Quantification of in vivo metabolic kinetics of hyperpolarized pyruvate in rat kidneys using dynamic 13C MRSI
Quantification of in vivo metabolic kinetics of hyperpolarized pyruvate in rat kidneys using dynamic 13C MRSI
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DOI：
10.1002/nbm.1719
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发表时间：
2011-10-01
影响因子：
2.9
通讯作者：
Spielman, Daniel
中科院分区：
文献类型：
--
作者：
Xu, Tao;Mayer, Dirk;Spielman, Daniel
随着信噪比增强约10，000倍，代谢活性底物的超极化MRSI允许在体内研究注射的底物和下游代谢产物。尽管超极化[1-C-13]丙酮酸盐已被用于证明各种动物模型中的代谢活性，但稳健的定量和代谢建模仍然是重要的研究领域。常用剂量的超极化[1-C-13]丙酮酸盐通常可观察到酶饱和效应;然而，迄今为止提出的大多数指标，包括代谢物比率、代谢产物的达峰时间和单一交换速率常数，均未能捕获这些饱和效应。此外，广泛使用的小翻转角激发方法不能正确模拟靶切片附近产生的新鲜下游代谢物的流入，这通常是体内的重要因素。在这项工作中，我们开发了一个有效的量化框架，采用螺旋为基础的动态光谱成像方法。该方法克服了上述局限性，并证明在推注[1-C-13]丙酮酸盐后乳酸盐和丙氨酸的体内C-13标记通过可饱和动力学很好地近似，其可以使用Michaelis-Menten样公式进行数学建模，与所得的估计的表观最大反应速度V-max和表观米氏常数K-M相对于关键实验参数（包括底物剂量、团形状和持续时间）是无偏的。虽然所提出的饱和模型具有与原始Michaelis-Menten动力学类似的数学公式，但它在概念上是不同的。在这项研究中，我们专注于C-13标记的乳酸和丙氨酸，不区分标记机制（净流量或同位素交换）或各种因素（器官灌注率，底物转运动力学，酶活性和未标记的乳酸和丙氨酸池的大小）的各自的贡献的标记过程。版权所有（C）2011约翰威利父子有限公司
With signal-to-noise ratio enhancements on the order of 10,000-fold, hyperpolarized MRSI of metabolically active substrates allows the study of both the injected substrate and downstream metabolic products in vivo. Although hyperpolarized [1-C-13]pyruvate, in particular, has been used to demonstrate metabolic activities in various animal models, robust quantification and metabolic modeling remain important areas of investigation. Enzyme saturation effects are routinely seen with commonly used doses of hyperpolarized [1-C-13] pyruvate; however, most metrics proposed to date, including metabolite ratios, time-to-peak of metabolic products and single exchange rate constants, fail to capture these saturation effects. In addition, the widely used small-flip-angle excitation approach does not correctly model the inflow of fresh downstream metabolites generated proximal to the target slice, which is often a significant factor in vivo. In this work, we developed an efficient quantification framework employing a spiral-based dynamic spectroscopic imaging approach. The approach overcomes the aforementioned limitations and demonstrates that the in vivo C-13 labeling of lactate and alanine after a bolus injection of [1-C-13] pyruvate is well approximated by saturatable kinetics, which can be mathematically modeled using a Michaelis-Menten-like formulation, with the resulting estimated apparent maximal reaction velocity V-max and apparent Michaelis constant K-M being unbiased with respect to critical experimental parameters, including the substrate dose, bolus shape and duration. Although the proposed saturatable model has a similar mathematical formulation to the original Michaelis-Menten kinetics, it is conceptually different. In this study, we focus on the C-13 labeling of lactate and alanine and do not differentiate the labeling mechanism (net flux or isotopic exchange) or the respective contribution of various factors (organ perfusion rate, substrate transport kinetics, enzyme activities and the size of the unlabeled lactate and alanine pools) to the labeling process. Copyright (C) 2011 John Wiley & Sons, Ltd.