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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