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

摘要 在体内，13C MRS/MRI提供了实时观察各种代谢过程的独特机会 当使用超极化技术时就会发生这种情况。最常见的超极化技术是 溶解动态核极化(DNP)。DNP的工作原理是通过微波增强核磁共振信号- 从电子到靶核的驱动极化转移。而溶解的DNP-核磁共振可以戏剧性地产生 增强的液态核磁共振信号，它有严重的局限性，包括昂贵的硬件，需要免费的 自由基偏振剂、低温下延长的偏振建立时间和批量操作。 13C超极化的另一种技术是对氢诱导极化(PhIP)，它包括 对位氢(富含对位自旋异构体的氢气)与不饱和化合物的化学加成 底物，然后将对-H2的单重态自旋顺序转换为13C自旋极化 磁场循环。尽管PhIP需要特定的化学成分，但PhIP相对于DNP的优势使得 技术非常吸引人：它的成本要低得多，速度快得多，而且能够大规模生产 超极化样品，潜在地以连续流动的方式。在这个探索性项目中，我们将开发 创新化学(重要代谢物和新型催化剂的13C富集物、不饱和前体 系统)，这将显著扩大~(13)C代谢研究的PHIP范围。目标1的目标是 ~(13)C标记的2-酮戊二酸不饱和前体的合成与PhIP 三氯乙烷循环。在目标2中，我们将探索13C标记的丙酮酸和丙酮酸的O-乙酰化烯醇衍生物的phip。 草酰乙酸酯。这些中间体的催化加氢将产生乳酸和苹果酸的衍生物。一位少校 这一目标的目标是开发手性催化剂体系，优先提供天然的L- 这些重要代谢物的形态。

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.