7-N-（PROXYL-3-基甲基）茶碱作为血脑屏障通透性探针的合成与评价

Synthesis and Evaluation as a Blood-Brain Barrier-Permeable Probe of 7-N-(PROXYL-3-yl-methyl)theophylline.

作者信息

Emoto Miho C, Sasaki Kota, Maeda Koya, Fujii Hirotada G, Sato Shingo

机构信息

Center for Medical Education, Sapporo Medical University.

Department of Biochemical Engineering, Graduate School of Science and Engineering, Yamagata University.

出版信息

Chem Pharm Bull (Tokyo). 2018;66(9):887-891. doi: 10.1248/cpb.c18-00333.

DOI:10.1248/cpb.c18-00333

PMID:30175747

Abstract

The drug-nitroxide radical hybrid-compound 7-N-((2,2,5,5-tetramethylpyrrolidine-1-yloxy(PROXYL))-3-yl-methyl)theophylline (3) was synthesized by coupling 7-N-tosyltheophylline with 3-hydroxymethyl-PROXYL, HMP). The stability of 3 relative to that of HMP was examined in the presence of the anti-oxidant, ascorbic acid (AsA). The initial reduction rate constants of 3 and HMP were 11.9±5.3 and 6.1±5.2 M min, respectively. In the presence of glutathione (GSH), these constants increased slightly to 22.3±6.8 and 9.1±2.4 M min, respectively. Two-dimensional cranial electron paramagnetic resonance imaging of mice intravenously injected with 3 via the tail vein revealed that probe 3 enters the mouse brain by passing through the blood-brain barrier (BBB).

摘要

药物 - 氮氧化物自由基杂化化合物7 - N - （（2,2,5,5 - 四甲基吡咯烷 - 1 - 氧基（PROXYL）） - 3 - 基 - 甲基）茶碱（3）是通过将7 - N - 甲苯磺酰基茶碱与3 - 羟甲基 - PROXYL（HMP）偶联合成的。在抗氧化剂抗坏血酸（AsA）存在下，研究了3相对于HMP的稳定性。3和HMP的初始还原速率常数分别为11.9±5.3和6.1±5.2 M·min⁻¹。在谷胱甘肽（GSH）存在下，这些常数分别略有增加至22.3±6.8和9.1±2.4 M·min⁻¹。通过尾静脉向小鼠静脉注射3后进行的二维颅骨电子顺磁共振成像显示，探针3穿过血脑屏障（BBB）进入小鼠大脑。