Laboratory of Functional and Metabolic Imaging, EPFL, Lausanne, Switzerland.
Department of Diagnostic and Interventional Radiology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland.
NMR Biomed. 2021 Nov;34(11):e4584. doi: 10.1002/nbm.4584. Epub 2021 Jul 10.
It was recently demonstrated that nonpersistent radicals can be generated in frozen solutions of metabolites such as pyruvate by irradiation with UV light, enabling radical-free dissolution dynamic nuclear polarization. Although pyruvate is endogenous, the presence of pyruvate may interfere with metabolic processes or the detection of pyruvate as a metabolic product, making it potentially unsuitable as a polarizing agent. Therefore, the aim of the current study was to characterize solutions containing endogenously occurring alternatives to pyruvate as UV-induced nonpersistent radical precursors for in vivo hyperpolarized MRI. The metabolites alpha-ketovalerate (αkV) and alpha-ketobutyrate (αkB) are analogues of pyruvate and were chosen as potential radical precursors. Sample formulations containing αkV and αkB were studied with UV-visible spectroscopy, irradiated with UV light, and their nonpersistent radical yields were quantified with electron spin resonance and compared with pyruvate. The addition of C-labeled substrates to the sample matrix altered the radical yield of the precursors. Using αkB increased the C-labeled glucose liquid-state polarization to 16.3% ± 1.3% compared with 13.3% ± 1.5% obtained with pyruvate, and 8.9% ± 2.1% with αkV. For [1- C]butyric acid, polarization levels of 12.1% ± 1.1% for αkV, 12.9% ± 1.7% for αkB, 1.5% ± 0.2% for OX063 and 18.7% ± 0.7% for Finland trityl, were achieved. Hyperpolarized [1- C]butyrate metabolism in the heart revealed label incorporation into [1- C]acetylcarnitine, [1- C]acetoacetate, [1- C]butyrylcarnitine, [5- C]glutamate and [5- C]citrate. This study demonstrates the potential of αkV and αkB as endogenous polarizing agents for in vivo radical-free hyperpolarized MRI. UV-induced, nonpersistent radicals generated in endogenous metabolites enable high polarization without requiring radical filtration, thus simplifying the quality-control tests in clinical applications.
最近的研究表明，非持久性自由基可以在丙酮酸等代谢物的冷冻溶液中通过紫外线照射产生，从而实现自由基自由溶解的动态核极化。虽然丙酮酸是内源性的，但丙酮酸的存在可能会干扰代谢过程或检测丙酮酸作为代谢产物，使其不太适合作为极化剂。因此，本研究的目的是表征含有内源性替代丙酮酸的溶液，作为用于体内高极化 MRI 的 UV 诱导的非持久性自由基前体。α-酮戊酸（αkV）和α-酮丁酸（αkB）是丙酮酸的类似物，被选为潜在的自由基前体。研究了含有 αkV 和 αkB 的样品配方，用紫外可见光谱进行了研究，用紫外线照射，并通过电子自旋共振对其非持久性自由基产率进行了定量，与丙酮酸进行了比较。向样品基质中添加 13C 标记的底物会改变前体的自由基产率。与使用丙酮酸获得的 13.3%±1.5%相比，使用 αkB 可将 13C 标记的葡萄糖液相极化度提高到 16.3%±1.3%，使用 αkV 可提高到 8.9%±2.1%。对于 1-13C 丁酸，αkV 的极化水平为 12.1%±1.1%，αkB 为 12.9%±1.7%，OX063 为 1.5%±0.2%，Finland trityl 为 18.7%±0.7%。在心脏中进行的高极化 1-13C 丁酸代谢研究表明，标记物掺入到 1-13C 乙酰肉碱、1-13C 乙酰乙酸盐、1-13C 丁酰肉碱、5-13C 谷氨酸和 5-13C 柠檬酸盐中。这项研究表明，αkV 和 αkB 作为内源性极化剂在体内自由基自由高极化 MRI 中具有潜力。在紫外线照射下，内源性代谢物中产生的非持久性自由基可以实现高极化，而无需进行自由基过滤，从而简化了临床应用中的质量控制测试。
