Novel approaches for CEST labeling, detection, quantification and translation

恶性胶质瘤患者的预后仍然令人沮丧。此外，神经成像的局限性 使这些患者的临床管理复杂化，并阻碍新疗法的有效测试。而当 磁共振成像已扩展到细胞和分子水平，为恶性成像提供了新的可能性 对于神经胶质瘤，大多数分子磁共振研究仅限于临床前阶段。最近，一种新型的 分子磁共振成像对比剂已经可以检测到人体自身的组成成分：氨基酸， 蛋白质和碳水化合物。这些自然物种产生的磁性对比是由于 可以与水上的质子交换的质子基团(NH、NH2、OH)，从而影响 MRI图像中的信号。这些化合物的命名是基于它们的第一个检测机制 磁共振成像，即“化学交换饱和转移”或“CEST”。酰胺质子转移加权 (APTw)MRI是一种内源性CEST方法，具有改善癌症诊断的潜力(识别和 确定恶性疾病的程度)、治疗监测(对肿瘤变化的客观评估 负担)，并区分复发肿瘤和治疗效果。然而，目前基于饱和度的 由于大量混杂背景信号的干扰，该方法对酰胺质子的特异性较低 来自半固态组织的直接水饱和度(DS)和常规磁化传递对比(MTC) 成分，以及来自其他内源性CEST代谢物的信号。我们建议通过以下方式解决这一问题 发展脉冲交换转移方法，即不是基于射频饱和标记，而是基于 质子激发和质子频率演化标记，可以消除这种混杂效应。 在目标1中，我们将开发能够实现可交换质子的磁性标记的脉冲序列 使用具有可变延迟的RF激励脉冲序列。我们用它们来编码可交换的质子 基于它们特定的化学位移演化(频率编码)和它们的交换转移特性， 其允许去除上述的混杂影响。在AIM 2中，目标是量化 汇兑转账对比。使用在AIM 1中开发的编辑方法，我们将设计 测量绝对浓度，并使用模体中的已知浓度进行验证。在活体内， 用于检测交换转移的水信号将作为内部标准。最后，在目标3中， 我们将把这种方法转化为在动物和人类系统上进行快速3D全脑扫描。 这些目标有望导致可量化的APT对比剂磁共振成像在慢性前列腺癌患者中的应用 神经胶质瘤。虽然我们集中展示了新方法在胶质瘤动物模型和 患者，这项建议中的技术发展预计将对 一般、其他几种病理(如中风、神经退行性变)，以及CEST对比成像 MTC、DS和内源性CEST背景信号干扰是主要问题的药物。

The prognosis of patients with malignant gliomas remains dismal. In addition, limitations in neuroimaging complicate the clinical management of these patients and impede efficient testing of new therapeutics. While extension of MRI to the cellular and molecular level has introduced new possibilities for imaging malignant gliomas, most molecular MRI studies have been limited to the pre-clinical setting. Recently, a new type of molecular MRI contrast has become available that detects the body's own building blocks: amino acids, proteins and carbohydrates. The magnetic contrast produced by these natural species is due to the presence of groups of protons (NH, NH2, OH) that can exchange with the protons on water and, as such, affect the signal in MRI images. The nomenclature for these compounds is based on their first mechanism of detection with MRI, namely “Chemical Exchange Saturation Transfer” or “CEST”. Amide proton transfer weighted (APTw) MRI is an endogenous CEST method with potential for improving cancer diagnosis (identifying and determining the extent of malignant disease), therapeutic monitoring (objective assessment of change in tumor burden), and distinguishing recurrent tumor from treatment effects. However, the current saturation-based approach has low specificity for amide protons due to interference of large confounding background signals from direct water saturation (DS) and conventional magnetization transfer contrast (MTC) from semisolid tissue components, as well as from signals from other endogenous CEST metabolites. We propose to address this by developing pulsed exchange transfer approaches, i.e. not based on RF saturation labeling but on proton excitation and proton frequency evolution labeling, that can remove such confounding effects. In AIM 1, we will develop pulse sequences that can achieve magnetic labeling of exchangeable protons using trains of RF excitation pulses with variable delays. We use these to encode the exchangeable protons based on their specific chemical shift evolution (frequency encoding) and their exchange transfer properties, which allows removal of the confounding effects mentioned above. In AIM 2, the goal is quantification of the exchange transfer contrast. Using the editing methods developed in AIM 1, we will design approaches to measure absolute concentrations and validate them using known concentrations in phantoms. In vivo, the water signal used for the detection of exchange transfer will be used as an internal standard. Finally, in AIM 3, we will translate the methodology to fast 3D whole-brain scanning on animal and human systems. These aims are expected to result in the availability of quantifiable APT contrast MRI in patients with gliomas. While we focus demonstration of the usefulness of the new methods on glioma animal models and patients, the technical developments in this proposal are expected to be important for tumor imaging in general, several other pathologies (e.g. stroke, neurodegeneration), and for the imaging of CEST contrast agents for which the interference of MTC, DS and endogeneous CEST background signals is a major problem.