TY - JOUR
T1 - First-in-Humans Brain PET Imaging of the GluN2B-Containing N-methyl-D-aspartate Receptor with (R)-C-11-Me-NB1
AU - Rischka, Lucas
AU - Vraka, Chrysoula
AU - Pichler, Verena
AU - Rasul, Sazan
AU - Nics, Lukas
AU - Gryglewski, Gregor
AU - Handschuh, Patricia
AU - Murgas, Matej
AU - Godbersen, Godber M.
AU - Silberbauer, Leo R.
AU - Unterholzner, Jakob
AU - Wotawa, Christoph
AU - Haider, Ahmed
AU - Ahmed, Hazem
AU - Schibli, Roger
AU - Mindt, Thomas
AU - Mitterhauser, Markus
AU - Wadsak, Wolfgang
AU - Hahn, Andreas
AU - Lanzenberger, Rupert
AU - Hacker, Marcus
AU - Ametamey, Simon M.
N1 - Publisher Copyright:
© 2022 Society of Nuclear Medicine Inc.. All rights reserved.
PY - 2022/6/1
Y1 - 2022/6/1
N2 - 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.
AB - 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.
KW - GluN2B-subunits
KW - Glutamate
KW - N-methyl-D-aspartate (NMDA)
KW - neurodegenerative disease
KW - positron emission tomography (PET)
UR - http://www.scopus.com/inward/record.url?scp=85131271281&partnerID=8YFLogxK
U2 - 10.2967/jnumed.121.262427
DO - 10.2967/jnumed.121.262427
M3 - Article
SN - 0161-5505
VL - 63
SP - 936
EP - 941
JO - Journal of Nuclear Medicine
JF - Journal of Nuclear Medicine
IS - 6
ER -
