Coumarin Aldehyde Chemosensors for Selective Recognition of Neurotransmitters

We present a series of fluorescent sensors based on the coumarin-3-aldehyde scaffold intended to sense primary amine neurotransmitters. Discussed are the major design considerations, syntheses, initial UV/Vis and fluorescence titrations, and fluorescence microscopy studies in living cells. NeuroSensor 521 was developed as a turn-on molecular sensor for norepinephrine and dopamine. It was designed to bind with lower affinity in order to monitor dynamic changes in neurotransmitter concentrations and was validated in both live and fixed cells. The sensor selectively bound to norepinephrine- over epinephrine-containing chromaffin cells producing prominent punctate fluorescence which is indicative of uptake into secretory granules. We later synthesized 17 benzene- and thiophene-based derivatives which differed only at the coumarin C4-substituent. The substituents modulated the fluorescence of the fluorophore by changing the EHOMO levels and thereby the ability of various analytes to quench the fluorescence by photoinduced electron transfer (PET). A thorough computational analysis was bolstered by experimental fluorescence titrations. Lastly, a near-infrared (NIR) sensor was developed for the turn-on fluorescent sensing of serotonin, a known fluorescence-quenching analyte. The electron-rich sensor gave a fluorescence increase at 710 nm upon titration with serotonin.