A Dual-Modal NIR-FLIM Probe for Hypothalamic Norepinephrine Imaging in Neurogenic Hypertension.

Hypothalamic norepinephrine (NE) dysregulation drives hypertensive pathogenesis, yet lacks precise in vivo quantitative monitoring tools. We engineered CyQs probes integrating near-infrared (NIR) intensity and fluorescence lifetime imaging (FLIM) for spatiotemporal NE tracking. CyQ-2 employs a hemicyanine scaffold conjugated to an S-phenyl carbonate moiety, enabling 16-fold fluorescence turn-on, 0.21 μM detection limit, and 0.8 ns lifetime extension upon NE-specific activation via nucleophilic cyclization. CyQ-2 mapped endogenous NE dynamics in PC12 cells and the K+-evoked neurotransmitter release. In the hypertensive mouse model, FLIM quantified hypothalamic NE elevation, correlating with 74% aortic wall thickening. Critically, Angiotensin II type 1 receptor (AT1R) blockade (irbesartan, IRB) normalized NE levels and reversed vasculopathy. This work establishes a molecular platform linking hypothalamic NE dynamics to vascular pathology, enabling the mechanistic dissection of neurogenic hypertension and the quantitative evaluation of neuromodulation therapies.