Pure parahydrogen-enhanced metabolic MRI contrast agents for molecular imaging

 描述（由申请人提供）：传统 MRI/MRS 的低检测灵敏度仍然是一个致命弱点，可能会阻碍许多其他有前途的方法的发展。例如，使用 MRI 检测和跟踪代谢标记物可能是筛查和诊断疾病以及评估治疗反应的有效方法，但相对较低的浓度可能导致难以在体内观察此类物质。然而，已经开发了许多方法，可以在选定的系统中实现高度非平衡的核自旋群体分布，从而将此类“超极化”（HP）物质的 MR 灵敏度提高几个数量级。例如，在传统的 PHIP（或仲氢诱导极化）中，仲氢 (pH2) 的纯反相自旋序被用作自旋极化源，通过使用它来氢化分子前体中的不饱和化学键。或者，在一种称为 SABER（可逆交换信号放大）的新型 PHIP 方法中，自旋顺序可以在瞬态复合物的寿命期间从 pH2 转移到目标分子，表面上不会发生永久性化学变化。重要的是，这两种 PHIP 方法都需要有机金属催化剂。无论哪种方式，PHIP 都具有许多独特的优势，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许多关键技术限制的限制，特别是现有 PHIP 催化剂的性质（包括将它们与所产生的 HP 试剂分离的难度），以及基础反应的效率和范围。因此，我们的目标是开发新方法，显着提高 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、评估和 MR 演示；水剂的超极化将是这两种情况下的重点。这些实验将得到具有原位 MR 检测功能的自动化 PHIP/SABRE 偏振器的构建和实施的支持（改编自已建立的范德比尔特设计，但针对多相催化工作进行了修改）。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，否则催化剂污染会对扩大 PHIP 的生物医学和临床适用性构成主要障碍。一个关键终点是在大鼠模型中使用制备的 HP 制剂进行低场 MRI 的体内演示。总体而言，我们的研究旨在开发 PHIP 大规模生产用于多种 MRI/MRS 应用的纯 HP 物质的能力，包括生产代谢 MRI 造影剂，用于筛选和跟踪对各种癌症和其他疾病治疗的反应。

 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.