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

被引:12
作者
Cai, Lisheng [1 ]
Liow, Jeih-San [1 ]
Morse, Cheryl L. [1 ]
Telu, Sanjay [1 ]
Davies, Riley [1 ]
Frankland, Michael P. [1 ]
Zoghbi, Sami S. [1 ]
Cheng, Ken [2 ]
Hall, Matthew D. [2 ]
Innis, Robert B. [1 ]
Pike, Victor W. [1 ]
机构
[1] NIMH, Mol Imaging Branch, NIH, 10 Ctr Dr,Bldg 10,Room B3 C346, Bethesda, MD 20892 USA
[2] NIH, NCATS Chem Genom Ctr, Rockville, MD USA
基金
美国国家卫生研究院;
关键词
NR2B subunit; NMDA receptor; GluN2B; sigma; 1; NR2B-SMe; D-ASPARTATE RECEPTORS; N-METHYL; SIGMA-RECEPTORS; LIGANDS; BINDING; IFENPRODIL; ELIPRODIL; BRAIN; DRUG; DERIVATIVES;
D O I
10.2967/jnumed.119.235143
中图分类号
R8 [特种医学]; R445 [影像诊断学];
学科分类号
1002 ; 100207 ; 1009 ;
摘要
[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.
引用
收藏
页码:1212 / 1220
页数:9
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