Imaging innate and adaptive immune response in MS using using [18F]F-AraG PET and hyperpolarized 13C MRSI

摘要 免疫细胞的活化是神经退行性疾病的起始和进展中的关键过程， 尤其是多发性硬化症（MS）。目前，还没有非侵入性成像方法， 在临床环境中检测激活的免疫细胞和神经炎症。 用于正电子发射断层扫描（PET）的放射性示踪剂的最新发展已经显示出用于正电子发射断层扫描（PET）的巨大潜力。 从适应性免疫系统中检测细胞。具体地，2 '-脱氧-2'-[18F]氟-9-β-D- 阿拉伯呋喃糖基鸟嘌呤（[18F]F-AraG）已显示能够检测活化的原代T细胞， 移植物抗宿主病同时，超极化13 C磁共振波谱成像（HP 13 C MRSI）作为一种新的代谢MR方法正在出现，以实时监测体内酶反应。HP 已证明[1- 13 C]丙酮酸盐对来自先天免疫的高度糖酵解促炎细胞敏感 在外周炎症、MS和创伤性脑损伤的动物模型中， 重要的是，[18F]F-AraG和HP [1- 13 C]丙酮酸盐在首次人体研究中显示出很大的前景， 癌 在这个项目中，我们建议研究HP [1- 13 C]丙酮酸和[18 F]F-AraG PET成像的潜力， 非侵入性评估脑损伤阶段，并监测对免疫调节治疗的反应， MS的鼠模型。 为此，将在疾病诱导期间的关键时间点进行HP 13 C MRSI和PET成像检查 和进步。接下来，HP [1- 13 C]丙酮酸盐和[18 F]F-AraG将用于评价来自以下患者的治疗反应： 两种临床相关的MS常用处方药，富马酸二甲酯和芬戈莫德。PET和MRI 将使用示踪剂生物分布和免疫组织病理学标记物的离体相关性来证实这些发现 用于炎症和病变表征。 因为HP [1- 13 C]丙酮酸和[18 F]F-AraG PET可容易地用于临床转化，所以药物和药物组合物可用于治疗。 成像结果，该项目的结果将确定临床相关的生物标志物， 诊断、预后和治疗信息，以更好地为MS患者提供精准医疗。 在临床转化后，这些方法可以帮助改进治疗方案，并导致更好的临床效果。 结果和患者生活质量。

ABSTRACT Activation of immune cells is a key process in the initiation and progression of neurodegenerative diseases, particularly multiple sclerosis (MS). Presently, there is no non-invasive imaging method that can specifically detect activated immune cells and neuroinflammation in clinical settings. Recent development of radiotracers for positron emission tomography (PET) have shown great potential for the detection of cells from the adaptive immune system. Specifically, 2'-deoxy-2'-[18F]fluoro-9-β-D- arabinofuranosylguanine ([18F]F-AraG) has been shown to enable the detection of activated primary T-cells in graft-versus-host disease. At the same time, hyperpolarized 13C magnetic resonance spectroscopic imaging (HP 13C MRSI) is emerging as a new metabolic MR method to monitor enzymatic reactions in vivo in real-time. HP [1-13C] pyruvate has proven to be sensitive to highly glycolytic pro-inflammatory cells from the innate immune system (i.e. Macrophages) in animal models of peripheral inflammation, MS and traumatic brain injury. Importantly, both [18F]F-AraG and HP [1-13C] pyruvate have shown great promise in first-in-human studies of cancer. In this project, we propose to investigate the potential of HP [1-13C] pyruvate and [18F]F-AraG PET imaging to non-invasively assess cerebral lesion stage and to monitor response to immunomodulatory therapies in a novel murine model for MS. To do so, HP 13C MRSI and PET imaging sessions will be performed at key time points during disease induction and progression. Next, HP [1-13C] pyruvate and [18F]F-AraG will be used to evaluate treatment response from two clinically relevant and commonly prescribed drugs for MS, Dimethyl-fumarate and Fingolimod. PET and MRI findings will be confirmed using ex vivo correlates of tracer biodistribution and immuno-histopathological markers for inflammation and lesion characterization. Because HP [1-13C] pyruvate and [18F]F-AraG PET are readily available for clinical translation, drugs and the imaging findings, outcomes from this project will identify clinically relevant biomarkers that could provide diagnostic, prognostic and therapeutic information to better achieve precision medicine for patients with MS. Upon clinical translation, such methods could help refine therapeutic regimens and lead to better clinical outcomes and patient quality of life.