Pure parahydrogen-enhanced metabolic MRI contrast agents for molecular imaging

 描述(申请人提供)：常规MRI/MRS的低检测灵敏度仍然是一个致命弱点，可能会排除许多其他有希望的方法。例如，使用核磁共振检测和跟踪代谢标志物可能是筛选和诊断疾病以及测量治疗反应的有效方式，但相对较低的浓度可能会使在体内观察此类物质变得困难。然而，已经开发出一些方法，可以在选定的系统中实现高度非平衡的核自旋布居分布-从而将这种超极化(HP)物种的MR灵敏度提高数量级。例如，在传统的PhIP(或对氢诱导极化)中，对氢的纯反相自旋顺序(PH2)被用作自旋极化的来源，利用它来氢化分子前体中的不饱和化学键。或者，在一种新的被称为SABRE(可逆交换信号放大)的PhIP方法中，在表面上没有永久化学变化的瞬时络合物的寿命期间，自旋顺序可能从PH2转移到目标分子。重要的是，有机金属催化剂对于两种PhIP方法都是必需的。无论哪种方式，PhIP都提供了许多独特的优势，包括与其他可能的方法相比，能够以更快的速度和更低的成本生成HP有机分子。然而，PhIP的生物医学应用受到一些关键技术限制--特别是现有PhIP催化剂的性质(包括将它们与所创建的HP试剂分离的困难)，以及潜在反应的效率和范围。因此，我们的目标是开发新的方法，极大地提高PhIP在生物医学研究和最终临床应用中的适用性。更具体地说，我们的工作将涉及用于传统PhIP和SABRE的新型多相催化剂的合成、评价和MR演示；水剂的超极化将是这两种情况下的重点。这些实验将通过建造和实施具有原位MR检测的自动PHIP/SABRE偏振器来支持(改编自已建立的Vanderbilt设计，但针对多相催化工作进行了改进)。我们将展示不受催化剂污染的HP水性有机试剂的创建和使用，否则这将是扩大PhIP生物医学和临床应用的主要障碍。一个关键的终点将是在大鼠模型中使用准备好的HP试剂进行低场MRI的活体演示。总体而言，我们的研究旨在开发PhIP大规模生产纯HP物质的能力，用于许多MRI/MRS应用，包括生产用于筛选和跟踪各种癌症和其他疾病的治疗反应的代谢MRI造影剂。

 DESCRIPTION (provided by applicant): Low detection sensitivity of conventional MRI/MRS remains an Achilles Heel that can preclude a number of otherwise promising approaches. For example, using MRI to detect and track metabolic markers could be a powerful way to screen and diagnose diseases and gauge response to treatment, but relatively low concentrations can make it difficult to observe such substances in vivo. However, a number of approaches have been developed that can achieve highly non-equilibrium nuclear spin population distributions in select systems-thereby improving the MR sensitivity of such "hyperpolarized" (HP) species by orders of magnitude. For example, in traditional PHIP (or, ParaHydrogen Induced Polarization) the pure anti-phase spin order of parahydrogen (pH2) is exploited as a source of spin polarization by using it to hydrogenate unsaturated chemical bonds in molecular precursors. Alternatively, in a newer PHIP approach called SABRE (Signal Amplification by Reversible Exchange), spin order may be transferred from pH2 to target molecules during the lifetime of transient complexes ostensibly without permanent chemical change. Importantly, organometallic catalysts are required for both PHIP approaches. Either way, PHIP offers a number of unique advantages, including the ability to generate HP organic molecules with much greater speed and lower costs compared to other possible methods. However, the biomedical application of PHIP is constrained by a number of key technical limitations-particularly the nature of the available PHIP catalysts (including the difficulty of separating them from the created HP agents), as well as the efficiency and scope of the underlying reactions. Thus, our objective is to develop new approaches that will dramatically improve the applicability of PHIP for biomedical research and ultimately, clinical use. More specifically, our efforts will concern the synthesis, evaluation and MR demonstration of new heterogeneous catalysts for traditional PHIP and SABRE; hyperpolarization of aqueous agents will be a point of emphasis in both cases. These experiments will be supported by the construction and implementation of an automated PHIP/SABRE polarizer with in situ MR detection (adapted from the established Vanderbilt design, but modified for heterogeneous catalysis work). We will demonstrate the creation and use of HP aqueous organic agents free from contamination from the catalysts-which otherwise presents a major obstacle to expanding the biomedical and clinical applicability of PHIP. A key end point will be the in vivo demonstration of low-field MRI using the prepared HP agents in a rat model. Overall, our research aims to develop the capability of PHIP for mass-scale production of pure HP substances for numerous MRI/MRS applications, including the production of metabolic MRI contrast agents for screening and tracking the response to treatment of various cancers and other illnesses.