Developing Hyperpolarized Nitrogen-15 MRI Agents for Probing Glutamine Metabolism

TITLE: Developing Hyperpolarized Nitrogen-15 MRI Agents for Probing Glutamine Metabolism PROJECT SUMMARY/ABSTRACT Glutamine is the most abundant free amino acid in the body. Glutamine has a versatile role in cell metabolism, participating in tricarboxylic acid (TCA) cycle supplementation and the biosynthesis of nucleotides, glutathione (GSH), and other nonessential amino acids. It is increasingly recognized that quantification of glutamine metabolism is abnormal in multiple diseases including cancer, diabetes, and neurodegeneration. Glutamine deprivation suppresses cancer growth and even induces cell death in several cancers. Various cancers develop glutamine dependence and addiction to maintain continuous growth, survival, invasion, metastasis, and resistance to cancer treatments. Imaging agents for effectively monitoring the stepwise metabolic process of glutamine in vivo will have significant impacts for a better understanding of glutaminolysis and their contribution to cancers. Our long-term goal is to develop hyperpolarized 15N-MRI probes for abnormal metabolism for diagnosis and treatment of diseases. The objective of this proposal is to develop nitrogen-15 (15N)-labeled probes that are capable of monitoring the stepwise process of glutamine metabolism by hyperpolarized (HP) magnetic resonance spectroscopy and imaging (MRS/MRI). Toward this goal, we will design, synthesize, and optimize novel 15N-labelled probes, with Aim 1 targeting the conversion of glutamine to glutamate by glutaminase and Aim 2 targeting the glutamine-derived production of alpha-ketoglutarate and 2-hydroxyglutarate. These 15N- labelled probes will be evaluated on their potentials as effective imaging agents to deliver long-lived hyperpolarized 15N NMR signals for sensitive and specific detection of the targeted metabolic step. Overall impacts of this R21 grant are two-fold. First, the developed HP 15N-MRI agents will advance the ability of imaging glutamine in vivo, convey more accurate and comprehensive information of abnormal glutaminolysis, and offer new metabolic biomarkers for cancers. Second, the successful in vivo imaging by 15N-tagged HP-MRI probe will unbridle 15N-MRI agents from traditional limitations restricted to 15N-isotope labeled nitrogen atoms in heteroarenes and peralkylatedamines, to achieve much greater potentials and broader applications in basic biomedical and translational research.