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

项目总结 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) 脑肿瘤的检测和大小，他们无法获得一种稳健的方法，显示活跃的 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)被广泛用于脑外许多实体肿瘤的代谢成像。FDG- PET检测到高葡萄糖摄取，这通常是活跃和生长的组织的迹象，例如在增殖过程中 肿瘤。然而，当用于扫描脑肿瘤时，FDG-PET往往是不确定的。 这不是由于任何技术限制，而仅仅是正常的高葡萄糖摄取率的结果。 大脑，导致高背景信号，从而降低了脑和肿瘤之间的代谢图像对比度。 胆碱是一种必需的营养物质，而增殖细胞需要胆碱来形成磷脂和细胞膜 综合。因此，许多类型的癌症都进化成具有高胆碱摄取能力和 新陈代谢。相比之下，正常大脑的胆碱摄取量相对较低。我们的初步数据显示 用氢代谢新技术检测去氢胆碱的摄取和代谢 成像(DMI)可以提供高的脑肿瘤特异性图像与周围脑的对比度。重氢的DMI (2H)标记的胆碱可以简单地通过改变时间来检测胆碱摄取和/或胆碱代谢 与胆碱注射开始有关的扫描结果。这些特征使胆碱DMI成为一种非常有前途的 用于脑肿瘤的代谢成像技术。 总体目标是研究胆碱DMI作为脑代谢成像方法的潜力。 癌症。在这项R03研究项目中，我们建议调查标测胆碱摄取和 以DMI为指标的代谢与脑肿瘤分级和预后的相关性(目标1)，并评价治疗效果 (目标2)。我们将使用两个已建立的脑肿瘤3级和4级胶质瘤小鼠模型，并测试 化疗标准替莫唑胺对肿瘤胆碱摄取和代谢的影响。 胆碱是一种基本的营养素，在临床环境内外用作营养补充剂， 剂量很高但很安全。氢是一种稳定的同位素，通常用作新陈代谢研究的示踪剂。 最后，DMI是一种高度可翻译的成像技术，已经在临床研究环境中应用。因此，如果 在这些啮齿动物模型中，建立了胆碱摄取和代谢的潜在图谱 在人类患者中，DMI用于检测氚标记的胆碱是相对简单的。

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.