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Para-hydrogen induced polarization of 13C labeled TCA cycle metabolite precursors

13C 标记的 TCA 循环代谢物前体的仲氢诱导极化

基本信息

批准号：
10434648
负责人：
Zoltan Kovacs
金额：
$ 24.6万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10434648
关键词：
Acetates Acids Bolus Infusion Carbon Cell Nucleus Chemicals Chemistry Citric Acid Cycle Development Electron Transport Formulation Free Radicals Gases Goals Hour Hydrogen Hydrogenation Individual Injections Isomerism L Forms Label Liquid substance Liver Magnetic Resonance Imaging Malates Metabolic Metabolism Molecular Mus N-methylacetamide-oxotremorine M Nature Nuclear Optics Oranges Oxaloacetates Positioning Attribute Positron-Emission Tomography Protein Isoforms Pyruvate Relaxation Sampling Series Signal Transduction System Techniques Temperature Testing Time Work alpha ketoglutarate catalyst chemical addition cold temperature cost effective cryogenics enol enolate in vivo innovation large scale production magnetic field metabolic abnormality assessment microwave electromagnetic radiation novel operation pi bond pressure prospective scale up virtual

项目摘要

Abstract In vivo 13C MRS/MRI offers the unique opportunity to observe various metabolic processes in real time as they happen when enabled by a hyperpolarization technique. The most common technique for hyperpolarization is dissolution Dynamic Nuclear Polarization (DNP). DNP works by enhancing the NMR signal via the microwave- driven polarization transfer from electrons to target nuclei. While dissolution DNP-NMR can produce dramatically enhanced liquid state NMR signals, it has severe limitations including expensive hardware, the need for a free radical polarizing agent, extended polarization build-up time at cryogenic temperatures and batch-wise operation. An alternative technique for 13C hyperpolarization is para-hydrogen induced polarization (PHIP), which involves the chemical addition of para-hydrogen (hydrogen gas enriched in the para spin isomer) to unsaturated substrates followed by the conversion of the singlet spin order of the para-H2 into 13C spin polarization by magnetic field cycling. Although PHIP requires specific chemistry, the advantages of PHIP over DNP make this technique very appealing: it is far less expensive, faster and capable of the large-scale production of hyperpolarized samples, potentially in a continuous flow manner. In this exploratory project we will develop innovative chemistries (13C-enriched, unsaturated precursors to important metabolites and novel catalyst systems) that will significantly widen the scope of PHIP for 13C metabolic studies. The goal of Aim 1 is the synthesis and PHIP of 13C-labeled, unsaturated precursors to 2-ketoglutarate, an important intermediate of the TCA cycle. In Aim 2, we will explore the PHIP of O-acetylated enol derivatives of 13C labeled pyruvate and oxaloacetate. Catalytic hydrogenation of these intermediates will yield lactate and malate derivatives. A major goal of this aim will be the development of chiral catalyst systems that would preferentially afford the natural L- form of these important metabolites.

摘要在体内13 C MRS/MRI提供了独特的机会，观察各种代谢过程中的真实的时间，因为他们发生时，启用超极化技术。最常用的超极化技术是溶解动态核极化（DNP）。DNP的工作原理是通过微波增强NMR信号- 从电子到靶核的驱动极化转移。而溶解DNP-NMR可以产生显着的增强的液态NMR信号，它有严重的限制，包括昂贵的硬件，需要免费的自由基极化剂，在低温下延长的极化建立时间和分批操作。用于13 C超极化的替代技术是仲氢诱导极化（PHIP），其涉及将仲氢（富含帕拉自旋异构体的氢气）化学加成到不饱和的衬底，然后通过以下步骤将对-H2的单重态自旋顺序转化为13 C自旋极化：磁场循环虽然PHIP需要特定的化学反应，但PHIP相对于DNP的优势使其技术非常有吸引力：它是更便宜，更快，能够大规模生产的超极化的样品，可能以连续流动的方式。在这个探索性的项目中，我们将开发创新化学（富含13 C的重要代谢物和新型催化剂的不饱和前体系统），这将显着扩大PHIP的13 C代谢研究的范围。目标1的目标是合成和PHIP的13 C标记的，不饱和的前体2-酮戊二酸，一个重要的中间体， TCA循环。在目标2中，我们将探索13 C标记的丙酮酸的O-乙酰化烯醇衍生物的PHIP，草酰乙酸。这些中间体的催化氢化将产生乳酸盐和苹果酸盐衍生物。一个主要这一目标的目标将是开发优先提供天然L- 这些重要的代谢物的形式。