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，可能会妨碍许多其他有前途的方法。例如，使用MRI来检测和跟踪代谢标志物可能是筛查和诊断疾病并衡量对治疗反应的有力方法，但相对较低的浓度可能使其难以在体内观察这些物质。然而，已经开发了一些方法，可以实现高度非平衡的核自旋布居分布在选定的系统，从而提高MR灵敏度的这种“超极化”（HP）的数量级的物种。例如，在传统的PHIP（或仲氢诱导极化）中，仲氢（pH 2）的纯反相自旋序通过使用其来破坏分子前体中的不饱和化学键而被用作自旋极化的来源。或者，在一种称为SABRE（可逆交换信号放大）的较新的PHIP方法中，自旋顺序可以在短暂复合物的寿命期间从pH 2转移到目标分子，表面上没有永久的化学变化。重要的是，两种PHIP方法都需要有机金属催化剂。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，以更快的速度和更低的成本生成HP有机分子的能力。然而，PHIP的生物医学应用受到许多关键技术限制，特别是可用的PHIP催化剂的性质（包括将它们与所产生的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，这将大大提高PHIP的生物医学研究，并最终，临床使用的适用性。更具体地说，我们的努力将关注传统的PHIP和SABRE的新的非均相催化剂的合成，评价和MR演示;超极化的水性试剂将在这两种情况下的一个重点。这些实验将支持的建设和实施的自动化PHIP/SABRE偏振器与原位MR检测（改编自既定的范德比尔特设计，但修改为多相催化工作）。我们将展示HP水性有机试剂的创建和使用，不受催化剂的污染，否则将成为扩大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制备的HP试剂进行低场MRI的体内演示。总的来说，我们的研究旨在开发PHIP大规模生产纯HP物质的能力，用于众多MRI/MRS应用，包括生产代谢MRI造影剂，用于筛查和跟踪对各种癌症和其他疾病的治疗反应。

 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.