Abstract
Despite 2 decades of research, no N-methyl-d-aspartate (NMDA) glutamate receptor (GluN) subtype 2B (GluN1/2B) radioligand is yet clinically validated. Previously, we reported on (rac)-(18)F-OF-NB1 as a promising GluN1/2B PET probe in rodents and its successful application for the visualization of GluN2B-containing NMDA receptors in postmortem brain tissues of patients with amyotrophic lateral sclerosis. In the current work, we report on the in vivo characterization of (rac)-, (R)-, and (S)-(18)F-OF-NB1 in nonhuman primates. Methods: PET scans were performed on rhesus monkeys. Plasma profiling was used to obtain the arterial input function. Regional brain time-activity curves were generated and fitted with the 1- and 2-tissue-compartment models and the multilinear analysis 1 method, and the corresponding regional volumes of distribution were calculated. Blocking studies with the GluN1/2B ligand Co 101244 (0.25 mg/kg) were performed for the enantiopure radiotracers. Receptor occupancy, nonspecific volume of distribution, and regional binding potential (BP (ND)) were obtained. Potential off-target binding toward σ(1) receptors was assessed for (S)-(18)F-OF-NB1 using the σ(1) receptor ligand FTC-146. Results: Free plasma fraction was moderate, ranging from 12% to 16%. All radiotracers showed high and heterogeneous brain uptake, with the highest levels in the cortex. (R)-(18)F-OF-NB1 showed the highest uptake and slowest washout kinetics of all tracers. The 1-tissue-compartment model and multilinear analysis 1 method fitted the regional time-activity curves well for all tracers and produced reliable regional volumes of distribution, which were higher for (R)- than (S)-(18)F-OF-NB1. Receptor occupancy by Co 101244 was 85% and 96% for (S)-(18)F-OF-NB1 and (R)-(18)F-OF-NB1, respectively. Pretreatment with FTC-146 at both a low (0.027 mg/kg) and high (0.125 mg/kg) dose led to a similar reduction (48% and 49%, respectively) in specific binding of (S)-(18)F-OF-NB1. Further, pretreatment with both Co 101244 and FTC-146 did not result in a further reduction in specific binding compared with Co 101244 alone in the same monkey (82% vs. 81%, respectively). Regional BP (ND) values ranged from 1.3 in the semiovale to 3.4 in the cingulate cortex for (S)-(18)F-OF-NB1. Conclusion: Both (R)- and (S)-(18)F-OF-NB1 exhibited high binding specificity to GluN2B subunit-containing NMDA receptors. The fast washout kinetics, good regional BP (ND) values, and high plasma free fraction render (S)-(18)F-OF-NB1 an attractive radiotracer for clinical translation.