Small-Molecule Fluorescent Sensors for Investigating Zinc Metalloneurochemistry

The metalloneurochemistry of Zn(II) is of substantial current interest. Zinc is the second most abundant d-block metal ion in the human brain, and its distribution varies with relatively high concentrations found in the hippocampus. Brain zinc is generally divided into two types, protein-bound and loosely bound, the latter also being termed histochemically observable, chelatable, labile, or mobile zinc. The neurophysiological and neuropathological significance of mobile Zn(II) remains enigmatic. Studies of Zn(II) distribution, translocation, and function in vivo require tools for its detection. Because Zn(II) has a closed-shell d(10) configuration and no convenient spectroscopic signature, fluorescence is a well-suited method for monitoring Zn(II) in biological contexts. This Account summarizes work by our laboratory addressing the design, preparation, characterization, and use of small-molecule fluorescent sensors for imaging Zn(II) in living cells and samples of brain tissue. These sensors provide "turn-on" or ratiometric Zn(II) detection in aqueous solution at neutral pH. By making alterations to the Zn(II)-binding unit and fluorophore platform, we have devised sensors with varied photophysical and metal-binding properties. Several of these probes have been applied to image Zn(II) distribution, uptake, and mobilization in a variety of cell types, including neuronal cultures.