Acetate and PET

Acetate is important intermediary two-carbon substrate in the form of acetyl-CoA. Acetyl-CoA can either enter into the TCA cycle in mitochondria (the main route in myocardium and brain), or it is incorporated into structural lipids (mainly in tumours) by fatty acid synthase or acetyl-CoA carboxylase (Grassi et al., 2012). Acetyl-CoA can also enter into synthesis of amino acids (mainly glutamate and glutamine) and cholesterol, and used in gluconeogenesis and histone acetylation.

Most of acetyl-CoA is produced from pyruvate or β-oxidation of fatty acids, though, since the amount of ingested acetate and acetate formed in the colon by bacterial fermentation is minimal compared to the other metabolic substrates. Acetate from gastrointestinal tract is mostly metabolized in the liver, but part of it can enter circulation. Acetate is cleared from blood rapidly. Monocarboxylate transporters and possibly sodium-dependent monocarboxylate transporter and aquaporins transport acetate across cell membranes.

In the cytosol and mitochondria, acetate is converted into acetyl-CoA by enzyme acetate-CoA ligase (acetyl-CoA synthetase, ACS) in a reaction that consumes ATP.

Acetate can relatively slowly pass the blood-brain barrier. In brain acetate is taken up by astrocytes. Brain is normally a net producer of acetate. The role of short chain fatty acids (SCFAs, including acetate, propionate, butyrate, isobutyrate, valerate and isovalerate) in gut-brain axis signalling is being researched (O'Riordan et al., 2022; Rosli et al., 2023). [¹¹C]Butyrate, with its good uptake in human brain, may be suitable for this purpose (Pakula et al., 2023). Acetate changes the expression profiles of regulatory neuropeptides that favour appetite suppression (Frost et al., 2014). Acetate infusion has been shown to increase endogenous opioid levels in the human brain (Ashok et al., 2021).

Acetate concentration in the blood plasma is usually <100 µM, higher after feeding, and can increase in liver diseases, ketogenic diet, acidosis, and after alcohol consumption. Acetate concentration depends on the blood sampling site, sample preparation, and storage (Tollinger et al., 1979; Scutches et al., 1979).

¹¹C-labelled acetate

Acetate molecule has two carbon atoms, either or both of which could be replaced with ¹¹C to produce a PET radiopharmaceutical which is chemically identical to natural acetate (Kihlberg et al., 1994).

The in vivo kinetics of [¹¹C]acetate depend on which position the radionuclide is labelled. The label from the C-1 position (carboxyl group) is released as [¹¹C]CO₂ in the second pass through the TCA cycle. The label from C-2 position (methyl group) can happen only after 2 passes, with ∼50% probability in each pass; thus much larger proportion of ¹¹C in [2-¹¹C]acetate would be incorporated in amino acid pool (van den Hoff et al., 1996; Klein et al., 2001). The administered ¹¹C is cleared from the body through lungs as [¹¹C]CO₂.

[1-¹¹C]Acetate ([¹¹C]acetate, [¹¹C]ACE) is a general PET radiopharmaceutical of cellular carbon flux and useful for clinical imaging in heart disease as well as prostate cancer and other tumours (Lindhe et al., 2009). Due to its high first-pass extraction its initial uptake is proportional to perfusion. In tissues where acetyl-CoA is directed to ATP production, the rapid efflux rate of tissue radioactivity can be used to assess regional oxidative metabolism. In tumours acetyl-CoA is directed to fatty acid and amino acid synthesis, leading to trapping of radioactivity, which enables assessment of tumour growth. [¹¹C]Acetate may have higher sensitivity than [¹⁸F]FDG for detection of prostate cancer, bladder cancer, hepatocellular carcinoma, and some other cancers. [1-¹¹C]Acetate could be used as a marker of astrocytic metabolism in the brain (Wyss et al., 2011).

¹⁸F-labelled acetate

The hydrogen atoms of the methyl group can be replaced with ¹⁸F to produce [¹⁸F]fluoroacetate ([¹⁸F]FAC, [¹⁸F]FACE). ¹⁸F has much longer half-life (110 min) than ¹¹C (20.4 min), making [¹⁸F]fluoroacetate better suited for clinics than [¹¹C]acetate (Ponde et al., 2007). However, [¹⁸F]fluoroacetate has much longer half-life in blood than [¹¹C]acetate, with little signs of specific retention in tissues, and therefore [¹⁸F]fluoroacetate cannot be regarded as a functional analogue of [¹¹C]acetate in normal physiology and appears to be of little use for studies of organ blood flow, intermediary metabolism or lipid synthesis. ¹⁸F is excreted into bile and urine. (Lindhe et al., 2009; Ho et al., 2012). Except for the kidneys, concentration of [¹⁸F]fluoroacetate is higher in blood than in organs, and the uptake in tumour may reflect the blood pool (Takemoto et al., 2014). Also [¹⁸F]fluoropyruvate has shown poor tissue uptake. [¹⁸F]Fluoroacetate has shown species-dependent defluorination.

Intracellular [¹⁸F]fluoroacetate can be converted to [¹⁸F]fluorocitrate (Yeh et al., 2013). Fluorocitrate is a suicide inhibitor of aconitate hydratase (aconitase), an enzyme that catalyzes the stereospecific isomerization of citrate to isocitrate in the TCA cycle. Fluorocitrate is highly toxic, but the dose of [¹⁸F]fluoroacetate in PET studies is so small that it can be safely used in human PET studies (Nishii et al., 2012). The [¹⁸F]fluoroacetate is trapped in cells as [¹⁸F]fluorocitrate in proportion to oxidative metabolism, but comparison of uptake in different tissues does not resemble the TCA cycle activities. (Lindhe et al., 2009). In brain, increased [¹⁸F]fluoroacetate uptake may indicate ischaemic regions (Yamauchi et al., 2015).

In the brain, [¹⁸F]fluoroacetate is taken up by glial cells, and it might be useful for assessing glial metabolism (Marik et al., 2009; Ouyang et al., 2014). Because of the poor BBB penetration of [¹⁸F]fluoroacetate, Mori et al (2009) esterified it with ethanol to increase lipophilicity. The resulting proradiotracer [¹⁸F]EFA entered the brain rapidly and was converted to TCA cycle metabolites (Mori et al., 2009).

2-[¹⁸F]fluoropropionate

2-[¹⁸F]fluoropropionate is another SCFA radiopharmaceutical that mimics acetate, and could be used in tumour imaging because of increased fatty acid synthesis (Pillarsetty et al., 2009; Zhao et al., 2019; Zhang et al., 2019 and 2021).

See also:

• [¹¹C]Acetate
• Pyruvate
• Lactate
• Ketone bodies
• Monocarboxylate transporters

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Literature

Clarke DD. Fluoroacetate and fluorocitrate: mechanism of action. Neurochem Res. 1991; 16(9): 1055-1058. doi: 10.1007/BF00965850.

Grassi I, Nanni C, Allegri V, Morigi JJ, Montini GC, Castellucci P, Fanti S. The clinical use of PET with ¹¹C-acetate. Am J Nucl Med Mol Imaging 2012; 2(1): 33-47. PMID: 23133801.

O'Riordan KJ, Collins MK, Moloney GM, Knox EG, Aburto MR, Fülling C, Morley SJ, Clarke G, Schellekens H, Cryan JF. Short chain fatty acids: Microbial metabolites for gut-brain axis signalling. Mol Cell Endocrinol. 2022; 546: 111572. doi: 10.1016/j.mce.2022.111572.

Pike VW, Eakins MN, Allan RM, Selwyn AP. Preparation of [1-11C]acetate - an agent for the study of myocardial metabolism by positron emission tomography. Int J Appl Radiat Isot. 1982; 33(7): 505-512. doi: 10.1016/0020-708x(82)90003-5.

Tags: Acetate, Acetyl-CoA, Fatty acids

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Updated at: 2023-02-21
Created at: 2008-11-27
Written by: Vesa Oikonen