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| Chemical name: | [11C]Acetoacetate |  |
| Abbreviated name: | [11C]ACAC | |
| Synonym: | [11C]Acetoacetic acid | |
| Agent Category: | Compound | |
| Target: | Acetoacetyl coenzyme A transferase and fatty acid synthetase | |
| Target Category: | Incorporation into membrane | |
| Method of detection: | PET | |
| Source of signal: | 11C | |
| Activation: | No | |
| Studies: |
| Click on the above structure for additional information in PubChem. |
[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 CO2 via 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).
[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).
[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.
[PubMed]
Authier et al. (8) studied the biodistribution of [11C]ACAC and [11C]acetate in mice bearing tumors of various cell lines (n = 2 - 10 mice/group). The optimal tumor accumulation of [11C]ACAC was between 5 and 30 min after injection, with maximal accumulation of 2.72 ± 0.38%, 2.42 ± 1.10%, 2.54 ± 0.87%, and 3.15 ± 0.58% ID/g for MC7-L1, MC4-L2, PC3, and LN-CaP tumors, respectively. The optimal tumor accumulation of [11C]acetate was reached at 5–15 min after injection, with maximal accumulation of 1.25 ± 0.05%, 2.30 ± 09%, and 0.96 ± 0.24% ID/g for MC7-L1, MC4-L2, and PC3, respectively. The tumor/muscle ratios and tumor accumulation tended to be higher for [11C]ACAC than [11C]acetate, but the differences did not reach statistical significance (P > 0.05). High to moderate accumulation was observed in the kidneys, spleen, liver, heart, lung, brain, and ovaries/testes for both tracers. Prenen et al. (9) performed PET imaging to study tissue accumulation of [11C]ACAC in rats (n = 6) at 20 min after injection. The organ with the highest uptake was the liver (3.6 ± 0.5% injected dose (ID)), followed by the brain (2.7 ± 0.4% ID), kidneys (2.5 ± 0.4% ID), and heart (2.0 ± 0.5% ID).
[PubMed]
Prenen et al. (9) performed PET imaging to study tissue accumulation of [11C]ACAC in cats (n = 2) at 1.5-20 min after injection. The organ with the highest uptake was the liver (8.5-12.7% ID), followed by the brain (6.6-10.4% ID), kidneys (4.8-6.6% ID), and heart (2.3-2.95% ID) at 20 min.
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