Neuroscience is an exciting and important scientific frontier, and understanding the molecular chemistry of the brain is essential for unlocking the secrets of basic neurological functions such as learning, memory, motor control, and senses, as well as diagnosing and treating neurodegenerative diseases like Alzheimer's and Parkinson's. We focus on studying 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, 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 help elucidate contributions of metal balance to brain function in various stages of health and disease, we are developing and applying new imaging sensors and related chemical tools to interrogate, in real time, molecular aspects of cellular metal accumulation, trafficking, and redox function.

Copper in Neurophysiology and Neurodegenerative Diseases. A distinguishing chemical feature of the brain is its requirement for the highest concentrations of metal ions in the body. We are particularly interested in the neurobiology of copper, as the brain provides a more complex system with its own unique and largely unexplored inorganic physiology compared to simple model bacterial or yeast microbes. In addition, misregulation of intra- and extracellular copper pools are connected to neurodegenerative disorders, including Alzheimer's, Menkes, and ALS. We are developing new chemical tools and tactics to track labile, tightly-bound, and total copper pools and their dynamic changes during situations of synaptic activity, neuron or neural stem cell development, injury, or disease. Coppersensor-1 (CS1) is a representative fluorescent sensor that can be used to image labile Cu(I) stores in living cells, including primary neurons. From this starting point, we are currently exploring the application of CS1 to live-cell molecular imaging in a variety of cellular and tissue applications, as well as exploiting the tunability of various fluorophore scaffold to create new CS analogs with improved turn-on responses, redox specificity for Cu(I) or Cu(II), a range of excitation/emission profiles, varying Kd values, and targetability to specific subcellular locations.

In addition to fluorescent indicators, we are developing complementary magnetic resonance imaging (MRI) agents that respond to copper ions by a change in relaxivity. Gadolinium-, manganese-, and iron-based complexes are being explored as high-spin, paramagnetic platforms for fast water exchange. Copper-Gad-1 (CG1) is a first-generation MRI sensor for Cu(II) ions. Newer CG molecules are being developed for Cu(I) detection. Finally, analogous sensors for studying iron in brain systems by molecular imaging are also being pursued.

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. Representative turn-on sensors for Hg(II) ions in water, cells, and tissue are Mercuryfluor-1 (MF1) and Mercury Green-1 (MG1), and Leadfluor-1 (LF1) is a first-generation probe for turn-on detection of Pb(II) ions in cellular systems. These chemical tools are being used to interrogate mechanisms of heavy metal accumulation and toxicity in biological and environmental samples. One example is the use of MF1 and MG1 for measuring 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.