1. First-in-Humans Brain PET Imaging of the GluN2B-Containing N-methyl-d-aspartate Receptor with (R)-(11)C-Me-NB1
- Author
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Lukas Nics, Gregor Gryglewski, Jakob Unterholzner, Matej Murgas, Marcus Hacker, Leo Silberbauer, Lucas Rischka, Hazem Ahmed, Ahmed Haider, Sazan Rasul, Markus Mitterhauser, Christoph Wotawa, Godber M Godbersen, Wolfgang Wadsak, Thomas L. Mindt, Chrysoula Vraka, Andreas Hahn, Rupert Lanzenberger, Simon M. Ametamey, Roger Schibli, Verena Pichler, and Patricia Handschuh
- Subjects
Male ,medicine.medical_specialty ,Neurology ,Coefficient of variation ,Pharmacology ,Receptors, N-Methyl-D-Aspartate ,Article ,Alzheimer Disease ,Radioligand ,Medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Receptor ,Aspartic Acid ,business.industry ,Glutamate receptor ,Brain ,Reproducibility of Results ,Human brain ,Benzazepines ,Logan plot ,PET ,Radiopharmaceuticals ,GluN2B-subunits ,Glutamate ,N-methyl-D-aspartate (NMDA) ,Neurodegenerative disease ,Positron emission tomography (PET) ,medicine.anatomical_structure ,Positron-Emission Tomography ,NMDA receptor ,business ,Tomography, X-Ray Computed - Abstract
The N-methyl-D-aspartate receptor (NMDAR) plays a crucial role in neurodegenerative diseases such as Alzheimer’s disease and in the treatment of major depression by new fast-acting antidepressants such as ketamine. Given their broad implications, GluN2B-containing NMDARs have been of large 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 novel radioligand in a first-in-human 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 standardized uptake values (SUV). Test-retest reliability was assessed with the absolute percentage difference (APD) and the coefficient of variation (COV). Exploratory total volumes of distribution (VT) were computed using an arterial input function and the Logan plot as well as a constrained two-tissue compartment model with 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 APD ranged from 6.8 - 8.5% and COV from 4.9 - 6.0%, indicating a high test-retest reliability. A moderate correlation was found between SUV averaged from 70-90 min and VT using Logan plot (Spearman’s rho = 0.44). Correlation between VT Logan and 2TCM was r= 0.76. Conclusion: The novel 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 NMDA receptor in the pathophysiology and treatment of neuropsychiatric disease such as Alzheimer’s disease and major depression. Additionally, it could help in the selection of appropriate doses of GluN2B-targeting drugs. ISSN:0097-9058 ISSN:0022-3123 ISSN:0161-5505 ISSN:2159-662X ISSN:1535-5667
- Published
- 2022