Neuroscience is one of the most exciting and important scientific frontiers today, and understanding the molecular chemistry of the brain is essential for unlocking the secrets of basic neurological functions such as motor control, learning, and memory, as well as diagnosing and treating neurodegenerative diseases like Alzheimer's and Parkinson's. We are particularly interested in the bioinorganic chemistry of the brain. The brain requires the highest amounts of copper and iron in the human body for normal function, but levels of these redox-active metals rise with aging, causing uncontrolled disruptions of metal homeostasis that can lead to oxidative damage and aggregation of proteins and subsequent neuronal death. In particular, Alzheimer's and Parkinson's diseases are characterized by protein-derived plaques that accumulate unusually high amounts of abnormally distributed copper and iron compared to normal brain tissue. To study metal balance in various stages of health and disease, we are developing new synthetic sensors and related chemical tools to interrogate, in real time, molecular aspects of cellular metal accumulation, trafficking, and redox function.

In addition to fluorescent reagents, we are developing complementary magnetic resonance imaging (MRI) agents that respond to copper or iron ions by a change in relaxivity. Gadolinium-, manganese-, and iron-based complexes are being explored as high-spin, paramagnetic platforms for fast water exchange.

Chemosensors for Neurotoxic Heavy Metals. Another important facet of brain chemistry is the accumulation of toxic heavy metals. Lead and mercury are particularly dangerous pollutants from the environment that can hinder brain development, memory, and motor functions upon acute or prolonged exposure. Current techniques for heavy metal screening, including atomic absorption or anodic stripping voltammetry, are often limited by their destructive nature, need for expensive and sophisticated instrumentation and/or sample preparation, and ability to measure only total metal content. We are developing selective and sensitive fluorescent chemosensors that can offer simple and rapid tracking of heavy metal ions. A representative example is Mercuryfluor-1 (MF1), a fluorescein-based turn-on sensor for Hg(II) ions in water. MF1 features an unsually large fluorescence increase (>170-fold) upon binding Hg(II), which is a notorious heavy metal quencher. Because of its large dynamic range and Hg(II) selectivity, MF1 can be used to measure safe and toxic levels of mercury in edible fish samples according to the U.S. EPA standard (0.55 ppm) using a simple microwave-based assay. Analogous chemosensors for Pb(II) in water and in living cells are also being pursued. These chemical tools are being used to interrogate mechanisms of heavy metal accumulation and toxicity in biological and environmental samples.