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Dicarboxylic acids as pH sensors for hyperpolarized 13C magnetic resonance spectroscopic imaging.

ABSTRACT: Imaging tumoral pH may help to characterize aggressiveness, metastasis, and therapeutic response. We report the development of hyperpolarized [2-13C,D10]diethylmalonic acid, which exhibits a large pH-dependent 13C chemical shift over the physiological range. We demonstrate that co-polarization with [1-13C,D9]tert-butanol accurately measures pH via13C NMR and magnetic resonance spectroscopic imaging in phantoms.

SUBMITTER: Korenchan DE

PROVIDER: S-EPMC5462110 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Dicarboxylic acids as pH sensors for hyperpolarized 13C magnetic resonance spectroscopic imaging.

Korenchan D E DE Taglang C C von Morze C C Blecha J E JE Gordon J W JW Sriram R R Larson P E Z PEZ Vigneron D B DB VanBrocklin H F HF Kurhanewicz J J Wilson D M DM Flavell R R RR

The Analyst 20170501 9

Imaging tumoral pH may help to characterize aggressiveness, metastasis, and therapeutic response. We report the development of hyperpolarized [2-13C,D10]diethylmalonic acid, which exhibits a large pH-dependent 13C chemical shift over the physiological range. We demonstrate that co-polarization with [1-13C,D9]tert-butanol accurately measures pH via13C NMR and magnetic resonance spectroscopic imaging in phantoms. ...[more]

PMID: 28322385

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Project description:In the heart, detection of hyperpolarized [(13)C]bicarbonate and (13)CO(2) by magnetic resonance (MR) after administration of hyperpolarized [1-(13)C]pyruvate is caused exclusively by oxidative decarboxylation of pyruvate via the pyruvate dehydrogenase complex (PDH). However, liver mitochondria possess alternative anabolic pathways accessible by [1-(13)C]pyruvate, which may allow a wider diagnostic range for hyperpolarized MR compared with other tissue. Metabolism of hyperpolarized [1-(13)C]pyruvate in the tricarboxylic acid (TCA) cycle was monitored in the isolated perfused liver from fed and fasted mice. Hyperpolarized [1-(13)C]pyruvate was rapidly converted to [1-(13)C]lactate, [1-(13)C]alanine, [1-(13)C]malate, [4-(13)C]malate, [1-(13)C]aspartate, [4-(13)C]aspartate, and [(13)C]bicarbonate. Livers from fasted animals had increased lactate:alanine, consistent with elevated NADH:NAD(+). The appearance of asymmetrically enriched malate and aspartate indicated high rates of anaplerotic pyruvate carboxylase activity and incomplete equilibration with fumarate. Hyperpolarized [(13)C]bicarbonate was also detected, consistent with multiple mechanisms, including cataplerotic decarboxylation of [4-(13)C]oxaloacetate via phosphoenolpyruvate carboxykinase (PEPCK), forward TCA cycle flux of [4-(13)C]oxaloacetate to generate (13)CO(2) at isocitrate dehydrogenase, or decarboxylation of [1-(13)C]pyruvate by PDH. Isotopomer analysis of liver glutamate confirmed that anaplerosis was sevenfold greater than flux through PDH. In addition, signal from [4-(13)C]malate and [4-(13)C]aspartate was markedly blunted and signal from [(13)C]bicarbonate was completely abolished in livers from PEPCK KO mice, indicating that the major pathway for entry of hyperpolarized [1-(13)C]pyruvate into the hepatic TCA cycle is via pyruvate carboxylase, and that cataplerotic flux through PEPCK is the primary source of [(13)C]bicarbonate. We conclude that MR detection of hyperpolarized TCA intermediates and bicarbonate is diagnostic of pyruvate carboxylase and PEPCK flux in the liver.

Dataset Information

Dicarboxylic acids as pH sensors for hyperpolarized 13C magnetic resonance spectroscopic imaging.

Publications

Dicarboxylic acids as pH sensors for hyperpolarized <sup>13</sup>C magnetic resonance spectroscopic imaging.

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