Synthetic Optimization of Organic Radicals for Dynamic Nuclear Polarization

动态核极化有机自由基的合成优化

• 批准号: 8782139
• 负责人: Graham Thomas Sazama
• 金额: $ 5.15万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8782139
• 关键词: Address; Alzheimer' s Disease; Amyloid Fibrils; Binding; Binding Proteins; Biological; Biological Assay; Cell Nucleus; Coupling; Development; Diabetes Mellitus; Disease; Effectiveness; Electronics; Electrons; Elements; Engineering; Equilibrium; Frequencies; Generations; Health; Human; Investigation; Lead; Libraries; Light; Link; Magnetism; Membrane; Membrane Proteins; Methods; Micelles; Molecular; NMR Spectroscopy; Nature; Nuclear; Nuclear Magnetic Resonance; Parkinson Disease; Pathologic Processes; Peptides; Peripheral; Process; Property; Relaxation; Scientist; Signal Transduction; Source; Structure; Techniques; Testing; Time; Transition Elements; Vesicle; amyloid peptide; base; design; electronic structure; falls; improved; interest; irradiation; microwave electromagnetic radiation; nanocrystal; novel; particle; public health relevance; research study; scaffold; signal processing; solid state; solid state nuclear magnetic resonance; success

DESCRIPTION (provided by applicant): Nuclear magnetic resonance (NMR) spectroscopy is uniquely suited to provide information about the structure and dynamics of non-crystalline materials; these include biologically relevant materials like non-crystalline proteins, membrane-bound proteins, amyloids, peptides, micelles and vesicles. Consequently, this technique promises to shed light on a number of pathological processes implicated in diseases including diabetes, Alzheimer's and Parkinson's, among many others. Because these NMR techniques generally involve observation of low-gamma nuclei with low equilibrium polarization, however, sensitivity in the NMR experiment is inherently low and experiments must be arduously long. A number of means to increase nuclear sensitivity in NMR experiments have been discovered, but perhaps the most generally applicable method is microwave-driven dynamic nuclear polarization (DNP). In a DNP-enhanced NMR experiment, mixtures of stable organic radicals and a molecule of interest are irradiated at particular microwave frequencies. The irradiation causes polarization to be transferred from the radical electrons-which are naturally more polarized-to the less polarized nuclei, resulting in enhanced NMR signal intensity. Until recently, DNP experiments have made use of conventional stable organic radicals as a source of polarized electrons. Because these radicals are not specifically designed for use in the DNP process, signal enhancements fall short of the theoretical maximum values. This proposal aims to improve overall signal enhancement in DNP experiments by design and synthesis of radicals specifically tailored for use as DNP agents. The strategies proposed include: 1) tuning radical electron g-values to precisely match the conditions ideal for the operative DNP mechanisms. This will be accomplished by incorporating heavy atoms and transition metals into the electronic structure of known radical DNP agents; 2) optimizing the electron spin-lattice relaxation times in order to reduce the necessary build-up time for nuclear polarization. This can be achieved by functionalizing the peripheral components of the radicals; and 3) maximizing electron-electron dipolar coupling while simultaneously minimizing exchange coupling to further increase polarization. Optimizing couplings will require assaying a number of potential linking units binding two radicals. Organic and inorganic synthetic methods will provide access to the proposed radicals, and detailed investigation of the electronic and magnetic properties of the synthesized radicals will inform further design. Success with any of these strategies stands to improve enhancement factors of DNP agents, thus rendering advanced NMR techniques more amenable for the investigation of crucial human health issues.

描述（由申请人提供）：核磁共振（NMR）光谱非常适合提供有关非晶体材料的结构和动力学的信息；这些包括与生物学相关的材料，例如非结晶蛋白，膜结合的蛋白，淀粉样蛋白，肽，胶束和囊泡。因此，这项技术有望阐明许多病理过程，其中涉及包括糖尿病，阿尔茨海默氏症和帕金森氏症等疾病。由于这些NMR技术通常涉及对低平衡极化的低γ核观察，但是，NMR实验中的灵敏度本质上很低，并且实验必须艰巨的时间长。已经发现了在NMR实验中提高核灵敏度的许多方法，但也许最普遍适用的方法是微波驱动的动态核极化（DNP）。在DNP增强的NMR实验中，稳定的有机自由基和感兴趣分子的混合物在特定的微波频率下被照射。辐照导致极化从自由基电子转移，这自然更偏振对较小的核，从而增强了NMR信号强度。 直到最近，DNP实验还将常规稳定的有机自由基作为偏振电子的来源。由于这些自由基不是专门为DNP过程中使用的，因此信号增强功能均未达到理论上的最大值。该建议旨在通过设计和合成专门用于使用DNP剂的自由基来改善DNP实验中的总体信号增强。 提出的策略包括：1）调整自由基电子g值，以与手术DNP机制的理想条件完全匹配。这将通过将重原子和过渡金属纳入已知自由基DNP药物的电子结构中来实现； 2）优化电子自旋晶格松弛时间，以减少核极化的必要积累时间。这可以通过使自由基的外围成分官能化来实现。 3）最大化电子电子偶极耦合，同时最大程度地减少交换耦合以进一步增加极化。优化耦合将需要测定一些绑定两个自由基的潜在链接单元。有机和无机合成方法将提供对所提出的自由基的访问，对合成自由基的电子和磁性的详细研究将为进一步的设计提供信息。这些策略的成功旨在改善DNP代理的增强因素，从而使高级NMR技术更适合研究关键的人类健康问题。