Improving Understanding, Utility and Generality of Hyperpolarized, Long-lived Spin States in Magnetic Resonance

提高磁共振中超极化、长寿命自旋态的理解、实用性和通用性

• 批准号: 1665090
• 负责人: Warren Warren
• 金额: $ 65万
• 依托单位: Duke University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2021-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1665090&HistoricalAwards=false
• 关键词: Improving; Understanding; Utility; Generality; Hyperpolarized

Nuclear magnetic resonance (NMR) spectroscopy is a powerful tool for chemists; it is useful for determining molecular structure and for monitoring the progress of chemical reactions. NMR's clinical cousin, magnetic resonance imaging (MRI) is also a useful tool for producing images of soft tissues in the body. Both methods usually suffer from relatively low sensitivity - meaning that it cannot detect small amounts of sample. "Hyperpolarization" methods, which can increase the signal by a factor of 1000 or more, have been extensively explored over the last decade, but fewer than 1% of all NMRs and MRIs have access to this technology. Hyperpolarization is technically challenging and extremely expensive. With support from the Chemical Measurement and Imaging Program, and partial co-funding from the Chemical Structure, Dynamics, and Mechanisms - A Program, Professors Warren Warren, Steven Malcolmson, and Thomas Theis and their groups at Duke University are working to expand the availability and utility of hyperpolarization (a readily prepared reagent). They are developing new catalysts to speed sample preparation and an instrument that can be built for about 1% of the cost of competitive approaches. This research is both expanding the range of possible molecular targets and increasing the attainable sensitivity. The project could ultimately enable low-cost, portable MRI instruments. The team is providing research and training opportunities in these critical technologies for members of underrepresented groups, and providing substantial K-12 science outreach.The low sensitivity of NMR and MRI is often a severe limitation. Hyperpolarization methods (mostly dynamic nuclear polarization, DNP) can increase the observable signal as much as 10,000 times in virtually any organic molecule, but hyperpolarization decays back to thermal equilibrium at a rate given by the nuclear spin lifetime T1, which in solution is commonly seconds. These short relaxation times limit the processes that can be studied by the method. In addition, the associated apparatus is complicated and expensive (ca. $2.5M for clinical systems). The team at Duke has shown that pulse sequences can load and unload long-lived states in many molecules, effectively lengthening homogeneous relaxation times to many minutes. Their new approaches to hyperpolarization (SABRE-SHEATH and LIGHT-SABRE) have increased 15Nitrogen or 13Carbon polarization by up to five orders of magnitude (relative to thermal populations) using an ultralow-field apparatus (about 1% of the Earth's field) that can be built by undergraduates. They are now working to improve polarization rates, total polarization, and the generality of these methods. The aim of this research project is to reduce the sensitivity to molecular parameters and increase reliability. The work includes a mixture of discovery, basic theoretical extensions of the density matrix understanding of magnetic resonance, detailed quantum mechanical and molecule dynamics simulations, targeted synthesis, and demonstration of useful applications. The research is addressing fundamental questions about spin dynamics. The systems reflect a new class of "reactive intermediates" which go back to their original state, yet create a useful product (spin polarized nuclei). Other extensions focus on the complex role of molecular symmetry in isolating states from their environment, and on developing tools to access ever-better protected states. Broader impacts arise from the potential to create a wide variety of Magnetic Resonance-trackable molecular targets, with applications from organometallic chemistry to clinical imaging.

核磁共振（NMR）光谱是化学家的有力工具;它可用于确定分子结构和监测化学反应的进展。核磁共振的临床表亲，磁共振成像（MRI）也是一种有用的工具，用于产生身体软组织的图像。 这两种方法通常都有相对较低的灵敏度-这意味着它不能检测到少量的样品。 “超极化”方法可以将信号增加1000倍或更多，在过去十年中已被广泛探索，但只有不到1%的NMR和MRI可以使用这项技术。 超极化在技术上具有挑战性并且极其昂贵。 在化学测量和成像计划的支持下，以及化学结构、动力学和机制- A计划的部分共同资助下，杜克大学的Warren Warren、Steven Malcolmson和托马斯Theis教授及其团队正在努力扩大超极化（一种现成的试剂）的可用性和实用性。 他们正在开发新的催化剂来加速样品制备，并开发一种仪器，其成本约为竞争性方法的1%。 这项研究既扩大了可能的分子靶点范围，又提高了可达到的灵敏度。 该项目最终可以实现低成本，便携式MRI仪器。 该团队正在为代表性不足的群体提供这些关键技术的研究和培训机会，并提供大量的K-12科学推广。核磁共振和核磁共振成像的低灵敏度通常是一个严重的限制。 超极化方法（主要是动态核极化，DNP）可以在几乎任何有机分子中将可观察到的信号增加多达10，000倍，但超极化以核自旋寿命T1给出的速率衰减回到热平衡，在溶液中通常为秒。 这些短的弛豫时间限制了可以通过该方法研究的过程。 此外，相关联的设备复杂且昂贵（约100美元）。250万美元用于临床系统）。 杜克大学的研究小组已经证明，脉冲序列可以在许多分子中加载和卸载长寿命状态，有效地将均匀弛豫时间延长到许多分钟。他们的超极化新方法（SABRE-SHEATH和LIGHT-SABRE）使用可以由本科生建造的超低场设备（约为地球场的1%）将15氮或13碳极化增加了5个数量级（相对于热人口）。 他们现在正在努力提高极化率、总极化率和这些方法的通用性。 该研究项目的目的是降低对分子参数的敏感性并提高可靠性。 这项工作包括发现的混合物，磁共振密度矩阵理解的基本理论扩展，详细的量子力学和分子动力学模拟，有针对性的合成，以及有用应用的演示。这项研究正在解决有关自旋动力学的基本问题。该系统反映了一类新的“活性中间体”，它们可以回到原始状态，但会产生有用的产物（自旋极化核）。 其他扩展集中在分子对称性在将状态与其环境隔离中的复杂作用，以及开发工具以获得更好的保护状态。 更广泛的影响来自于创造各种各样的磁共振可跟踪分子靶点的潜力，其应用范围从有机金属化学到临床成像。

项目成果

Application of 15 N 2 -Diazirines as a Versatile Platform for Hyperpolarization of Biological Molecules by d-DNP

15 N 2 -二氮丙啶作为 d-DNP 生物分子超极化的多功能平台的应用

• DOI: 10.1021/acs.bioconjchem.0c00028
• 发表时间: 2020
• 期刊: Bioconjugate Chemistry
• 影响因子: 4.7
• 作者: Park, Hyejin;Zhang, Guannan;Bae, Junu;Theis, Thomas;Warren, Warren S.;Wang, Qiu
• 通讯作者: Wang, Qiu

Rational ligand choice extends the SABRE substrate scope

• DOI: 10.1039/d0cc01330g
• 发表时间: 2020-08-21
• 期刊: CHEMICAL COMMUNICATIONS
• 影响因子: 4.9
• 作者: Colell, Johannes F. P.;Logan, Angus W. J.;Theis, Thomas
• 通讯作者: Theis, Thomas

Selective hyperpolarization of heteronuclear singlet states via pulsed microtesla SABRE

通过脉冲微特斯拉 SABRE 实现异核单线态的选择性超极化

• DOI: 10.1063/1.5108644
• 发表时间: 2019
• 期刊: The Journal of Chemical Physics
• 作者: Tanner, Christian P. N.;Lindale, Jacob R.;Eriksson, Shannon L.;Zhou, Zijian;Colell, Johannes F. P.;Theis, Thomas;Warren, Warren S.
• 通讯作者: Warren, Warren S.

Decoupled LIGHT-SABRE variants allow hyperpolarization of asymmetric SABRE systems at an arbitrary field

• DOI: 10.1016/j.jmr.2019.106577
• 发表时间: 2019-10-01
• 期刊: JOURNAL OF MAGNETIC RESONANCE
• 影响因子: 2.2
• 作者: Lindale, Jacob R.;Tanner, Christian P. N.;Warren, Warren S.
• 通讯作者: Warren, Warren S.

Terminal Diazirines Enable Reverse Polarization Transfer from 15 N 2 Singlets

末端二氮丙啶可实现 15 N 2 单峰的反向极化转移

• DOI: 10.1002/anie.201904026
• 发表时间: 2019
• 期刊: Angewandte Chemie International Edition
• 作者: Zhang, Guannan;Colell, Johannes F. P.;Glachet, Thomas;Lindale, Jacob R.;Reboul, Vincent;Theis, Thomas;Warren, Warren S.
• 通讯作者: Warren, Warren S.