Yan Huming, Wang Yuting, Huo Fangjun, Yin Caixia
Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Key Laboratory of Materials for Energy Conversion and Storage of Shanxi Province, Institute of Molecular Science, Shanxi University, Taiyuan, Shanxi 030006, China.
Research Institute of Applied Chemistry, Shanxi University, Taiyuan, Shanxi 030006, China.
J Am Chem Soc. 2023 Feb 8;145(5):3229-3237. doi: 10.1021/jacs.2c13223. Epub 2023 Jan 26.
Norepinephrine (NE) is synthesized in the locus coeruleus and widely projected throughout the brain and spinal cord. It regulates various actions and consciousness linked to a variety of neurological diseases. A "hunting-shooting" strategy was proposed in this work to improve the specificity and response rate of an NE fluorescent probe: 2-(cyclohex-2-en-1-ylidene)malononitrile derivatives were chosen as a fluorophore. To create a dual-site probe, an aldehyde group was added to the of the ester group (or benzene sulfonate). Because of its excellent electrophilic activity, the aldehyde group could rapidly "hunt" the amino group and then form an intramolecular five-membered ring the nucleophilic reaction with the β-hydroxyl group. The -NH- in the five-membered ring "shoots" the adjacent ester group, releasing the fluorophore and allowing for rapid and specific NE detection. The NE release and reuptake ″emetic″-″swallow″ transient process is captured and visualized under the action of the primary NE receptor drug. Furthermore, by introducing halogen into the fluorophore to lengthen the absorption wavelength, improve lipid solubility, and adjust the p appropriately, the probe successfully penetrated the blood-brain barrier (BBB). synchronous probe imaging was used to detect the NE level in the brains of epileptic and normal mice, and abnormal expression of NE in the brain was discovered during epilepsy. Brain anatomy was used to examine the distribution and level changes of NE in various brain regions before and after epilepsy. This research provides useful tools and a theoretical foundation for diagnosing and treating central nervous system diseases early.
去甲肾上腺素（NE）在蓝斑核中合成，并广泛投射至整个大脑和脊髓。它调节与多种神经系统疾病相关的各种行为和意识。本研究提出了一种“狩猎-射击”策略来提高NE荧光探针的特异性和响应率：选择2-(环己-2-烯-1-亚基)丙二腈衍生物作为荧光团。为了构建双位点探针，在酯基（或苯磺酸盐）的 处添加醛基。由于醛基具有优异的亲电活性，它可以迅速“捕获”氨基，然后通过与β-羟基的亲核反应形成分子内五元环。五元环中的-NH-“射击”相邻的酯基，释放荧光团，从而实现对NE的快速特异性检测。在主要NE受体药物的作用下，捕获并可视化了NE释放和再摄取的“呕吐”-“吞咽”瞬态过程。此外，通过在荧光团中引入卤素以延长吸收波长、提高脂溶性并适当调节p，该探针成功穿透了血脑屏障（BBB）。采用同步探针成像检测癫痫小鼠和正常小鼠大脑中的NE水平，发现癫痫发作时大脑中NE表达异常。利用脑解剖学研究癫痫前后不同脑区NE的分布和水平变化。本研究为早期诊断和治疗中枢神经系统疾病提供了有用的工具和理论基础。 （注：原文中部分位置有缺失信息，用“ ”表示）
