UCLA

Positron emission tomography (PET) is an imaging modality that is capable of 3-dimmensional images where radiolabeled molecules are taken up in the body through absorption, biodistributed in vivo, and metabolized. Bioactive molecules with a specific affinity towards pathways or targets of interest can be radiolabeled and visualized. The PET tracer 4-[18F]Fluorobenzyl-triphenylphosphonium ([18F]FBnTP) is capable of targeting the mitochondria membrane potential (ΔΨm) due to its cationic and lipophilic properties. The three pot, four step radiochemical synthesis of [18F]FBnTP was successfully developed using the automated radiosynthesizer ELIXYS, which allowed for a multidose synthesis. The [18F]FBnTP PET tracer was then used for the in vivo imaging of non-small cell lung cancer (NSCLC) in disease model mice. This allowed for the profiling of the mitochondrial membrane potential in autochthondous mouse models of lung cancer and find distinct functional mitochondrial heterogeneity for subtypes of lung tumors. The second area of research included developing a drug analogue containing a 4-(nitrophenylsulfonyl) piperazine backbone, since this class of compounds has been shown to have the ability to decrease murine mortality in hematopoietic acute radiation syndrome (hARS) for the mitigation of radiation damage. The synthesis and characterization, and pharmacokinetics was performed for 52A1, which successfully showed to mitigate radiation damage in vivo. The third area of research included the inhibition of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) by ambient electrophiles. GAPDH is an important enzyme for energy metabolism as well as cell proliferation and tumorigenesis. However, upon exposure to ambient pollutants that are produced from incomplete combustion, they can react with the cysteine sites on proteins. The chemical properties of these pollutants make them inherently electrophiles, wherein the cysteine sites are nucleophilic in biological conditions. The cysteine modification then reacts via the Michael Addition, which is an irreversible chemical modification. It was found that when exposed to ambient electrophiles, the Cys 152 and Cys 247 residues of the Human GAPDH were chemically modified, which lead to inhibition and reduced catalytic activity. The quantification and localization of the ambient electrophile modification on GAPDH were determined using intact protein analysis, catalytic activity studies, and bottom-up proteomics approaches.