Comparison of three novel radiotracers for GluN2B-containing NMDA receptors in non-human primates: -[C]NR2B-Me, -[F]of-Me-NB1, and -[F]of-NB1.

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 . Here we report direct comparisons in non-human primates of three GluN2B-targeting radioligands: -[C]NR2B-Me, -[F]OF-Me-NB1, and -[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 -[C]NR2B-Me and -[F]OF-Me-NB1 and higher for -[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 for -[C]NR2B-Me, 8-16 mL/cm for -[F]OF-Me-NB1, and 15-35 mL/cm for -[F]OF-NB1. Estimates of regional non-displaceable binding potential were in the range of 2-3 for -[C]NR2B-Me and -[F]-OF-NB1, and 0.5-1 for -[F]OF-Me-NB1. Altogether, each radiotracer showed an acceptable profile for quantitative imaging of GluN2B. -[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.