Characterization in Non-human Primates of (R)-[18F]OF-Me-NB1 and (S)-[18F]OF-Me-NB1 for Imaging the GluN2B Subunits of the NMDA Receptor
Authors: Zheng Ming-Qiang , Ahmed Hazem , Smart Kelly , Xu Yuping , Holden Daniel , Kapinos Michael , Felchner Zachary , Haider Ahmed , Tamagnan Gilles , Carson Richard E. , Huang Yiyun , Ametamey Simon M. 
Published: November 2021

Abstract
PurposeGluN2B containing N-methyl-D-aspartate receptors (NMDARs) play an essential role in neurotransmission and are a potential treatment target for multiple neurological and neurodegenerative diseases, including stroke, Alzheimer’s disease, and Parkinson’s disease. In a previous report (R)-[18F]OF-Me-NB1 was reported to be more specific and selective for targeting the GluN2B subunits of the NMDAR. Here we report a comprehensive evaluation of (R)-[18F]OF-Me-NB1 and (S)-[18F]OF-Me-NB1 in non-human primates.MethodsThe radiosynthesis of (R)-[18F]OF-Me-NB1 and (S)-[18F]OF-Me-NB1 was accomplished as reported previously with minor modifications. PET scans in two rhesus monkeys were conducted on the Focus 220 scanner. Blocking studies were performed after treatment of the animals with the GluN2B antagonist Co101,244 or the sigma-1 receptor antagonist FTC-146. One-tissue (1T) compartment model and multilinear analysis-1 (MA1) method with arterial input function were used to obtain regional volume of distribution (VT, mL/cm3). Occupancy values by the two blockers were obtained by the Lassen plot. Regional non-displaceable binding potential (BPND) was calculated from the corresponding baseline VT and the VND derived from the occupancy plot of the Co101,244 blocking scans. Results(R)- and (S)-[18F]OF-Me-NB1 were produced in >99% radiochemical and enantiomeric purity, with molar activity of 224.22 ± 161.69 MBq/nmol at the end of synthesis (n=10). Metabolism was moderate, with ~30% parent compound remaining for (R)-[18F]OF-Me-NB1 and 20% for (S)-[18F]OF-Me-NB1 at 30 min post injection. Plasma free fraction was 1-2%. In brain regions both (R)- and (S)-[18F]OF-Me-NB1 displayed fast uptake with slower clearance for the (R)- than (S)-enantiomer. For (R)-[18F]OF-Me-NB1, both the 1T model and MA1 method gave reliable estimates of regional VT values, with MA1 VT (mL/cm3) ranging from 8.9 in the cerebellum to 12.8 in the cingulate cortex. Blocking with 0.25 mg/kg of Co101,244 greatly reduced the uptake of (R)-[18F]OF-Me-NB1 across all brain regions, resulting in an occupancy of 77% and VND of 6.36, while 0.027 mg/kg of FTC-146 reduced specific binding by 30%. Regional BPND, as a measure of specific binding signals, ranged from 0.40 in the cerebellum to 1.01 in the cingulate cortex.ConclusionsIn rhesus monkeys, (R)-[18F]OF-Me-NB1 exhibited fast kinetics and heterogeneous uptake across brain regions, while the (S)-enantiomer displayed a narrower dynamic range of uptake across regions. Blocking study with a GluN2B antagonist indicated binding specificity. Value of BPND were >0.5 in most brain regions, suggesting good in vivo specific binding signals. Taken together, results from the current study demonstrated the potential of (R)-[18F]OF-Me-NB1 as a useful radiotracer for imaging the GluN2B receptor.