Hyperpolarized Diethyl Ether for Sub-second Pulmonary MRI

项目总结(30行为限) 致命疾病，如慢性阻塞性肺疾病(COPD)、哮喘、肺损伤、缩窄性 毛细支气管炎和肺纤维化影响着全球3亿人，每年导致约300万人死亡。 然而，目前还没有广泛的临床成像手段来进行高分辨率的功能性肺成像。 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-告知肿瘤和肺炎等病理情况-但很少或根本没有关于肺部的信息 换气、灌流、肺泡大小、气体交换效率等。这种情况与癌症形成对比 成像，包括核磁共振、CT、超声波、乳房X光照相、正电子发射断层扫描(PET)等， 共同实现早期检测(通过人口筛查)、诊断和监测对 治疗。超极化惰性气体(129Xe和3He)的MRI报告肺功能：呼吸，弥散， 和气体交换。尽管在这一领域取得了显著的研究突破，证明了 超极化稀有气体MRI检测多种肺部疾病和监测疗效的安全性 治疗(过去20年的研究)，这种成像在临床上广泛适应的前景 运输方式面临重大挑战，包括：(1)生产的设备成本高、复杂 超极化惰性气体，以及(Ii)需要高度专业化的定制核磁共振扫描仪，能够 129Xe或3He成像-请注意，所有FDA批准的临床MRI扫描仪只能成像质子。我们一直在 开发生产纯质子的对氢诱导极化(PhIP)新技术-- 通过向不饱和前体(例如，乙烯基)进行成对的仲氢加成超极化碳氢气体 这里提出了以太)。这种高通量技术非常简单，成本也很低。最重要的是，它 可部署在FDA批准的核磁共振扫描仪上，无需任何额外的硬件和软件升级。 在此，我们建议将该技术应用于乙醚的生产，乙醚具有丰富的使用历史。 第一种吸入性麻醉剂，它彻底改变了医学领域。具体地说，我们建议发展和 优化临床规模生产人体剂量低于100毫升的气体的工艺。一旦吸入，这一点 低剂量的乙醚在体内会呈现浓缩性，不再是易燃的。因此，我们设想 使用低剂量质子超极化乙醚作为一种安全的MRI造影剂。我们还将表演 详细绘制了这种新型HP造影剂的弛豫特性图，并将进行可行性成像 关于幻影和切除动物肺的研究。我们设想这种新的安全的可吸入造影剂可以 彻底改变了肺部影像和肺部医学。

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.