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

项目摘要 我们的长期目标是建立一个新的和强大的磁共振成像（MRI）平台， 跟踪广泛的目标分子，实现实时的体外和体内检测， 特异性和精确度。该R21应用的目的是证明15 N2-二氮杂环丙烷的潜力 作为MRI的一种新颖的通用标签。15 N2-二氮杂环丙烯作为MRI中有希望的候选物的理由源于 它的独特之处：（1）两个15 N原子不直接与质子结合，化学位移接近， 强耦合，从而可能提供长寿命的超极化状态;（2）二氮丙啶尺寸小， 已知其易于掺入药物、代谢物和生物分子中，而不会显著改变它们的 内在功能;和（3）在体外和体内条件下，二氮丙啶是稳定的和生物相容的。这 我们的初步结果支持了这一假设，即15 N2-二氮杂环丙烷化合物可以提供长寿命的 利用SABRE实验简单和成本有效的超极化方法的超极化信号 （可逆交换信号放大）。 基于这些令人兴奋的初步发现，本申请将研究15 N2- 作为通用超极化标记物的二氮杂环丙烷， 核磁共振该方法克服了超极化MRI信号时间短的局限性 (in秒）和高昂的仪器成本（百万美元）。这项工作建立在我们现有的 我们在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 物理化学家对SABRE超极化NMR的研究。R21应用中的研究将证明 15 N2-二氮杂环丙烷作为新型MRI标记物的一般适用性，其能够通过微电子显微镜递送长寿命信号。 简单和廉价超极化方法。拟议研究的完成还提供了一个 我们的长期目标是建立一个变革性的MRI平台，可以成像广泛的范围， 以高特异性和灵敏度在真实的时间内检测结构多样的靶分子。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，并将导致广泛的 在生物医学和临床研究中的实用性和深远影响， 过程，跟踪动态代谢反应，疾病诊断。

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.