[11C]CO2 as metabolite
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 labeled metabolites, [11C]methanol, [11C]formaldehyde and [11C]formate (from -O-11CH3 compounds).
Further metabolism
[11C]CO2/[11C]HCO2- 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).
Distribution
[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 HCO2- (Gjedde, 1992).
Blood [11C]CO2 concentration is dependent on pulmonary clearance and the rate of [11C]CO2 formation.
Correction of blood and plasma TACs
Determination of [11C]CO2 fraction
To measure the total blood radioactivity, CO2 is fixed by collecting the blood into samle 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.
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 non-volatile labeled metabolites may not not distribute equally between plasma and 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:
- Calculate [11C]CO2 TAC in blood (CbCO2(t)) by multiplying total blood TAC by fbCO2(t)
- Convert [11C]CO2 blood TAC to plasma TAC (CpCO2(t)) by multiplying CbCO2(t) by 1.15
- Subtract CpCO2(t) from total plasma TAC
- Apply normal metabolite correction to get plasma curve that is corrected for both non-volatile and volatile ([11C]CO2) metabolites (Cparent(t)).
Alternatively, after step 2, correct the plasma fractions (determined with HPLC/TLC) by multiplication by (1 - CpCO2(t)), and then apply these corrected plasma fractions to calculate Cparent(t), and if needed, Cmetabolites(t) (non-volatile 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.
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., 2000).
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, K1/k2=0.670 ml/g, 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 (Eary et al., 1999; Gjedde 1999).
