Enabling Metabolic Imaging Using Hyperpolarized 13C Magnetic Resonance

描述（由申请人提供）：13C富集分子的信号太低，无法通过MRI在体内观察到。为了克服这个问题，研究人员已经转向使用超极化（HP） 13C分子；超极化极大地增加了分子中13C核的信号，并且通过这种方式可以获得高达10,000的信噪比（SNR）的增加。增加的信噪比使得建立心脏代谢过程的图像成为可能，这些图像可用于构建各种形式心脏病的代谢特征模型。现有的超极化方法存在缺陷，这将严重影响HP 13C分子的临床部署。例如，目前唯一的商用超极化剂需要将13C分子与有毒物质混合才能使13C原子核超极化。此外，目前的超偏光片不容易扩展到商业供应所需的生产水平。MKT开发了一种超极化方法和相关的业务模型，直接解决了这些问题。样品的超极化是通过允许原子核在非常低的温度，非常高的场环境中松弛来实现的。“量子”液体he和he的使用使得弛豫过程非常迅速，并且在不使用有毒物质的情况下进行。HP样品从低温恒温器中提取，没有过度的极化损失；这使得它们能够远距离传输，从而消除了偏光镜靠近核磁共振成像仪的需要。该工艺可扩展，适用于各种样品，包括代谢感兴趣的样品，如13C富集的乙酸。我们的长期目标是为临床MRI市场生产和供应HP材料。我们的短期目标是利用我们的专有技术证明富含13C的乙酸可以超极化，从低温恒温器中提取，运送到附近的医院，与氢氧化钠碱溶液反应形成HP醋酸钠溶液，然后用于进行各种超极化磁共振波谱（MRS）实验。我们将证明，与室温下处于热平衡状态的乙酸样品相比，QRS技术在HP乙酸样品中产生的信噪比增益超过5000 （Aim I）。我们将证明HP 13C乙酸可以运输2小时（或更长时间）而不会有明显的极化损失（Aim II）。这将证明醋酸可能在一个位点超极化，并被运输到另一个位点，用于不同的MRS应用。接下来，我们将演示将HP 13C乙酸转化为HP 13C醋酸溶液，与室温下热平衡的醋酸样品相比，信噪比超过1000 （Aim III）。HP醋酸钠溶液将用于在酵母呼吸悬浮液和离体灌注大鼠心脏中进行的MRS实验中跟踪代谢（Aim IV）。公共卫生相关性：今年将有超过70万美国人死于心脏病。心脏代谢过程成像的能力有可能极大地改善心脏病的诊断和治疗。心脏代谢图像的生成需要开发富含13C的超极化分子，如乙酸钠；Millikelvin Technologies开发了一种制造超极化醋酸钠的方法，该方法不需要添加有毒材料，可以按比例扩大以满足广泛的需求，并且通过将超极化醋酸钠作为消耗品交付，可以降低成本。

DESCRIPTION (provided by applicant): The signal from 13C enriched molecules is much too low to permit them to be observed in vivo using MRI. To overcome this problem, researchers have turned to the use of hyperpolarized (HP) 13C molecules; hyperpolarization dramatically increases the signal from the 13C nuclei in the molecules and an increase in signal to noise ratio (SNR) by as much as 10,000 can be obtained in this manner. The increased SNR makes it possible to build images of metabolic processes in the heart which can be used to construct models as to the metabolic signature of various forms of heart disease. Present methods of hyperpolarization suffer from drawbacks that will severely impact clinical deployment of HP 13C molecules. For example, the only currently commercially available hyperpolarizer requires that the 13C molecule be mixed with toxic substances to hyperpolarize the 13C nuclei. In addition, present hyperpolarizers are not readily scalable to production levels needed for commercial supply. MKT has developed a method of hyperpolarization and associated business model that directly addresses these issues. Hyperpolarization of samples is carried out by allowing nuclei to relax in a very low temperature, very high field environment. The use of the "quantum" liquids 3He and 4He allow the relaxation process to be very rapid and carried out without the use of toxic materials. The HP samples are extracted from the cryostat without undue loss of polarization; this enables them to be transported over large distances thus removing the need for the polarizer to be in close proximity to the MRI machine. The process is scalable and applicable to a wide variety of samples including those of metabolic interest such as 13C enriched acetic acid. Our long term goal is to manufacture and supply HP materials to the clinical MRI marketplace. Our short term goal is to demonstrate that 13C enriched acetic acid can be hyperpolarized using our proprietary technique, extracted from the cryostat, transported to a nearby hospital, reacted with a sodium hydroxide base solution to form HP sodium acetate solution and then used to carry out a variety of hyperpolarized Magnetic Resonance Spectroscopy (MRS) experiments. We will demonstrate that the QRS technique produces SNR gains in excess of 5000 in HP acetic acid samples as compared to acetic acid samples in thermal equilibrium at room temperature (Aim I). We will demonstrate that HP 13C acetic acid may be transported for 2 hours (or more) without significant loss of polarization (Aim II). This will demonstrate that acetic acid may be hyperpolarized at one site and transported to another for use in different MRS applications. Next, we will demonstrate conversion of HP 13C acetic acid to an HP 13C acetate solution with SNR in excess of 1000 as compared to acetic acid samples in thermal equilibrium at room temperature (Aim III). The HP sodium acetate solution will then be used to follow metabolism in MRS experiments conducted in a respiring suspension of yeast and in isolated perfused rat hearts (Aim IV). PUBLIC HEALTH RELEVANCE: Over 700,000 Americans will die from heart disease this year. The ability to image metabolic processes of the heart has the potential to greatly improve both diagnosis and treatment of heart disease. The production of metabolic images of the heart requires the development of hyperpolarized 13C enriched molecules such as sodium acetate; Millikelvin Technologies has developed a method of manufacturing hyperpolarized sodium acetate that does not require the addition of poisonous materials, can be scaled up to meet widespread demand and will keep costs down by delivering the hyperpolarized sodium acetate as a consumable.