Probing Hyperpolarized 15N2-diazirine as A Universal Molecular Tag in MRI

探索超极化 15N2-二氮丙啶作为 MRI 中的通用分子标签

• 批准号: 9754138
• 负责人: Qiu Wang
• 金额: $ 19.43万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9754138
• 关键词: Address; Biological Process; Biology; Biomedical Research; Chemicals; Choline; Clinic; Clinical Research; Collaborations; Complex; Coupled; Detection; Diazomethane; Face; Foundations; Goals; Hour; Image; In Vitro; Iridium; Magnetic Resonance Imaging; Metabolic; Methods; Molecular; Monitor; Pharmaceutical Preparations; Process; Property; Protons; Reaction; Research; Sensitivity and Specificity; Signal Transduction; Specificity; Structure; Synthesis Chemistry; Technology; Time; Water; Work; analog; base; biomaterial compatibility; catalyst; cost; cost effective; disease diagnosis; functional group; imaging platform; in vivo; in vivo imaging; instrument; molecular imaging; novel; stem; success

PROJECT ABSTRACT Our long-term goal is to establish a novel and robust magnetic resonance imaging (MRI) platform that can track a broad range of target molecules to achieve the real-time in vitro and in vivo detection with high specificity and precision. The objective of this R21 application is to demonstrate the potential of 15N2-diazirine as a novel and general tag for MRI. The rationale for 15N2-diazirine as a promising candidate in MRI stems from its unique features: (1) the two 15N-atoms, are not directly bound to protons and are close in chemical shift and strongly coupled, thereby likely delivering a long-lived hyperpolarization state; (2) the diazirine is small in size, known to be readily incorporated into drugs, metabolites and biomolecules, without drastically altering their intrinsic function; and (3) the diazirine is stable and biocompatible in vitro and in vivo conditions. This hypothesis is supported by our preliminary results that 15N2-diazirine compounds can provide long-lived hyperpolarization signal using an experimentally simple and cost-effective hyperpolarization method by SABRE (Signal Amplification By Reversible Exchange). Based on these exciting initial findings, this application will investigate the feasibility and capability of 15N2- diazirines as a universal hyperpolarizable tag to achieve long-lived, enhanced signals for broad applications in MRI. This strategy will overcome the severe limitations in current hyperpolarization MRI by its short time signal (in seconds) and prohibitive instrument cost (in million dollars). The proposed work builds on our existing expertise in synthetic chemistry and chemical biology, as well as our strong collaborations with inorganic and physical chemists on SABRE hyperpolarization NMR. The research in this R21 application will demonstrate the general applicability of 15N2-diazirine as a novel MRI tag that is capable of delivering long-lived signal by a simple and inexpensive hyperpolarization method. The completion of the proposed research also provides a foundation toward our long-term goal of building a transformative MRI platform that can image a broad scope of structurally diverse target molecules in real time with high specificity and sensitivity. New capabilities in MRI obtained from the success of this research are expected to be readily adapted by others and will lead to broad utility and profound impact in biomedical and clinical research ranging from understanding biological processes, tracking dynamic metabolic reactions, to disease diagnosis.

项目摘要 我们的长期目标是建立一个新颖且强大的磁共振成像（MRI）平台，可以 追踪广泛的目标分子，实现高实时体外和体内检测 特异性和精确度。此 R21 应用的目的是展示 15N2-二氮丙啶的潜力 作为 MRI 的新颖且通用的标签。 15N2-二氮丙啶作为 MRI 有前途的候选者的基本原理源于 其独特之处在于：（1）两个 15N 原子不直接与质子结合，并且化学位移接近， 强耦合，从而可能产生长期的超极化状态； (2)二氮丙啶尺寸小， 已知很容易融入药物、代谢物和生物分子中，而不会显着改变它们的性质 内在功能； (3)二氮丙啶在体外和体内条件下是稳定的且具有生物相容性。这 我们的初步结果支持了这一假设，即 15N2-二氮丙啶化合物可以提供长寿命 使用 SABRE 的实验简单且经济高效的超极化方法来生成超极化信号 （通过可逆交换放大信号）。 基于这些令人兴奋的初步发现，该应用将研究 15N2- 的可行性和功能 二氮丙啶作为通用超极化标签，可实现长寿命、增强的信号，广泛应用于 核磁共振成像。该策略将通过其短时间信号克服当前超极化 MRI 的严重局限性 （以秒为单位）和高昂的仪器成本（以百万美元为单位）。拟议的工作建立在我们现有的基础上 合成化学和化学生物学方面的专业知识，以及我们与无机和化学领域的密切合作 物理化学家使用 SABRE 超极化 NMR。 R21 应用中的研究将证明 15N2-二氮丙啶作为新型 MRI 标签的普遍适用性，能够通过 简单且廉价的超极化方法。拟议研究的完成还提供了 为实现我们的长期目标奠定基础，即构建一个可以对广泛范围进行成像的变革性 MRI 平台 具有高特异性和灵敏度的实时结构多样的目标分子。 MRI 的新功能 从这项研究的成功中获得的成果预计将很容易被其他人采用，并将带来广泛的应用 在生物医学和临床研究中的实用性和深远影响，包括理解生物学 过程，跟踪动态代谢反应，以进行疾病诊断。

项目成果

15N-Azides as practical and effective tags for developing long-lived hyperpolarized agents.

15N-叠氮化物作为实用且有效的标签，用于开发长寿命的超极化剂。

• 发表时间: 2021-11-03
• 影响因子: 8.4
• 作者: Bae, Junu;Zhang, Guannan;Park, Hyejin;Warren, Warren S;Wang, Qiu
• 通讯作者: Wang, Qiu

Application of 15N2-Diazirines as a Versatile Platform for Hyperpolarization of Biological Molecules by d-DNP.

15N2-二氮丙啶作为 d-DNP 生物分子超极化的多功能平台的应用。

• 发表时间: 2020
• 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

Diazirines as Potential Molecular Imaging Tags: Probing the Requirements for Efficient and Long-Lived SABRE-Induced Hyperpolarization.

二氮丙啶作为潜在的分子成像标签：探讨高效且长寿命的 SABRE 诱导超极化的要求。

• 发表时间: 2017
• 作者: Shen, Kun;Logan, Angus W J;Colell, Johannes F P;Bae, Junu;Ortiz Jr, Gerardo X;Theis, Thomas;Warren, Warren S;Malcolmson, Steven J;Wang, Qiu
• 通讯作者: Wang, Qiu