Evaluation of 11C-NR2B-SMe and Its Enantiomers as PET Radioligands for Imaging the NR2B Subunit Within the NMDA Receptor Complex in Rats

[S-methyl-11C](+/-)-7-methoxy-3-(4-(4-(methylthio)phenyl)butyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-ol (C-11-NR2B-SMe) and its enantio-mers were synthesized as candidates for imaging the NR2B subunit within the N-methyl-D-aspartate receptor with PET. Methods: Brains were scanned with PET for 90 min after intravenous injection of one of the candidate radioligands into rats. To detect any NR2B-specific binding of radioligand in brain, various preblocking or dis-placing agents were evaluated for their impact on the PET brain imaging data. Radiometabolites from brain and other tissues were measured ex vivo and in vitro. Results: Each radioligand gave high early whole-brain uptake of radioactivity, followed by a brief fast decline and then a slow final decline. C-11-(S)-NR2B-SMe was studied exten-sively. Ex vivo measurements showed that radioactivity in rat brain at 30 min after radioligand injection was virtually unchanged radioligand. Only less lipophilic radiometabolites appeared in plasma. High-affinity NR2B ligands, Ro-25-6981, ifenprodil, and CO101244, showed increasing preblocking of whole-brain radioactivity retention with increasing dose (0.01-3.00 mg/kg, intravenously). Five sigma 1 antagonists (FTC146, BD1407, F3, F4, and NE100) and 4 sigma 1 agonists ((+)-pentazocine, (+/-)-PPCC, PRE-084, and (+)-SKF10047) were ineffective preblock-ing agents, except FTC146 and F4 at a high dose. Two potent sigma 1 receptor agonists, TC1 and SA4503, showed dose-dependent pre -blocking effects in the presence or absence of pharmacologic sigma 1 receptor blockade with FTC146. Conclusion: 11C-(S)-NR2B-SMe has adequate NR2B-specific PET signal in rat brain to warrant further evaluation in higher species. TC1 and SA4503 likely have off -target binding to NR2B in vivo.