RT Journal Article
SR Electronic
T1 Evaluation of <sup>11</sup>C-NR2B-SMe and Its Enantiomers as PET Radioligands for Imaging the NR2B Subunit Within the NMDA Receptor Complex in Rats
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 1212
OP 1220
DO 10.2967/jnumed.119.235143
VO 61
IS 8
A1 Cai, Lisheng
A1 Liow, Jeih-San
A1 Morse, Cheryl L.
A1 Telu, Sanjay
A1 Davies, Riley
A1 Frankland, Michael P.
A1 Zoghbi, Sami S.
A1 Cheng, Ken
A1 Hall, Matthew D.
A1 Innis, Robert B.
A1 Pike, Victor W.
YR 2020
UL http://jnm.snmjournals.org/content/61/8/1212.abstract
AB [S-methyl-11C](±)-7-methoxy-3-(4-(4-(methylthio)phenyl)butyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-ol (11C-NR2B-SMe) and its enantiomers 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 displacing 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. 11C-(S)-NR2B-SMe was studied extensively. 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 σ1 antagonists (FTC146, BD1407, F3, F4, and NE100) and 4 σ1 agonists ((+)-pentazocine, (±)-PPCC, PRE-084, and (+)-SKF10047) were ineffective preblocking agents, except FTC146 and F4 at a high dose. Two potent σ1 receptor agonists, TC1 and SA4503, showed dose-dependent preblocking effects in the presence or absence of pharmacologic σ1 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.