic modeling; positron emission tomography; quantitative imaging.

Figure 1.

(a) Mean (± SD) of parent, polar fractions, and plasma to whole blood ratios for all available scans (N = 15), parent fractions for 75 and 90 min could not be measured. (b) Typical metabolite corrected plasma input functions (Y-axis, logarithmic scale) for baseline and S-ketamine challenge scans.

Figure 2.

Mean (±SD) plasma levels of S-ketamine in six healthy volunteers after intravenous administration of 0.3 mg kg⁻¹ S-ketamine in a pseudo-steady state manner.

Figure 3.

Transaxial image of [¹¹C]GMOM uptake (Bq ml⁻¹) in a healthy volunteer at different times postinjection (p.i.), at baseline (top) and after S-ketamine challenge (bottom).

Figure 4.

Time activity curves (TACs) corrected for injected activity (%ID mL⁻¹) from selected regions: hippocampus, thalamus, striatum, cerebellum, frontal, temporal, parietal and occipital cortex, for a typical subject (a) at baseline, (b) after S-ketamine, and (c) from whole brain gray matter at baseline and after S-ketamine.

Figure 5.

Number of preferred fits (y-axis) per model (x-axis) according to AIC for the 90 min datasets.

Figure 6.

Bar plots (mean with SD error bars) illustrating the effect of S-ketamine on Ki values for all regions of interests investigated. The outlier subject has been excluded for this plot.