Comprehensive Assessment of Pulmonary Disorders Using Polarized 13C Technology

描述（由申请人提供）：该生物工程研究合作伙伴关系的目标是通过生产超极化示踪分子（碳酸氢盐/二氧化碳，甜菜碱，环丙二甲醇和丙酮酸）来开发用于正常和病变肺的MR成像和光谱的肺功能综合评估的新技术。我们将使用动态核极化（DNP）的方法来制备在此应用中提出的超极化13c标记化合物。首先，我们将通过构建一个在5.0 T磁场下工作的偏振器来改善超偏振示踪成像的信噪比。其次，我们将确定13c -碳酸氢盐、甜菜碱、环丙二甲醇和[1-13C]丙酮酸盐在与分子冷冻、超极化、溶解和运输相关的条件下的特性。这些技术参数的管理和理解是成功的体内研究和获得高水平的分子极化的先决条件。虽然DNP过程的物理描述不包括样品化学环境的显著影响，但可实现的极化水平代表了自旋扩散、极化转移和弛豫之间的平衡。为此，我们将确定最佳极化条件，包括每个分子的具体配方及其浓度、自由基的浓度、极化增强剂（钆配合物）、共冷冻剂和DNP的最佳微波频率，并将其与极化建立时间、T1弛豫时间和平台极化水平进行比较。第三，我们将建立这些超极化底物的体外模型，并将在生理相关环境中表征它们的核磁共振和生化特性。为了确定这些分子作为超极化剂的有效性，在提出的研究中，仅证明分子在DNP装置中可以在合理的时间尺度内高度极化是不够的。当示踪剂通过循环系统进入肺部时，表征其特性同样重要。第四，我们将开发一种通过测量静脉注射13c -碳酸氢盐后13c -碳酸氢盐/13CO2平衡来绘制肺部pH值的技术，以及通过测量CO2/碳酸氢盐表观T1来评估13CO2从肺血管到肺泡间隙的交换。pH值是大多数病理的关键参数，通过局部测量pH依赖的碳酸氢盐/二氧化碳平衡，已经证明了这一数量的映射。最后，我们将研究具有超极化13c -碳酸氢盐和13c -丙酮酸的COPD动物模型的pH、气体交换和代谢。肺功能和病理的评估仍然是一个临床问题。我们将测试上述方法在肺部疾病（COPD）模型中的应用，并完善早期开发的代谢和灌注的定性测量。我们将寻找患病受试者特有的模式，并在可能的情况下，将它们与现有的测量pH值、灌注、气体交换和代谢的方法进行比较。关键词：动态核极化，超极化碳-13磁共振成像，肺代谢，pH测量，气体交换。

DESCRIPTION (provided by applicant): The goal of this Bioengineering Research Partnership is to develop new techniques for the comprehensive assessment of lung function by producing hyperpolarized tracer molecules (bicarbonate/CO2, betaine, cyclopropanedimethanol, and pyruvate) for MR imaging and spectroscopy of both normal and diseased lungs. We will use the method of dynamic nuclear polarization (DNP) to produce hyperpolarized 13C-labeled compounds proposed in this application. First, we will improve the signal-to-noise for hyperpolarized tracer imaging by building a polarizer that operates in a 5.0 T magnetic field. Second, we will determine the characteristics of 13C-bicarbonate, betaine, cyclopropanedimethanol, and [1-13C]pyruvate under conditions relevant to molecule freezing, hyperpolarization, dissolution, and transport. The management and understanding of these technical parameters is a prerequisite to successful in vivo studies and to obtaining high levels of polarization of the proposed molecules. Although the physical descriptions of the DNP process do not include significant influence from the chemical environment of the sample, the achievable polarization level represents a balance between spin-diffusion, polarization transfer, and relaxation. To this end, we will determine the optimal polarization conditions, including the specific formulation of each molecule and its concentration, the concentration of the radical, polarization enhancer (gadolinium complex), co-freezing agents and the optimal microwave frequency for DNP, all compared against polarization build-up time, T1 relaxation time and the plateau polarization level. Third, we will establish in vitro models of these hyperpolarized substrates and will characterize their NMR and biochemical properties in physiologically relevant environments. To determine the effectiveness of these molecules as hyperpolarized agents for the proposed study, it is not sufficient to show that the molecule can be highly polarized in a reasonable time-scale in the DNP apparatus. It is equally important to characterize the properties of the tracers as they travel through the circulatory system towards the lungs. Forth, we will develop a technique for pH mapping of the lung through measurement of the 13C-bicarbonate/13CO2 balance after intravenous administration of 13C-bicarbonate, as well as assessing exchange of 13CO2 from the pulmonary vasculature to the alveolar space through measurement of the CO2/bicarbonate apparent T1. pH is a key parameter in most pathologies and mapping of this quantity has already been demonstrated through localized measurement of the pH-dependent bicarbonate/CO2 balance. Finally we will study pH, gas exchange and metabolism in an animal model of COPD with hyperpolarized 13C-bicarbonate and 13C-pyruvate. Assessment of lung function and pathology remains a clinical problem. We will test the application of methods developed above to a model of lung disease (COPD), and refine qualitative measures of metabolism and perfusion developed earlier. We will seek patterns characteristic to the diseased subject and, where possible, compare them to established methods of measuring pH, perfusion, gas exchange and metabolism. Keywords: Dynamic Nuclear Polarization, Hyperpolarized Carbon-13 MR Imaging, Lung Metabolism, pH Measurements, Gas Exchange.