Modelling of [¹¹C]CO₂

[¹¹C]CO₂ is distributed in blood and tissues; initial distribution is dependent on perfusion, but it soon redistributes according to pH, because pH determines the position of equilibrium between CO₂ and HCO₃^- (Gjedde, 1992). CO₂-HCO₃^- is the most important buffer system in the body. Acid-base homeostasis is maintained largely by the kidneys reabsorbing filtered bicarbonate (HCO₃^-) and generating new bicarbonate. CO₂ is eliminated through respiration.

Continues inhalation of [¹¹C]CO₂ gas has been used to measure regional acid-base status (Buxton et al., 1984, 1985, 1987; Brooks et al., 1984 and 1986; Senda et al., 1989). Two-tissue compartmental model accounts for the ¹¹C fixation in tissue with rate constant k₃ or k₃ and k₄. Equilibrium partition coefficient for [¹¹C]CO₂, K₁/k₂, is related to the effective tissue pH (Buxton et al., 1984). Continuous inhalation of [¹¹C]CO₂ for 10-15 min instead of a single bolus inhalation decreases the impact of fixed ¹¹C.

Prieto et al. (1999) have studied the secretion of biliary bicarbonate in the liver by PET using intravenously administered [¹¹C]NaHCO₃.

Notice that ¹¹C- and ¹⁵O-labelled CO₂ are completely different radiotracers.

[¹¹C]CO₂ as metabolite

[¹¹C]CO₂, or [¹¹C]HCO₃^- are produced by peripheral and local metabolism from ¹¹C-labelled radiotracers during the PET study. Time-coarse of [¹¹C]CO₂/[¹¹C]HCO₃^- in the blood can be estimated by measuring the exhaled [¹¹C]CO₂ (Gunn et al., 2000a). In brain studies the blood-brain barrier is often assumed to be impermeable to polar metabolites, but this is not strictly true in case of small polar metabolites, such as [¹¹C]CO₂/[¹¹C]HCO₃^- and [¹¹C]formaldehyde; these can substantially affect the brain tissue concentrations and reduce the signal-to-background ratio (Johansen et al., 2018).

Formation

¹¹C label is usually attached to ligands as methyl group, -11CH3, which tends to be detached in demethylation reactions, mainly in the liver, producing [¹¹C]CO₂ either directly (especially from -N-11CH3 compounds), or via hydrophilic labelled metabolites, [¹¹C]methanol, [¹¹C]formaldehyde and [¹¹C]formate (from -O-11CH3 compounds).

Further metabolism

[¹¹C]CO₂/[¹¹C]HCO₃^- is further incorporated into nonvolatile compounds like [¹¹C]urea, [¹¹C]glucose, and [¹¹C]lactate; urea distributes quickly in all water phase of the body (Lockwood and Finn, 1982; Gjedde, 1992).

Blood [¹¹C]CO₂ concentration is dependent on pulmonary clearance and the rate of [¹¹C]CO₂ formation.

Metabolite correction of plasma and blood TACs

Determination of [¹¹C]CO₂ fraction

To measure the total blood radioactivity, the evaporation of [¹¹C]CO₂ from the sample must be prevented by collecting the blood into sample tubes containing NaOH. From another set of blood samples CO₂ is removed by adding HCl and bubbling with nitrogen or argon gas. From these measurements the fraction of [¹¹C]CO₂ of the total blood radioactivity can be calculated. Depending on the radiopharmaceutical, venous blood samples may be sufficient for the metabolite analysis (Ng et al., 2013).

Effect on other metabolite fractions

When other labeled metabolites exist, it may be that the HPLC or TLC determination method does not take into account the volatile metabolites, especially [¹¹C]CO₂. In that case the fractions determined from blood plasma need to be corrected.

Fraction of [¹¹C]CO₂ of total blood radioactivity is often different than the fraction in blood plasma, because the parent radioligand and nonvolatile labelled metabolites may not not distribute equally between plasma and red blood cells. Plasma [¹¹C]CO₂ activity is 15±5% higher than arterial blood activity in steady-state study (Brooks et al., 1984).

Plasma TAC can be corrected for [¹¹C]CO₂ with the following procedure:

1. Calculate [¹¹C]CO₂ TAC in blood (C_bCO2(t)) by multiplying total blood TAC by f_bCO2(t)
2. Convert [¹¹C]CO₂ blood TAC to plasma TAC (C_pCO2(t)) by multiplying C_bCO2(t) by 1.15
3. Subtract C_pCO2(t) from total plasma TAC
4. Apply the usual metabolite correction to get plasma curve that is corrected for both nonvolatile and volatile ([¹¹C]CO₂) metabolites (C_parent(t)).

Alternatively, after step 2, correct the plasma fractions (determined with HPLC/TLC) by multiplication by (1 - C_pCO2(t)), and then apply these corrected plasma fractions to calculate C_parent(t), and if needed, C_metabolites(t) (nonvolatile metabolites, excluding [¹¹C]CO₂).

Correction of tissue TACs

Contribution of [¹¹C]CO₂ to the total tissue radioactivity must be taken into account in the kinetic models for radioligands that produce large amounts of [¹¹C]CO₂ (Mankoff et al., 1999).

In compartmental models [¹¹C]CO₂ and its fixed metabolites could have their own compartments. Rate constants for these compartments would be most accurately measured by performing a separate injection of [¹¹C]CO₂ and fitting the results to a model (Shields et al., 1992; Eary et al., 1999; Gunn et al., 2000b).

As an alternative, population average values for the rate constants for [¹¹C]CO₂ and its metabolites could be used, if they are relatively stable in a given tissue or if their contribution to total radioactivity is relatively small. From a steady-state study with plasma input, Brooks et al. (1986) reported that one-tissue compartmental model fitted the data adequately, giving K₁=0.30±0.05 min^-1 and K₁/k₂=0.43±0.03 min^-1 for brain cortex. Eary et al. (1999) reported two-tissue compartmental model parameters for the brain (K₁=0.640 ml×(min×g)^-1, K₁/k₂=0.670 ml×g^-1, and k₃=0.005 min^-1) from a single subject with blood input.

In some cases, tissue curves might even be corrected simply by assuming a 1:2 ratio between tissue and blood concentrations of [¹¹C]CO₂ (Gjedde, 1992; Eary et al., 1999).

See also:

• Blood sampling
• Metabolite correction
• [¹⁵O]CO₂
• Aquaporins

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Literature

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Brooks DJ, Beaney RP, Thomas DGT, Marshall J, Jones T. Studies on regional cerebral pH in patients with cerebral tumours using continuous inhalation of ¹¹CO₂ and positron emission tomography. J Cereb Blood Flow Metab. 1986; 6: 529-535. doi: 10.1038/jcbfm.1986.98.

Buxton RB, Wechsler LR, Alpert NM, Ackerman RH, Elmaleh DR, Correia JA. Measurement of brain pH using ¹¹CO₂ and positron emission tomography. J Cereb Blood Flow Metab. 1984; 4: 8-16. doi: 10.1038/jcbfm.1984.2.

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Tags: Carbon dioxide, Metabolite correction, pH

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Updated at: 2018-07-17
Created at: 2009-04-24
Written by: Vesa Oikonen