Evaluation of (rac)-, (R)-, and (S)-¹⁸F-OF-NB1 for Imaging GluN2B Subunit–Containing N-Methyl-d-Aspartate Receptors in Nonhuman Primates

Structures of (R)-¹¹C-Me-NB1, the lead radiotracer recently evaluated in clinical trial; (R)-¹⁸F-OF-Me-NB1, the first radiofluorinated derivative of (R)-¹¹C-Me-NB1 evaluated in rats; and (rac)-, (R)-, and (S)-¹⁸F-OF-NB1 evaluated in the current work.

Radiosynthesis of (rac)-, (R)-, and (S)-¹⁸F-OF-NB1. DMA = dimethylacetamide; rt = room temperature.

Parent fraction remaining of (rac)-, (R)-, and (S)-¹⁸F-OF-NB at different time points under baseline and blockade conditions. For GluN1/2B blockade, dose of 0.25 mg/kg of Co 101244 was used. For σ₁R blockade, either low dose (0.027 mg/kg) or high dose (0.125 mg/kg) of FTC-146 was used.

(Top) Representative PET SUV images (summed from 45 to 60 min) and time–activity curves in selected brain regions from baseline, GluN1/2B blockade (0.25 mg/kg dose of Co 101244), σ₁R blockade (0.125 mg/kg dose of FTC-146), and sequential GluN1/2B/σ₁R blockade (0.25 mg/kg dose of Co 101244 + 0.125 mg/kg dose FTC-146) scans of (S)-¹⁸F-OF-NB1 obtained in the same rhesus monkey (monkey 2). (Bottom) PET SUV images and time–activity curves from baseline and GluN1/2B blockade (0.25 mg/kg dose of Co 101244) scans of (R)-¹⁸F-OF-NB1 (monkey 1).

Lassen occupancy plots of (R)- and (S)-¹⁸F-OF-NB1 after pretreatment with either GluN1/2B ligand Co 101244 (0.25 mg/kg) only or with addition of σ₁R ligand FTC-146 (0.125 mg/kg). Each point represents unique brain region.