First-in-Humans Brain PET Imaging of the GluN2B-Containing N -methyl- d

The Journal of Nuclear Medicine

article

Lucas Rischka¹  Chrysoula Vraka²  Verena Pichler²  Sazan Rasul²  Lukas Nics²  Gregor Gryglewski¹  Patricia Handschuh¹  Matej Murgaš¹  Godber M. Godbersen¹  Leo R. Silberbauer¹  Jakob Unterholzner¹  Christoph Wotawa¹  Ahmed Haider³  Hazem Ahmed³  Roger Schibli³  Thomas Mindt²  Markus Mitterhauser²  Wolfgang Wadsak²  Andreas Hahn¹  Rupert Lanzenberger¹  Marcus Hacker²  Simon M. Ametamey³ 

[1] Department of Psychiatry and Psychotherapy, Medical University of Vienna;Division of Nuclear Medicine, Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna;Centre for Radiopharmaceutical Sciences ETH-PSI-USZ, Institute of Pharmaceutical Sciences ETH;Ludwig Boltzmann Institute Applied Diagnostics;Institute of Inorganic Chemistry, University of Vienna;Center for Biomarker Research in Medicine

关键词: glutamate;    N-methyl-d-aspartate (NMDA);    GluN2B subunits;    neurodegenerative disease;    PET;   

DOI  :  10.2967/jnumed.121.262427

学科分类：医学（综合）

来源: Society of Nuclear Medicine

【 摘 要 】

The N-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, (R)-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. Methods: Six healthy male subjects were scanned twice on a fully integrated PET/MR scanner with (R)-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 (VT) 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 (K1/k2) coupled (2TCM). SUV was correlated with VT to investigate its potential as a surrogate marker of GluN2B expression. Results: 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 VT using Logan plot (Spearman ρ = 0.44). Correlation between VT Logan and 2TCM was r = 0.76. Conclusion: The radioligand (R)-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.

【 授权许可】

CC BY