Central Nervous System (CNS) disorders such as schizophrenia, Alzheimer’s, and Huntington’s disease, among others, affect a large portion of the population. Although therapeutics do exist for some disorders, there are many unmet medical needs for patients. To rationally pursue novel and effective therapeutics, the underlying biological mechanisms of the disorders must be understood. Recent evidence indicates that a loss of neurons and microglia activation due to dysregulated synaptic pruning and neuroinflamation are common features of CNS disorders. Our goal is to design a covalent Positron Emission Tomography (PET) radiotracer to image microglia-dependent neuroinflammation. A PET tracer would potentially allow to diagnose disease state, follow disease progression, and help define ideal patient groups for clinical trials. Cyclooxygenase 2 (COX-2) is highly upregulated during inflammation and may constitute an ideal biomarker. Our design for potential novel tracers is based on Aspirin, a covalent but non-selective inhibitor of COX-2, and Coxibs, that are non-covalent but highly selective COX-2 inhibitors. Based on docking studies, we have designed hybrid compounds as potential covalent COX-2 selective ligands. Synthesis of these compounds was accomplished via various organic chemistry techniques, which were characterized using Nuclear Magnetic Resonance (NMR) and Liquid Chromatography Mass Spectrometry (LCMS). We will present the design and synthesis of these hybrid compounds. The next steps are to test the biological activity of these compounds, and discuss their potential as a COX-2 selective PET tracer. Additionally, these new COX-2 ligands could serve as probe compounds in order to better understand the role of neuorinflammation in development and disease.
PROJECT: Development of a covalent COX-2 PET Tracer for imaging microglia-dependent neuroinflammation in Central Nervous System disorders
What makes the BSRP program is so great is its focus on our growth and development, as scientists but also as people. Yes, I’ve done amazing research this summer and the experience further fostered my love for medicinal chemistry, but the strong emphasis on mentorship and meaningful interactions with Broad scientists allowed me to learn so much more about myself and being a scientist. I am so thankful for the unforgettable nine weeks I spent here.