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.

抽象的 In Vivo 13C MRS/MRI提供了独特的机会，可以实时观察各种代谢过程通过超极化技术启用时发生。超极化最常见的技术是溶解动态核极化（DNP）。 DNP通过微波炉增强NMR信号的工作原理从电子到靶核的驱动极化转移。溶解DNP-NMR可以急剧产生增强的液态NMR信号，它具有严重的限制，包括昂贵的硬件，需要免费的激进的偏振剂，在低温温度下扩展极化时间和批处理操作。 13C超极化的另一种技术是para-Hydragen诱导的极化（PHIP），涉及化学添加para-氢气（富含Para旋转异构体中的氢气）至不饱和底物随后通过para-h2的单线自旋顺序转化为13c旋转极化磁场循环。尽管PHIP需要特定的化学反应，但PHIP比DNP的优点使得技术非常吸引人：它的价格要便宜得多，更快且能够大规模生产超极化样品，有可能以连续的流动方式。在这个探索性项目中，我们将开发创新化学（13C富集的，不饱和的前体，重要的代谢物和新型催化剂系统）将显着扩大PHIP的范围，以进行13C代谢研究。目标1的目标是 13C标记的不饱和前体的合成和pHIP与2-酮戊二酸酯，这是一个重要的中间体 TCA周期。在AIM 2中，我们将探索13C标记的丙酮酸和丙烯酸烯醇衍生物的PHIP 草乙酸。这些中间体的催化氢化将产生乳酸和苹果酸衍生物。专业这个目标的目标是发展手性催化剂系统，这些系统优先提供天然L- 这些重要代谢物的形式。