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

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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.