快速特异性荧光探针可视化去甲肾上腺素信号通路及其在癫痫小鼠大脑中的通量,Journal of the American Chemical Society

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快速特异性荧光探针可视化去甲肾上腺素信号通路及其在癫痫小鼠大脑中的通量
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2023-01-26 , DOI: 10.1021/jacs.2c13223
Huming Yan ₁ , Yuting Wang ₁ , Fangjun Huo ₂ , Caixia Yin ₁

Affiliation

去甲肾上腺素 (NE) 在蓝斑中合成，并广泛投射到整个大脑和脊髓。它调节与各种神经系统疾病相关的各种行为和意识。本工作提出了一种“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-(cyclohex-2-en-1-ylidene) 丙二腈衍生物作为荧光团。为了创建双位点探针，将醛基添加到酯基（或苯磺酸盐）的邻位。由于其优异的亲电活性，醛基可以快速“猎杀”氨基，进而形成分子内五元环与β-羟基的亲核反应。五元环中的-NH-“射击”相邻的酯基，释放荧光团并允许快速和特异性检测 NE。在主要 NE 受体药物的作用下，NE 释放和再摄取“催吐”-“吞咽”瞬态过程被捕获和可视化。此外，通过在荧光团中引入卤素来延长吸收波长，提高脂溶性，并适当调整p K _a，探针成功穿透血脑屏障（BBB）。就地采用同步探针成像技术检测癫痫小鼠和正常小鼠脑内NE水平，发现癫痫期间脑内NE异常表达。脑解剖学用于检查癫痫前后各脑区NE的分布和水平变化。该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。

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Fast-Specific Fluorescent Probes to Visualize Norepinephrine Signaling Pathways and Its Flux in the Epileptic Mice Brain

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 ortho 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 via 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 pK_a appropriately, the probe successfully penetrated the blood–brain barrier (BBB). In situ 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.

更新日期：2023-01-26

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