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

描述（由申请人提供）：化学交换饱和转移（CEST）对比最近被引入MRI。对比依赖于交换基团的选择性预饱和和随后对交换结果水信号减少的观察。具有-OH、- nhh、-NH2等交换基团的内源性或外源性分子均可作为CEST试剂（DIACEST）。顺磁性镧系元素的外源配合物也可用作CEST试剂（PARACEST）。开发了许多DIACEST和PARACEST应用程序，旨在定量成像pH和肿瘤（如酰胺质子转移，APT），代谢物（如glycoCEST）和软骨降解（gagCEST）。CEST方法提供了许多吸引人的特性。首先，CEST提供了一种放大机制，允许检测存在于微至毫摩尔浓度范围内的代谢物，这通常是MRI无法实现的。其次，CEST对比可以切换“开”和“关”在操作员的自由裁量权，通过射频应用。如果RF“关闭”，则药剂是不可见的和/或不会干扰常规的MR成像序列。如果RF处于“开启”状态，则在药剂浓度区域产生对比。第三，CEST对比依赖于交换过程，因此对代理环境非常敏感。这开辟了成像定量参数的可能性，如pH值，代谢物浓度，或定量变化的交换由于结合白蛋白或氢化磷酸酯剂。一些技术挑战可能仍然阻碍该技术在临床环境中的准确应用。CEST对比对B0和B1的不均匀性很敏感，这可能导致不准确的定量结果。通常，在强背景信号存在的情况下，需要检测到信号强度的微小下降。采用差分图像进行量化，强背景信号可能导致伪影的积累。此外，一些CEST应用需要获取短TR的多幅图像或涉及PARACEST试剂，可能需要应用超过FDA批准指南的RF沉积。在这里，我们提出了几种方法来克服上述挑战，并创建健壮的CEST方案，易于在临床环境中执行，用于动物和人类的定量体内研究。首先，我们提出探索复合脉冲序列和成形射频脉冲的应用，以提高B0和B1的鲁棒性。其次，我们引入了积极的CEST方案，它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空间饱和和平行成像相结合以降低SAR。最后，我们将调整现有的定量方案以适应上述所有变化，以便创建一个将成像过程中测量的参数与定量参数（如pH、交换速率或浓度）连接起来的协议。公共卫生相关性：近年来，利用化学交换饱和转移的MRI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复合物，所有这些都旨在提供有关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，以充分挖掘其在临床环境中的体内定量成像潜力。

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.