Characterization of ()- and ()-[F]OF-NB1 in Rodents as Positron Emission Tomography Probes for Imaging GluN2B Subunit-Containing -Methyl-d-Aspartate Receptors.

The -methyl-d-aspartate receptor (NMDAR) subtype 2B (GluN1/2B) is implicated in various neuropathologies. Given the lack of a validated radiofluorinated positron emission tomography (PET) probe for the imaging of GluN1/2B receptors, we comprehensively investigated the enantiomers of [F]OF-NB1 in rodents. Particularly, the ()- and ()- enantiomers were evaluated using docking, autoradiography, PET imaging, and biodistribution studies. A select panel of GluN1/2B antagonists (CP-101,606, CERC-301, and eliprodil) and the off-target sigma-1 receptor ligands (fluspidine and SA4503) were used to determine the specificity and selectivity of the tested enantiomers. Additionally, a nonmetal-mediated radiofluorination strategy was devised that harnesses the potential of diaryliodoniums in the nucleophilic radiofluorination of nonactivated aromatic compounds. Both enantiomers exhibited known GluN1/2B binding patterns; however, the -enantiomer showed higher GluN1/2B-specific accumulation in rodent autoradiography and higher brain uptake in PET imaging experiments compared to the -enantiomer. Molecular simulation studies provided further insights with respect to the difference in binding, whereby a reduced ligand-receptor interaction was observed for the -enantiomer. Nonetheless, both enantiomers showed dose dependency when two different doses (1 and 5 mg/kg) of the GluN1/2B antagonist, CP-101,606, were used in the PET imaging study. Taken together, ()-[F]OF-NB1 appears to exhibit the characteristics of a suitable PET probe for imaging of GluN2B-containing NMDARs in clinical studies.