First-in-Humans Brain PET Imaging of the GluN2B-Containing <i>N</i>-methyl-d-aspartate Receptor with (<i>R</i>)-¹¹C-Me-NB1.

Abstract

The <i>N</i>-methyl-d-aspartate receptor (NMDAR) plays a crucial role in neurodegenerative diseases such as Alzheimer disease and in the treatment of major depression by fast-acting antidepressants such as ketamine. Given their broad implications, GluN2B-containing NMDARs have been of interest as diagnostic and therapeutic targets. Recently, (<i>R</i>)-¹¹C-Me-NB1 was investigated preclinically and shown to be a promising radioligand for imaging GluN2B subunits. Here, we report on the performance characteristics of this radioligand in a first-in-humans PET study. <b>Methods:</b> Six healthy male subjects were scanned twice on a fully integrated PET/MR scanner with (<i>R</i>)-¹¹C-Me-NB1 for 120 min. Brain uptake and tracer distribution over time were investigated by SUVs. Test-retest reliability was assessed with the absolute percentage difference and the coefficient of variation. Exploratory total volumes of distribution (V_T) were computed using an arterial input function and the Logan plot as well as a constrained 2-tissue-compartment model with the ratio of rate constants between plasma and tissue compartments (<i>K</i>₁/<i>k</i>₂) coupled (2TCM). SUV was correlated with V_T to investigate its potential as a surrogate marker of GluN2B expression. <b>Results:</b> High and heterogeneous radioligand uptake was observed across the entire gray matter with reversible kinetics within the scan time. SUV absolute percentage difference ranged from 6.9% to 8.5% and coefficient of variation from 4.9% to 6.0%, indicating a high test-retest reliability. A moderate correlation was found between SUV averaged from 70 to 90 min and V_T using Logan plot (Spearman ρ = 0.44). Correlation between V_T Logan and 2TCM was <i>r</i> = 0.76. <b>Conclusion:</b> The radioligand (<i>R</i>)-¹¹C-Me-NB1 was highly effective in mapping GluN2B-enriched NMDARs in the human brain. With a heterogeneous uptake and a high test-retest reliability, this radioligand offers promise to deepen our understanding of the GluN2B-containing NMDAR in the pathophysiology and treatment of neuropsychiatric disease such as Alzheimer disease and major depression. Additionally, it could help in the selection of appropriate doses of GluN2B-targeting drugs.