Mapping of choline uptake and metabolism in brain tumors with deuterium metabolic imaging (DMI)

项目摘要 虽然神经肿瘤学家严重依赖医学成像，特别是磁共振成像（MRI）， 检测和脑肿瘤的大小，他们没有获得一个强大的方法，显示积极的 肿瘤病变的代谢。放射性葡萄糖类似物的正电子发射断层扫描（PET）检测 18F-脱氧葡萄糖（FDG）广泛用于脑外许多实体癌的代谢成像。脱氧葡萄糖- PET检测高葡萄糖摄取，这通常是活跃和生长组织的标志，例如在增殖中。 肿瘤的然而，当用于扫描脑中的肿瘤时，FDG-PET已显示出通常是不确定的。 这不是由于任何技术限制，而仅仅是正常人高葡萄糖摄取的结果。 这导致高背景信号，从而导致脑和肿瘤之间的低代谢图像对比度。 胆碱是一种必需的营养素，增殖细胞需要胆碱来提供磷脂和膜 合成.因此，许多类型的癌症已经进化为具有高胆碱摄取能力， 新陈代谢.相比之下，正常大脑中的胆碱摄取相对非常低。我们的初步数据显示 使用氘代谢新技术检测氘代胆碱的摄取和代谢， 成像（MRI）可以提供与周围脑的高脑肿瘤特异性图像对比度。氘的同位素 （2 H）-标记的胆碱允许检测胆碱摄取和/或胆碱代谢，简单地通过改变时间 扫描与胆碱给药开始的关系。这些特点使得胆碱酯酶很有前途 代谢成像技术用于脑肿瘤。 总的目标是研究胆碱酯酶作为脑代谢成像方法的潜力， 癌在这个R 03研究项目中，我们建议调查胆碱摄取的映射价值， 代谢与脑肿瘤分级及预后相关（目的1），评价治疗效果 (Aim 2）。我们将使用两种已建立的3级脑肿瘤和4级神经胶质瘤小鼠模型，并测试 替莫唑胺，化疗标准治疗，对肿瘤胆碱摄取和代谢的影响。 胆碱是一种必需的营养素，在临床环境内外用作营养补充剂， 剂量很高但很安全氘是一种稳定的同位素，通常用作代谢研究的示踪剂。 最后，MRI是一种高度可转换的成像技术，已经应用于临床研究环境。因此如果 在这些啮齿动物模型中建立了胆碱摄取和代谢绘图的潜力， 用于检测人类患者中的氘标记胆碱的翻译相对简单。

PROJECT SUMMARY While neuro-oncologists rely heavily on medical imaging, particularly magnetic resonance imaging (MRI) for detection and sizing of brain tumors, they do not have access to a robust method that shows the active metabolism of tumor lesions. Positron emission tomography (PET) detection of the radioactive glucose analog 18F-deoxyglucose (FDG) is widely used for metabolic imaging of many solid cancers outside of the brain. FDG- PET detects high glucose uptake, which is often a sign of active and growing tissue, such as in proliferating tumors. However, when used for scanning tumors in the brain FDG-PET has shown to be often inconclusive. This is not due to any technical limitation, but merely the consequence of the high glucose uptake of normal brain, leading to high background signal and thus low metabolic image contrast between brain and tumor. Choline is an essential nutrient, and proliferating cells need choline for phospholipid and membrane synthesis. As a result, many types of cancer have evolved with a high capacity for choline uptake and metabolism. In contrast, choline uptake in normal brain is in comparison very low. Our preliminary data indicate that the detection of deuterated choline uptake and metabolism using the novel technique Deuterium Metabolic Imaging (DMI) can provide high brain tumor-specific image contrast with surrounding brain. DMI of deuterium (2H)-labeled choline allows detection of choline uptake and/or choline metabolism, simply by varying the timing of the scan in relation to the start of the choline administration. These features make choline DMI a very promising metabolic imaging technique for use in brain tumors. The overall objective is to investigate the potential of choline DMI as a metabolic imaging method for brain cancer. In this R03 research project we propose to investigate the value of mapping choline uptake and metabolism with DMI as correlate for brain tumor grade and prognosis (Aim 1), and evaluating treatment effect (Aim 2). We will use two established mouse models of brain tumor grade 3, and grade 4 glioma, and test the effect of temozolomide, the standard of care chemotherapeutic, on tumor choline uptake and metabolism. Choline is an essential nutrient and used as a nutritional supplement within and outside of clinical settings, at very high but safe doses. Deuterium is a stable isotope and commonly used as a tracer for metabolic studies. Finally, DMI is a highly translatable imaging technique, already applied in clinical research settings. Therefore, if the potential of mapping of choline uptake and metabolism is established in these rodent models, rapid translation of DMI for detection of deuterium-labeled choline in human patients is relatively straightforward.