Ketone bodies, mainly acetoacetate (AcAc) and β-hydroxybutyrate (β-HB, BHB, βOHB), are important alternative fuels. In addition, β-HB is an endogenous inhibitor of histone deacetylases (HDACs) and a ligand for cell surface receptors HCAR2 and GPR41 (FFAR3, free fatty acid receptor 3) (Newman and Verdin, 2014).
Ketone bodies labelled with positron emitting radionuclides allows in vivo PET studies of ketone metabolism (Bouteldja et al., 2014). The β-hydroxybutyrate has been labelled with 11C and 18F, giving R-β-[1-11C]hydroxybutyrate ([11C]β-HB, [11C]OHB) (Thorell et al., 1991), and (3S)-4-[18F]fluoro-3-hydroxybutyric acid ([18F]FBHB) (Mattingly et al., 2020). Effective doses of [11C]β-HB are 3.28 µSv/MBq after intravenous administration and 12.51 µSv/MBq after oral administration (Luong et al., 2023).
R-β-[1-11C]hydroxybutyrate and [1-11C]acetoacetate ([11C]AcAc) follow the same transport and metabolism pathway through acetyl-CoA as acetate, enabling the use of the same models as are used to analyse [11C]acetate PET studies (Blomqvist et al., 1995; Tremblay et al., 2007; Bentourkia et al., 2009; Croteau et al., 2014). [11C]β-HB and [11C]AcAc even equilibrate rapidly in vivo, and a mixture of these radiopharmaceuticals will be present in blood after administration of either of those (Blomqvist et al., 2002; Bentourkia et al., 2009).
In humans the β-HB plasma concentrations are normally in the µM range, but can reach 1-2 mM after fasting (Newman and Verdin, 2014). In rats, the concentration of [14C]acetoacetate is much lower than the concentration of [14C]β-HB (Cremer and Heath, 1974; Hawkins and Mans, 1991), and if that is true also in humans, as could be expected by the ratio of unlabelled compounds in humans (Hasselbalch et al., 1996), then the radioactivity uptake in R-β-[1-11C]hydroxybutyrate study mainly represents the utilization of β-HB (Blomqvist et al., 2002).
The first 10 min of the brain [11C]β-HB PET data can be analysed using Patlak plot or irreversible one-tissue compartment model (Blomqvist et al., 1995 and 2002). Regional metabolic rate of ketones can be calculated from Ki or compartmental model K1 as:
, where CK is the concentration of ketones (AcAc and β-HB) in plasma, and LC is the lumped constant. LC=1.0, because [11C]β-HB is chemically identical to the native β-hydroxybutyrate.
Arterial input function
Arterial blood sampling is recommended. Blood TAC collected using automated blood sampling system and image-derived input need to be converted to plasma TAC. Blomqvist et al (2002) used a straight line to represent the plasma-to-blood ratio, with intercept 1.21 and slope 0.00016 for nondiabetic subjects and intercept 1.19 and slope -0.00004 for IDDM patients, during the first 10 min p.i. Luong et al (2023) observed that blood-to-plasma ratio was close to 0.8 during a 90-min scan.
The main radioactive metabolite in [11C]β-HB study is [11C]CO2. Blomqvist et al (1995 and 2002) did not measure the fraction of [11C]CO2 in plasma or correct the input function for metabolites in the 10-min brain studies. The [11C]CO2 formed in the tissue is cleared away by perfusion. Blomqvist et al (1995) estimated that during the 10 min brain study the loss of [11C]CO2 from tissue leads to about 6% underestimation of the metabolic rate, which was taken into account in the 1995 publication, and not corrected in the later publication (Blomqvist et al., 2002). Luong et al (2023) reported that [11C]CO2 fraction increases throughout the study, reaching a plateau at 90 min p.i. at 55.85 ± 11.90%.
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Luong TV, Nielsen EN, Falborg L, Kjærulff MLG, Tolbod LP, Søndergaard E, Møller N, Munk OL, Gormsen LC. Intravenous and oral whole body ketone dosimetry, biodistribution, metabolite correction and kinetics studied by (R)-[1-11C]β-hydroxybutyrate ([11C]OHB) PET in healthy humans. EJNMMI Radiopharm Chem. 2023; 8(1): 12. doi: 10.1186/s41181-023-00198-z.
Newman JC, Verdin E. β-hydroxybutyrate: much more than a metabolite. Diabetes Res Clin Pract. 2014; 106(2): 173-181. doi: 10.1016/j.diabres.2014.08.009.
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Updated at: 2023-08-24
Created at: 2017-06-28
Written by: Vesa Oikonen