Hyperpolarized Diethyl Ether for Sub-second Pulmonary MRI

项目摘要（30行限制） 慢性阻塞性肺疾病（COPD）、哮喘、肺损伤、收缩性肺炎等致命疾病 细支气管炎和肺纤维化影响全世界> 3亿人，并且每年造成约300万人死亡。 然而，目前还没有广泛的临床成像模式来执行高分辨率功能肺 成像：计算机断层扫描（CT）、常规MRI和X射线只能提供致密的结构图像。 组织-提供肿瘤和肺炎等病理信息，但很少或根本没有关于肺的信息 通气、灌注、肺泡大小、气体交换效率等。这种状态与癌症形成对比 成像，包括MRI、CT、超声、乳房X线摄影、正电子发射断层扫描（PET）等， 这些措施共同实现了早期检测（通过人群筛查）、诊断和监测对 治疗超极化惰性气体（129 He和3 He）的MRI报告肺功能：通气，弥散， 气体交换。尽管在这一领域取得了显着的研究突破， 超极化惰性气体MRI检测各种肺部疾病并监测对 治疗（在过去20多年的研究），这种成像的广泛临床适应的前景 （i）生产的设备成本高，复杂性高， 超极化惰性气体，以及（ii）对高度专业化的定制MRI扫描仪的要求， 129氚或3 He成像-注意，所有FDA批准的临床MRI扫描仪只能成像质子。我们一直 开发了一种新的氢诱导极化（PHIP）技术，用于生产纯质子- 通过成对仲氢加成到不饱和前体的超极化烃气体（例如，乙烯基 在此提出）。这种高通量技术非常简单且成本低。最重要的是它 可以部署在FDA批准的MRI扫描仪上，无需任何额外的硬件和软件升级。 在这里，我们建议将这种技术应用于生产乙醚，乙醚作为 第一种吸入式麻醉剂，它彻底改变了医学领域。具体而言，我们建议发展和 优化临床规模生产人体剂量小于100 mL气体的工艺。一旦吸入， 低剂量乙醚将使体内浓度，这是不再易燃。因此，我们设想 使用低剂量质子超极化乙醚作为安全的MRI造影剂。我们还将表演 详细绘制这种新型HP造影剂的弛豫特性，并将进行可行性成像 在幻影和切除的动物肺中的研究。我们设想这种新的安全的可吸入造影剂可以 彻底改变了肺部成像和肺部医学。

PROJECT SUMMARY (30-line limit) Deadly diseases such as chronic obstructive pulmonary disease (COPD), asthma, lung injury, constrictive bronchiolitis, and pulmonary fibrosis affect >300 million people worldwide and cause ~3 million annual deaths. However, there is currently no widespread clinical imaging modality to perform high-resolution functional lung imaging: Computed Tomography (CT), conventional MRI, and X-ray can only provide structural images of dense tissues—informing about pathologies like tumors and pneumonia—but yielding little or no information about lung ventilation, perfusion, alveoli size, gas-exchange efficiency, etc. This state of affairs contrasts with cancer imaging, which includes MRI, CT, ultrasound, mammography, Positron Emission Tomography (PET) and others, which collectively enable early detection (via population screening), diagnoses, and monitoring response to treatment. MRI of hyperpolarized noble gases (129Xe and 3He) reports on lung function: ventilation, diffusion, and gas exchange. Despite remarkable research breakthroughs in this field demonstrating the effectiveness and safety of hyperpolarized noble gas MRI to detect a wide range of lung diseases and monitor response to treatment (over the past 20+ years of studies), the prospects for widespread clinical adaptation of this imaging modality face major challenges, including (i) the high cost and complexity of the equipment for production of hyperpolarized noble gases, and (ii) the requirement for a highly specialized custom MRI scanner capable of 129Xe or 3He imaging – note, all FDA-approved clinical MRI scanners can image only protons. We have been developing a new technology of Parahydrogen Induced Polarization (PHIP) for production of pure proton- hyperpolarized hydrocarbon gases via pairwise parahydrogen addition to an unsaturated precursor (e.g., vinyl ether proposed here). This high-throughput technology is remarkably simple and low-cost. Most importantly, it can be deployed on FDA-approved MRI scanners without any additional of hardware and software upgrades. Here we propose applying this technology for production of diethyl ether, which has a rich history of use as the first inhalable anesthetic, which has revolutionized the field of medicine. Specifically, we propose to develop and optimize the process of clinical-scale production of a human dose of less than 100 mL of gas. Once inhaled, this low dose diethyl ether will render in vivo concentration, which is no longer is flammable. Therefore, we envision the use of low-dose proton-hyperpolarized diethyl ether as a safe MRI contrast agent. We will also perform detailed mapping of relaxation properties of this novel HP contrast agents, and will perform feasibility imaging studies in phantoms and excised animal lungs. We envision that this new safe inhalable contrast agent can revolutionize pulmonary imaging and pulmonary medicine in general.