Sub-100 ms Level Ultrafast Detection and Near-Infrared Ratiometric Fluorescence Imaging of Norepinephrine in Live Neurons and Brains

Norepinephrine (NE) is a key neurotransmitter in the central and sympathetic nervous systems, whose content fluctuates dynamically and rapidly in various brain regions during different physiological and pathophysiological processes. However, it remains a great challenge to directly visualize and precisely quantify the transient NE dynamics in living systems with high accuracy, specificity, sensitivity, and, in particular, high temporal resolution. Herein, we developed a series of small-molecular probes that can specifically detect NE through a sequential nucleophilic substitution–cyclization reaction, accompanied by a ratiometric near-infrared fluorescence response, within an impressively short time down to 60 ms, which is 3 orders of magnitude faster than that of present small-molecular probes. A unique water-promoted intermolecular proton transfer mechanism is disclosed, which dramatically boosted the recognition kinetics by ∼680 times. Benefiting from these excellent features, we quantitatively imaged the transient endogenous NE dynamics under external stimuli at the single living neuron level and further revealed the close correlations between NE fluctuations and Parkinson’s disease pathology at the level of acute brain slices and live mouse brains in vivo.