CHEMISTRY and NEUROSCIENCE

We use organic synthesis and molecular design to address exciting problems in neuroscience and brain medicine. The main theme in our research group is to develop new methods for both the imaging and repair of synapses in the brain. We use the entire spectrum of molecular space (small organic molecules, proteins, polymers, nanomaterials), develop in vitro and in vivo assays, and partner with neurobiologists, neuropharmacologists, and clinicians to take on a range of projects.
Organic Synthesis
Organic synthesis is one of the core lines of expertise in our group. We have formulated and documented the key concepts of C-H bond functionalization as a new and general approach to chemical assembly of complex organic compounds and materials (¡°C-H bonds as ubiquitous functionality¡±) and developed a number of new chemical transformations. We also formulated the two major consequences of C-H bond functionalization: 1) Novel strategic opportunities for construction of carbon skeletons, and 2) Complex core diversification or late stage functionalization, both now widely pursued in both academia and industry. We apply this approach to the design and synthesis of imaging agents, biological probes, and experimental therapeutics (see Synaptic Imaging, Chemical Biology, and Experimental Therapeutics). We also develop new reactions in the context of specific projects (e.g., synthesis of brain receptor modulators or direct chemical synthesis of drug metabolites via C-H bond oxidation). We draw inspiration from complex natural products, leads identified via high throughput screening of diverse chemical libraries, and exciting nanomaterials (as sensors or delivery vehicles).

For representative examples see:

Science 2006

JACS 2011

JACS 2013

Synaptic Imaging
We have developed a new class of imaging agents (in collaboration with Prof. David Sulzer, Departments of Psychiatry, Neurology and Pharmacology) termed ¡°Fluorescent False Neurotransmitters¡± (FFNs) that act as fluorescent tracers of neurotransmitters. FFNs provide the first means for optical imaging (via multiphoton microscopy) of neurotransmitter release at discreet presynaptic terminals in the brain. We are developing both ex vivo and in vivo imaging methods in rodents, and study the synaptic release properties of our imaging agents in both normal and pathological states. We are also interested in using FFNs and other imaging probes to provide the ability to study the effects of pharmacological agents on synaptic activity. This work spans a wide range of approaches including organic synthesis, molecular design, viral delivery of sensors, optogenetics, and in vivo microscopy. We are developing a number of experimental platforms for discovery and development of novel imaging probes. We aim to develop chemical imaging agents and biomarker probes that may enable imaging in different modalities (e.g., optical, PET) and that may also be applicable to humans.

For representative examples see:

Science 2009, PNAS 2012, and

JACS 2010

ACS Chem. Neurosci. 2013

Chemical Biology and Experimental Therapeutics
We study natural products with interesting neurobiological activities. In this context we develop robust synthetic approaches to enable not only the synthesis of the natural products themselves but also complete mapping of the structural space of these compounds. We then study their receptor modulation and signaling activity in living cells (transfected cell lines, primary neurons), animal disease models and develop the required quantitative assays (e.g. for quantitation of kinase signaling pathways). We also study drugs with established clinical efficacy but unknown molecular mechanisms. We are particularly interested in chemical entities that can stimulate synaptic and or circuit repair, neuro- and synaptogenesis. The important central idea is to enable both the repair and imaging of synaptic function in the brain.

For representative examples see:

JBC 2014 and

Translational Psychiatry 2014