Parahydrogen-induced hyperpolarization of 13C labeled keto carboxylic acids for medical applications: synthesis, polarization transfer, 13C-MRI

可以说，医学中最关键的3D成像方式是MRI和CT。磁共振成像正变得越来越重要，因为它不使用电离辐射，而且它允许可视化，而不仅仅是解剖或结构成像。代谢过程中的异常通常是疾病非常早期阶段的可靠指标，在解剖变化(例如肿瘤)在结构成像中可见之前。然而，核磁共振成像是出了名的不敏感，新陈代谢成像比单纯的解剖成像需要更高的信噪比。超极化可能是迄今为止最有希望的方法，可以将核磁共振和核磁共振的灵敏度提高到可以检测到代谢途径中的中间产物，并用空间分辨率可视化它们的浓度的水平。在众多的生物标志物中，α-酮羧酸是关键分子，因为它们是柠檬酸循环和糖酵解等能量代谢途径的中间体。尤其是丙酮酸/乳酸的转化被认为是早期癌症的一个重要指标(Warburg效应)。本研究项目的最终目的是为使用所谓的对氢诱导极化(PhIP)方法的MRI进行体内分子和代谢成像提供科学和技术基础。为此，我们将开发一种经济高效的合成13C和2H标记的丙酮酸乙烯酯和其他α-酮羧酸衍生物作为PhIP的前体(目标1)，我们将设计硬件和中间磁场中的PhIP实验，以便于为13C磁共振成像生产丙酮酸和其他α-酮羧酸(目标2)。活体实验将与独立于该项目的其他小组合作进行。

Arguably the most critical 3D imaging modalities in medicine are MRI and CT. MRI is gaining importance because it does not use ionizing radiation, and it allows visualization beyond just anatomic or structural imaging. Anomalies in metabolic processes are often reliable indicators of diseases at very early stages of illness before anatomical changes (e.g., tumors) are visible in structural imaging. However, MRI is notoriously insensitive, and metabolic imaging requires even higher signal-to-noise ratios than mere anatomical imaging. Hyperpolarization to date is probably the most promising approach to increase the sensitivity of NMR and MRI to a level where intermediates in metabolic pathways can be detected, and their concentration visualized with spatial resolution. Among a plethora of biomarkers, α-ketocarboxylic acids are key molecules because they are intermediates in energy metabolism pathways such as the citric acid cycle and glycolysis. Particularly the pyruvate/lactate conversion is known to be an instrumental indicator for early-stage cancer (Warburg effect). The ultimate goal of this research project is to provide the scientific and technological basis for in vivo molecular and metabolic imaging by MRI using the so-called parahydrogen-induced polarization (PHIP) method. Towards this end, we will develop a cost-efficient synthesis of 13C and 2H labeled vinyl esters of pyruvate and other derivates of α-ketocarboxylic acids as precursors for PHIP (goal 1), and we will design hardware and PHIP experiments in intermediate magnetic fields for the scalable and convenient production of pyruvate and other α-ketocarboxylic acids for 13C MRI (goal 2). In vivo experiments will be performed in collaboration with other groups independently from this project.