Hyperpolarized [1,3-C-13(2)]ethyl acetoacetate is a novel diagnostic metabolic marker of liver cancer

Pernille Rose Jensen, Sonia Colombo Serra, Luigi Miragoli, Magnus Karlsson, Claudia Cabella, Luisa Poggi, Luca Venturi, Fabio Tedoldi, Mathilde Hauge Lerche

Research output: Contribution to journalJournal articleResearchpeer-review


An increased prevalence of liver diseases such as hepatitis C and nonalcoholic fatty liver results in an augmented incidence of the most common form of liver cancer, hepatocellular carcinoma (HCC). HCC is most often found in the cirrhotic liver and it can therefore be challenging to rely on anatomical information alone when diagnosing HCC. Valuable information on specific cellular metabolism can be obtained with high sensitivity thanks to an emerging magnetic resonance (MR) technique that uses C-13 labeled hyperpolarized molecules. Our interest was to explore potential new high contrast metabolic markers of HCC using hyperpolarized C-13-MR. This work led to the identification of a class of substrates, low molecular weight ethyl-esters, which showed high specificity for carboxyl esterases and proved in many cases to possess good properties for signal enhancement. In particular, hyperpolarized [1,3-C-13(2)]ethyl acetoacetate (EAA) was shown to provide a metabolic fingerprint of HCC. Using this substrate a liver cancer implanted in rats was diagnosed as a consequence of an approximate to 4 times higher metabolic substrate-to-product ratio than in the surrounding healthy tissue, (p=0.009). Unregulated cellular uptake as well as cosubstrate independent enzymatic conversion of EAA, made this substrate highly useful as a hyperpolarized C-13-MR marker. This could be appreciated by the signal-to-noise (SNR) obtained from EAA, which was comparable to the SNR reported in a literature liver cancer study with state-of-the-art hyperpolarized substrate, [1-C-13]pyruvate. Also, the contrast-to-noise (CNR) in the EAA based metabolic ratio images was significantly improved compared with the CNR in equivalent images reported using [1-C-13]pyruvate.What's New? An emerging approach to metabolic imaging in cancer is based on C-13-hyperpolarized magnetic resonance (MR) spectroscopy. But metabolic markers specific to cancer must be identified to realize its promise. Here, metabolic conversion of hyperpolarized esters was explored as a potential means of detecting hepatocellular carcinoma (HCC). Hyperpolarized [1,3-C-13(2)]ethyl acetoacetate (EAA) was found to be an exceptionally good substrate for carboxyl esterase-1, concentrations and activities of which are altered in cancer cells. Metabolic conversion of EAA as a substrate for C-13-hyperpolarized MR significantly enhanced the detection of implanted liver cancer in rats.
Original languageEnglish
JournalInternational Journal of Cancer
Issue number4
Pages (from-to)E117-E126
Publication statusPublished - 2015
Externally publishedYes


  • Cancer Research
  • Oncology
  • Medicine (all)
  • 13C-DNP
  • Carboxyl esterase
  • Metabolism
  • Tumor
  • carbon 13
  • carboxylesterase
  • nuclear magnetic resonance imaging agent
  • unclassified drug
  • [1,3 (carbon 13)2 ] ethyl acetoacetate
  • acetoacetic acid derivative
  • contrast medium
  • ethyl acetoacetate
  • tumor marker
  • animal cell
  • animal experiment
  • animal model
  • animal tissue
  • Article
  • carbon nuclear magnetic resonance
  • cell metabolism
  • cell transport
  • chemical shift imaging
  • contrast to noise ratio
  • controlled study
  • disease marker
  • drug structure
  • enzyme activity
  • enzyme mechanism
  • human
  • human cell
  • hyperpolarization
  • imaging and display
  • in vivo study
  • liver cell carcinoma
  • molecular weight
  • nonhuman
  • rat
  • sensitivity and specificity
  • signal noise ratio
  • signal processing
  • animal
  • Buffalo rat
  • cancer transplantation
  • diagnostic use
  • HepG2 cell line
  • liver
  • Liver Neoplasms, Experimental
  • metabolism
  • Acetoacetates
  • Animals
  • Carboxylesterase
  • Contrast Media
  • Hep G2 Cells
  • Humans
  • Liver
  • Neoplasm Transplantation
  • Rats, Inbred BUF
  • Signal-To-Noise Ratio
  • Tumor Markers, Biological
  • Biomarkers, Tumor
  • carboxyl esterase
  • tumor
  • NMR
  • hepatocellular carcinoma Carcinoma, Hepatocellular (MeSH) Liver Neoplasms (MeSH) digestive system disease, neoplastic disease diagnosis
  • Primates Mammalia Vertebrata Chordata Animalia (Animals, Chordates, Humans, Mammals, Primates, Vertebrates) - Hominidae [86215] HepG2 cell line cell_line human hepatocellular carcinoma cells
  • Rodentia Mammalia Vertebrata Chordata Animalia (Animals, Chordates, Mammals, Nonhuman Vertebrates, Nonhuman Mammals, Rodents, Vertebrates) - Muridae [86375] rat common strain-Buffalo McA-RH 7777 cell line cell_line rat Morris hepatoma cells
  • [1-carbon-13]pyruvate diagnostic-drug
  • carboxyl esterase 9016-18-6
  • hyperpolarized [1,3-13-carbon-2]ethyl acetoacetate diagnostic-drug
  • 02506, Cytology - Animal
  • 02508, Cytology - Human
  • 06504, Radiation biology - Radiation and isotope techniques
  • 12504, Pathology - Diagnostic
  • 12512, Pathology - Therapy
  • 14006, Digestive system - Pathology
  • 22002, Pharmacology - General
  • 22005, Pharmacology - Clinical pharmacology
  • 24001, Neoplasms - Diagnostic methods
  • 24004, Neoplasms - Pathology, clinical aspects and systemic effects
  • Human Medicine, Medical Sciences
  • Medical Sciences
  • hyperpolarized carbon-13 magnetic resonance imaging clinical techniques, diagnostic techniques
  • Gastroenterology
  • Pharmacology
  • Radiology
  • 13C‐DNP


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