Optimization of DIACEST and PARACEST methodology for quantitative in-vivo imaging

描述(申请人提供)：化学交换饱和转移(CEST)造影剂最近被引入MRI。对比度依赖于交换基团的选择性预饱和以及随后观察到作为交换结果的水信号的减少。具有-OH、-NH和-NH等交换基团的内源或外源分子可用作CEST试剂(DIACEST)。顺磁性稀土外源络合物也可用作CEST试剂(PARACEST)。许多DIACEST和PARACEST应用被开发用于对pH和肿瘤(例如，酰胺质子转移，APT)、代谢物(例如，糖CEST)和软骨降解(GagCEST)进行定量成像。CEST方法提供了许多有吸引力的功能。首先，CEST提供了一种放大机制，允许检测存在于微摩尔到毫摩尔浓度范围内的代谢物，而MRI通常无法获得这些代谢物。其次，CEST对比度可以通过射频应用程序由操作员自行决定是否打开或关闭。如果RF被关闭，则该试剂是不可见的和/或不会干扰常规的MR成像序列。如果射频是“开”的，则在试剂浓度区域产生对比度。第三，CEST对比依赖于交换过程，因此对主体环境非常敏感。这为成像定量参数，如pH、代谢物浓度，或量化由于试剂与白蛋白或氢克沙培酸结合而引起的交换变化提供了可能性。几乎没有什么技术挑战仍然可能阻碍该技术在临床环境中的准确应用。CEST对比度对B0和B1不均匀很敏感，这可能导致结果的不准确量化。通常，需要在存在强背景信号的情况下检测到信号强度的小幅降低。采用差值图像进行量化，强背景信号可能会导致伪影的积累。此外，一些CEST应用程序需要采集短TR的多个图像或涉及PARACEST试剂，可能需要应用超过FDA批准的指南的射频沉积。在这里，我们提出了几种克服上述挑战的方法，并创建了易于在临床环境中执行的稳健的CEST方案，用于动物和人类的体内定量研究。首先，我们建议探索复合脉冲序列和整形RF脉冲的应用，以提高B0和B1的稳健性。其次，我们引入了积极的CEST方案，应该允许显著减少背景信号。第三，我们将探索将该技术与部分k空间饱和和并行成像相结合来降低SAR。最后，我们将调整现有的量化方案，以适应所有上述变化，以创建一个协议，将成像过程中测量的参数与诸如pH、汇率或浓度等定量参数联系起来。公共卫生相关性：近年来，使用化学交换饱和转移的磁共振成像应用越来越多。这些应用包括利用内源性基团和开发新的外源性顺磁性络合物，所有这些都旨在提供关于pH、代谢物浓度、肿瘤分期或靶标结合事件的定量信息。该项目的目标是完善和改进CEST方法学，以充分发掘其在临床环境下体内定量成像的潜力。

DESCRIPTION (provided by applicant): Chemical Exchange Saturation Transfer (CEST) contrast was recently introduced to MRI. The contrast relies on the selective pre-saturation of an exchanging group and subsequent observation of the decrease of the water signal as the result of the exchange. Endogenous or exogenous molecules with the exchanging groups such as -OH, -NH and -NH2 can be used as CEST agents (DIACEST). Exogenous complexes of paramagnetic lanthanides can also be used as the CEST agents (PARACEST). A number of DIACEST and PARACEST applications were developed aimed at quantitative imaging of pH and tumors (e.g. amide proton transfer, APT), metabolites (e.g. glycoCEST) and cartilage degradation (gagCEST). The CEST approach offers number of attractive features. First, CEST provides an amplification mechanism, allowing detection of metabolites present in the micro- to milli- Molar concentration ranges, normally inaccessible for MRI. Second, CEST contrast can be switched "on" and "off" at the operator's discretion, via RF application. If RF is "off" the agent is invisible and/or, does not interfere with conventional MR imaging sequences. If the RF is "on" the contrast is generated in the areas of agent concentration. Third, CEST contrast relies on the exchange process, and, hence, is very sensitive to the agent environment. This opens up possibility of imaging the quantitative parameters such as pH, metabolite concentration, or quantify changes in exchange due to binding of an agent to albumin or hydroxiapetate. Few technical challenges may still impede accurate application of the technique in clinical settings. The CEST contrast is sensitive to B0 and B1 inhomogeneities that may result in inaccurate quantification of the results. Typically, a small decrease in the signal intensity needs to be detected in the presence of the strong background signal. A difference image is employed for quantification, and a strong background signal may lead to an accumulation of artifacts. In addition, some CEST applications requiring acquisitions of multiple images with short TR or involving PARACEST agents, may require application of RF deposition exceeding FDA approved guidelines. Here we propose several ways to overcome the abovementioned challenges and create robust CEST scheme readily executable in clinical environment for quantitative in-vivo studies in animals and humans. First, we propose to explore applications of composite pulse trains and shaped RF pulses to improve B0 and B1 robustness. Second, we have introduced positive CEST scheme that should allow significant reduction of the background signal. Third, we will explore combinations of the technique with partial k-space saturation and parallel imaging for SAR reduction. Finally, we will adjust existing quantification schemes to accommodate all the above mentioned changes, in order to create a protocol connecting parameters measured in imaging session with quantitative parameters such as pH, exchange rate or concentration. PUBLIC HEALTH RELEVANCE: In recent years, there is an increasing number of MRI applications utilizing Chemical Exchange Saturation Transfer. These applications include utilization of endogenous groups and development of new exogenous paramagnetic complexes, all aimed at providing quantitative information about pH, metabolite concentration, tumor stage, or target-binding event. The goal of the project is the refinement and improvement of CEST methodology to fully explore its potential for quantitative imaging in-vivo in clinical environment.