[1-11C]Acetoacetate PET

acetoacetic acid

Ketones, mainly acetoacetate (AcAc) and β-hydroxybutyrate (β-HB), are important alternative fuels to glucose for the brain, the heart, kidneys, skeletal muscle, and tumours. Cerebral metabolic rate of glucose increases almost in proportion to the rise in plasma ketones, independent on the concentration of glucose in plasma (Hasselbach et al., 1996; Blomqvist et al., 2002; Courchesne-Loyer et al., 2017). Increased plasma concentration of ketone bodies also decreases myocardial glucose uptake (Gormsen et al., 2017).

In normal conditions small quantities of the ketone bodies (including also acetone) are produced in the liver as the break-down product of fatty acids in mitochondrial β-oxidation, but during fasting the production of ketones increases. Hepatocytes do not metabolize acetoacetate but release it into the circulation. In other tissues, acetoacetate can be converted to acetoacetyl-CoA and acetyl-CoA in cytosol and mitochondria, and used in energy production or synthesis of several products including amino acids, fatty acids, and sterols (Bentourkia et al., 2009; Croteau et al., 2014).

Acetoacetate, β-HB, pyruvate, lactate, and α-keto acids are transported across the BBB by passive and active diffusion. MCT1 is a common carrier for these molecules in endothelial cells and pericytes, and MCT2 in neurons and astrocytes (Bentourkia et al., 2009).

Ketone bodies labelled with positron emitting radionuclides allows in vivo studies of ketone metabolism (Bouteldja et al., 2014). [1-11C]Acetoacetate (Tremblay et al., 2007), R-β-[1-11C]hydroxybutyrate, and [11C]acetate follow the same transport and metabolism pathway through acetyl-CoA, enabling the use of the same models as are used to analyze [11C]acetate PET studies (Bentourkia et al., 2009; Croteau et al., 2014). R-β-[1-11C]hydroxybutyrate and [1-11C]acetoacetate even equilibrate rapidly in vivo, and both of these tracers, but mostly R-β-[1-11C]hydroxybutyrate, will be present in blood after administration of either of those (Blomqvist et al., 2002; Bentourkia et al., 2009). [11C]AcAc brain data can be analyzed using Patlak plot (Roy et al., 2012; Nugent et al., 2014; Castellano et al., 2015; Courchesne-Loyer et al., 2017). Cerebral metabolic rate of ketones can be calculated from Patlak plot slope (Ki) as:

, where CK is the concentration of ketones (AcAc and β-HB) in plasma, and LC is the lumped constant (LC). LC=1.0, because [11C]AcAc is chemically identical to the native acetoacetate. Bentourkia et al. (2009) fitted a two-tissue compartment model to rat brain and heart data, using Ki = K1*k3/(k2+k3) multiplied by plasma concentration of unlabelled acetoacetate as the outcome parameter.

[11C]AcAc may have some potential use in cancer studies. PET study in mouse models showed that uptake in tumours was clearly higher than in skeletal muscle, and slightly higher than the uptake of [11C]acetate (Authier et al., 2008).

Arterial input function

Arterial sampling is recommended, but image-derived input from left myocardial cavity and internal carotid arteries have also been used (Bentourkia et al., 2009; Roy et al., 2012; Nugent et al., 2014; Castellano et al., 2015).

Plasma-to-blood ratio in a [11C]AcAc mice study (Authier et al., 2008) was about 1.41 at 5 min p.i., and the ratio then stayed at the same level at 15 min and 30 min, and decreased to 1.25 at 60 min, suggesting that unchanged [11C]acetate and its possible first radioactive metabolites stay in plasma, and only late metabolites can penetrate the red blood cell membrane.

The main radioactive metabolite in [11C]AcAc studies is [11C]CO2. Bentourkia et al. (2009) applied an empiric two-parameter function to correct for the fraction of metabolites in the plasma, and fitted these parameters with the compartmental model fit to the PET data. Nugent et al. (2014) and Castellano et al. (2015) corrected the estimate of the metabolic rate for the loss of [11C]CO2 from tissue with the assumption that it is the same as in [1-11C]β-HB study (Blomqvist et al., 1995).


See also:



References:

Authier S, Tremblay S, Dumulon V, Dubuc C, Ouellet R, Lecomte R, Cunnane SC, Bénard F. [11C] Acetoacetate utilization by breast and prostate tumors: a PET and biodistribution study in mice. Mol Imaging Biol. 2008; 10(4): 217-223.

Bentourkia M, Tremblay S, Pifferi F, Rousseau J, Lecomte R, Cunnane S. PET study of 11C-acetoacetate kinetics in rat brain during dietary treatments affecting ketosis. Am J Physiol Endocrinol Metab. 2009; 296(4): E796-E801. doi: 10.1152/ajpendo.90644.2008.

Blomqvist G, Alvarsson M, Grill V, Von Heijne G, Ingvar M, Thorell JO, Stone-Elander S, Widén L, Ekberg K. Effect of acute hyperketonemia on the cerebral uptake of ketone bodies in nondiabetic subjects and IDDM patients. Am J Physiol Endocrinol Metab. 2002; 283: E20-E28.

Blomqvist G, Thorell JO, Ingvar M, Grill V, Widen L, Stone-Elander S. Use of R-β-[1-11C]hydroxyburyrate in PET studies of regional cerebral uptake of ketone bodies in humans. Am J Physiol. 1995; 269(5 Pt 1): E948-E959.

Bouteldja N, Andersen LT, Møller N, Gormsen LC. Using positron emission tomography to study human ketone body metabolism: A review. Metabolism 2014; 63(11): 1375-1384.

Castellano CA, Nugent S, Paquet N, Tremblay S, Bocti C, Lacombe G, Imbeault H, Turcotte É, Fulop T, Cunnane SC. Lower brain 18F-fluorodeoxyglucose uptake but normal 11C-acetoacetate metabolism in mild Alzheimer’s disease dementia. J Alzheimers Dis. 2015; 43(4): 1343-1353.

Courchesne-Loyer A, Croteau E, Castellano C-A, St-Pierre V, Hennebelle M, Cunnane SC. Inverse relationship between brain glucose and ketone metabolism in adults during short-term moderate dietary ketosis: A dual tracer quantitative positron emission tomography study. J Cereb Blood Flow Metab. 2017; 37(7): 2485-2493.

Croteau E, Tremblay S, Gascon S, Dumulon-Perreault V, Labbé SM, Rousseau JA, Cunnane SC, Carpentier AC, Bénard F, Lecomte R. [11C]-Acetoacetate PET imaging: a potential early marker for cardiac heart failure. Nucl Med Biol. 2014; 41: 863-870. doi: 10.1016/j.nucmedbio.2014.08.006.

Gormsen LC, Svart M, Thomsen HH, Søndergaard E, Vendelbo MH, Christensen N, Tolbod LP, Harms HJ, Nielsen R, Wiggers H, Jessen N, Hansen J, Bøtker HE, Møller N. Ketone body infusion with 3-hydroxybutyrate reduces myocardial glucose uptake and increases blood flow in humans: A positron emission tomography study. J Am Heart Assoc. 2017; 6(3): e005066.

Hasselbach SG, Madsen PL, Hageman LP, Olsen KS, Justesen N, Holm S, Paulson OB. Changes in cerebral blood flow and carbohydrate metabolism during acute hyperketonemia. Am J Physiol. 1996; 270(5 Pt 1): E746-E751.

Nugent S, Tremblay S, Chen KW, Ayutyanont N, Roontiva A, Castellano CA, Fortier M, Roy M, Courchesne-Loyer A, Bocti C, Lepage M, Turcotte E, Fulop T, Reiman EM, Cunnane SC. Brain glucose and acetoacetate metabolism: a comparison of young and older adults. Neurobiol Aging. 2014; 35(6): 1386-1395.

Pifferi F, Tremblay S, Croteau E, Fortier M, Tremblay-Mercier J, Lecomte R, Cunnane SC. Mild experimental ketosis increases brain uptake of 11C-acetoacetate and 18F-fluorodeoxyglucose: a dual-tracer PET imaging study in rats. Nutr Neurosci. 2011; 14(2): 51-58.

Roy M, Nugent S, Tremblay-Mercier J, Tremblay S, Courchesne-Loyer A, Beaudoin JF, Tremblay L, Descoteaux M, Lecomte R, Cunnane SC. The ketogenic diet increases brain glucose and ketone uptake in aged rats: a dual tracer PET and volumetric MRI study. Brain Res. 2012; 1488: 14-23.

Tremblay S, Ouellet R, Rodrigue S, Langlois R, Beacute;nard F, Cunnane SC. Automated synthesis of 11C-acetoacetic acid, a key alternate brain fuel to glucose. Appl Radiat Isot. 2007; 65(8): 934-940.



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Created at: 2017-06-28
Updated at: 2018-01-10
Written by: Vesa Oikonen