Background

[PubMed]

Acetate is readily taken up by cells and is activated to acetyl-CoA in both the cytosol and mitochondria by acetyl-CoA synthetase. Acetyl-CoA is a common metabolic intermediate for synthesis of cholesterol and fatty acids, which are then incorporated into membrane tissue (1). Acetyl-CoA is oxidized in mitochondria by the tricarboxylic acid (TCA) cycle to carbon dioxide and water. Some of the acetate is converted to amino acids. In normal myocardium, acetate is metabolized to CO₂via the TCA cycle as the dominant pathway. In contrast, tumor cells convert most of the acetate into fatty acids by a key enzyme fatty acid synthetase, which is overexpressed in cancer cells (2). Acetate is predominantly incorporated into intracellular phosphatidylcholine membrane microdomains that are important for tumor growth and metastasis (3). [¹¹C]Acetate is used as a positron emission tomography (PET) tracer in the study of myocardial oxidative metabolism and regional myocardial blood flow (4). [¹¹C]Acetate is a promising PET tracer for renal, pancreatic, and prostate tumors (5).

Under normal conditions, glucose is converted to acetate to feed into the TCA cycle for energy generation. However, ketone bodies (acetoacetate and hydroxybutyrate) are produced by the liver when the carbohydrate intake is low or during fasting. Liver cells do not utilize the ketone bodies because of a lack of acetoacetyl-CoA transferase for the metabolism of acetoacetate. The ketone bodies became the primary source of energy for the brain, heart, kidney, and skeletal muscle, where they are converted to acetyl-CoA. Human mammary carcinomas and rat hepatomas were found to express increased levels of acetoacetyl-CoA transferase activity in correlation with their growth rates (6, 7). [¹¹C]Acetoacetate ([¹¹C]ACAC ) is being evaluated as a PET agent to measure ketone body utilization by the tumors and brain (8, 9).

Synthesis

[PubMed]

[¹¹C]ACAC was produced by a reaction of the enolate anion of acetone with [¹¹C]carbon dioxide in tetrahydrofuran followed by hydrolysis (9). This method produced [¹¹C]ACAC with a radiochemical yield of 24–58% (decay-corrected) in 30 min with a specific activity of 22.2 GBq/mmol (0.6 Ci/mmol) at the end of bombardment. The radiochemical purity of [¹¹C]ACAC was found to be ~97%. An automated one-pot synthesis system provided radiochemical yields of 22–47% (decay-corrected, n = 20) and radiochemical purity of >97% in 18 min (10).

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Authier et al. (8) compared [¹¹C]ACAC and [¹¹C]acetate uptake in two murine breast cancer cell lines MC7-L1 and MC4-L2 (8). For MC7-L1 cells, 65.5% and 53.0% of total radioactivity were in the cellular lipids at 60 min of incubation with [¹¹C]ACAC and [¹¹C]acetate, respectively. For MC4-L2 cells, 60.4% and 65.6% of total radioactivity accumulation of [¹¹C] ACAC and [¹¹C]acetate was found in the cellular lipids at 60 min of incubation, respectively. Therefore, both [¹¹C]ACAC and [¹¹C]acetate may be metabolized using the similar metabolic pathways leading to lipid synthesis.

Animal Studies

Human Studies

[PubMed]

No publication is currently available.

References

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Howard B.V. , Howard W.J. Lipids in normal and tumor cells in culture. Prog Biochem Pharmacol. 1975; 10 :135–66. [PubMed: 1093205]

2.

Swinnen J.V. , Heemers H. , Deboel L. , Foufelle F. , Heyns W. , Verhoeven G. Stimulation of tumor-associated fatty acid synthase expression by growth factor activation of the sterol regulatory element-binding protein pathway. Oncogene. 2000; 19 (45):5173–81. [PubMed: 11064454]

3.

Swinnen J.V. , Van Veldhoven P.P. , Timmermans L. , De Schrijver E. , Brusselmans K. , Vanderhoydonc F. , Van de Sande T. , Heemers H. , Heyns W. , Verhoeven G. Fatty acid synthase drives the synthesis of phospholipids partitioning into detergent-resistant membrane microdomains. Biochem Biophys Res Commun. 2003; 302 (4):898–903. [PubMed: 12646257]

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Visser F.C. Imaging of cardiac metabolism using radiolabelled glucose, fatty acids and acetate. Suppl 1Coron Artery Dis. 2001; 12 :S12–8. [PubMed: 11286301]

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Schoder H. , Larson S.M. Positron emission tomography for prostate, bladder, and renal cancer. Semin Nucl Med. 2004; 34 (4):274–92. [PubMed: 15493005]

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Fenselau A. , Wallis K. , Morris H.P. Subcellular localization of acetoacetate coenzyme A transferase in rat hepatomas. Cancer Res. 1976; 36 (12):4429–33. [PubMed: 187322]

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Kallinowskil F. , Davel S. , Vaupell P. , Baessler K.H. , Wagner K. Glucose, lactate, and ketone body utilization by human mammary carcinomas in vivo. Adv Exp Med Biol. 1985; 191 :763–73. [PubMed: 3832881]

8.

Authier S. , Tremblay S. , Dumulon V. , Dubuc C. , Ouellet R. , Lecomte R. , Cunnane S.C. , Benard F. [(11)C] Acetoacetate Utilization by Breast and Prostate Tumors: a PET and Biodistribution Study in Mice. Mol Imaging Biol. 2008; 10 (4):217–23. [PubMed: 18454299]

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Prenen G.H. , Go K.G. , Zuiderveen F. , Paans A.M. , Vaalburg W. An improved synthesis of carbon-11 labeled acetoacetic acid and an evaluation of its potential for the investigation of cerebral pathology by positron emission tomography. Int J Rad Appl Instrum [A] 1990; 41 (12):1209–16. [PubMed: 1963420]

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Tremblay S. , Ouellet R. , Rodrigue S. , Langlois R. , Benard F. , Cunnane S.C. Automated synthesis of 11C-acetoacetic acid, a key alternate brain fuel to glucose. Appl Radiat Isot. 2007; 65 (8):934–40. [PubMed: 17544283]