Comparison of three novel radiotracers for GluN2B-containing NMDA receptors in non-human primates: (R)-[11C]NR2B-Me, (R)-[18F]of-Me-NB1, and (S)-[18F]of-NB1. Issue 8 (August 2022)

• Record Type: Journal Article
• Authors: Smart, Kelly; Zheng, Ming-Qiang; Ahmed, Hazem; Fang, Hanyi; Xu, Yuping; Cai, Lisheng; Holden, Daniel; Kapinos, Michael; Haider, Ahmed; Felchner, Zachary; Ropchan, Jim R; Tamagnan, Gilles; Innis, Robert B; Pike, Victor W; Ametamey, Simon M; Huang, Yiyun; Carson, Richard E
• Is Part Of: Journal of cerebral blood flow & metabolism. Volume 42:Issue 8(2022)
• Page Start: 1398
• Page End: 1409
• Publication Date: 2022-08
• Subjects: Positron emission tomography -- glutamate -- NMDA receptor -- GluN2B subunit -- (S)-[18F]OF-NB1 -- (R)-[18F]OF-Me-NB1 -- (R)-[11C]NR2B-Me; Cerebral circulation -- Periodicals; Brain -- Metabolism -- Periodicals; Brain -- Blood-vessels -- Periodicals; Cerebrovascular disease -- Periodicals; 612.824
• DOI: 10.1177/0271678X221084416
• Languages: English
• ISSNs: 0271-678X

Abstract

The NMDA receptor GluN2B subunit is a target of interest in neuropsychiatric disorders but to date there is no selective radiotracer available to quantify its availability in vivo . Here we report direct comparisons in non-human primates of three GluN2B-targeting radioligands: (R) -[ 11 C]NR2B-Me, (R) -[ 18 F]OF-Me-NB1, and (S) -[ 18 F]OF-NB1. Plasma free fraction, metabolism, tissue distribution and kinetics, and quantitative kinetic modeling methods and parameters were evaluated in two adult rhesus macaques. Free fraction in plasma was <2% for (R) -[ 11 C]NR2B-Me and (R) -[ 18 F]OF-Me-NB1 and higher for (S) -[ 18 F]OF-NB1 (15%). All radiotracers showed good brain uptake and distribution throughout grey matter, with substantial (>68%) blockade across the brain by the GluN2B-targeting drug Co-101, 244 (0.25 mg/kg), including in the cerebellum. Time-activity curves were well-fitted by the one-tissue compartment model, with volume of distribution values of 20–40 mL/cm 3 for (R) -[ 11 C]NR2B-Me, 8–16 mL/cm 3 for (R) -[ 18 F]OF-Me-NB1, and 15–35 mL/cm 3 for (S) -[ 18 F]OF-NB1. Estimates of regional non-displaceable binding potential were in the range of 2–3 for (R) -[ 11 C]NR2B-Me and (S) -[ 18 F]-OF-NB1, and 0.5-1 for (R) -[ 18 F]OF-Me-NB1. Altogether, each radiotracer showed an acceptable profile for quantitative imaging of GluN2B. (S) -[ 18 F]OF-NB1 has particularly promising imaging characteristics for potential translation into humans. However, the source of unexpected displaceable binding in the cerebellum for each of these compounds requires further investigation.