1. Comparison of three novel radiotracers for GluN2B-containing NMDA receptors in non-human primates: (R) -[ 11 C]NR2B-Me, (R) -[ 18 F]of-Me-NB1, and (S) -[ 18 F]of-NB1.
- Author
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Smart K, Zheng MQ, Ahmed H, Fang H, Xu Y, Cai L, Holden D, Kapinos M, Haider A, Felchner Z, Ropchan JR, Tamagnan G, Innis RB, Pike VW, Ametamey SM, Huang Y, and Carson RE
- Subjects
- Animals, Brain diagnostic imaging, Brain metabolism, Macaca mulatta metabolism, Positron-Emission Tomography methods, Radiopharmaceuticals metabolism, Receptors, N-Methyl-D-Aspartate metabolism
- 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/cm3 for (R) -[11 C]NR2B-Me, 8-16 mL/cm3 for (R) -[18 F]OF-Me-NB1, and 15-35 mL/cm3 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.- Published
- 2022
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