Real time imaging of immune cells and glutamate dynamics by PET and metabolic MRI

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ABSTRACT Activation of immune cells plays a critical role in initiation and progression of multiple sclerosis (MS), leading to progressive neurodegeneration of the central nervous system (CNS). While glutamate imbalance has been described in MS brains and has been proposed to contribute to axonal damage and tissue destruction, the relationships between glutamate dynamics and immune activation during disease progression remain unclear. Presently, the lack of clinically available noninvasive imaging methods to detect immune cells and glutamate metabolism limits our understanding of MS pathogenesis and monitoring of responses to therapies. Recent development of radiotracers for positron emission tomography (PET) have shown great potential for detection of cells from the immune system and for imaging glutamate reuptake by astroglial excitatory amino acid transporter-2 (EAAT2). Specifically, 2'-deoxy-2'-[18F]fluoro-9-β-D-arabinofuranosylguanine ([18F]F-AraG) enables the detection of activated T-cells in inflammatory diseases and cancer models. [18F]Fluoro- fluorenylaspartyl amide ([18F]FFAA) has demonstrated the ability to measure EAAT2 activity in the CNS. Hyperpolarized 13C magnetic resonance spectroscopic imaging (HP 13C MRSI) is an emerging imaging technique which measures enzymatic reactions in vivo in real-time. HP 13C pyruvate has been shown to detect highly glycolytic cells from the innate immune system in peripheral and CNS inflammation models. Recently, pyruvate labelled on the second carbon position, [2-13C]pyruvate, provided a new way to monitor glutamate production in the human brain. This project proposes to validate these innovative noninvasive PET and MR methods to provide a new way to investigate the relationships between innate and adaptive immune responses and glutamate dynamics in preclinical MS models. The mentored phase of this project will develop and validate new neuroimaging technologies: Aim 1 will investigate the potential of [18F]F-AraG and [18F]FFAA PET imaging to visualize activated T-cells and glutamate reuptake during disease progression. Aim 2 will develop and validate HP [2-13C]pyruvate as a method to simultaneously detect pro-inflammatory innate immune cells and determine real-time brain glutamate production. The independent phase of this project will build on these initial results and Aim 3 will evaluate the potential of this multimodal PET and MRI approach to monitor immune responses, glutamate production, and astrocyte functions following therapy. Central to the success of this proposal, Dr. Guglielmetti will have the support and guidance from an established group of experts in neuroimaging, particularly HP 13C MR technology (Dr. Myriam Chaumeil and Dr. Peder Larson) and PET imaging (Dr. Henry VanBrocklin) as well as in neuroimmunology and MS (Dr. Ari Green and Dr. Zamvil), providing her with the necessary skillsets to embark on a career as an independent scientist.