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 tracers.
[11C]CO2, or [11C]HCO3- are produced by peripheral and local metabolism from 11C-labelled radiotracers during the PET study. 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).
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]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 tracer, 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 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 the usual metabolite correction to get plasma curve that is corrected for both nonvolatile 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) (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.
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)-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 (Eary et al., 1999; Gjedde 1999).
Brooks DJ, Lammertsma AA, Beaney RP, Leenders KL, Buckingham PD, Marshall J, Jones T. Measurement of regional cerebral pH in human subjects using continuous inhalation of 11CO2 and positron emission tomography. J Cereb Blood Flow Metab. 1984; 4: 458-465. doi: 10.1038/jcbfm.1984.65.
Brooks DJ, Beaney RP, Thomas DGT, Marshall J, Jones T. Studies on regional cerebral tumours using continuous inhalation of 11CO2 and positron emission tomography. J Cereb Blood Flow Metab. 1986; 6: 529-535.
Buxton RB, Wechsler LR, Alpert NM, Ackerman RH, Elmaleh DR, Correia JA. Measurement of brain pH using 11C02 and positron emission tomography. J Cereb Blood Flow Metab. 1984; 4: 8-16. doi: 10.1038/jcbfm.1984.2.
Buxton RB, Alpert NM, Wechsler LR, Ackerman RH, Elmaleh DR, Correia JA, Taveras JM. A kinetic model for the measurement of brain pH with 11C02 and positron emission tomography. In: Greitz T et al. (Ed.) The metabolism of the human brain studied with positron emission tomography. pp 273-278, 1985.
Buxton RB, Alpert NM, Babikian V, Weise S, Correia JA, Ackerman RH. Evaluation of the 11C02 positron emission tomographic method for measuring brain pH. I. pH changes measured in states of altered PCO2. J Cereb Blood Flow Metab. 1987; 7: 709-719.
Eary JF, Mankoff MA, Spence AM, Berger MS, Olshen A, Link JM, O’Sullivan F, Krohn KA. 2-[C-11]Thymidine imaging of malignant brain tumors. Cancer Res. 1999; 59: 615-621.
Gjedde A. Labeled carbon dioxide: How transient a metabolite? J Nucl Med. 1992; 32(4): 585-586.
Gunn RN, Yap JT, Wells P, Osman S, Price P, Jones T, Cunningham VJ. A general method to correct PET data for tissue metabolites using a dual-scan approach. J Nucl Med. 2000; 41: 706-711.
Lockwood AH, Finn RD. 11C-carbon dioxide fixation and equilibration in rat brain: effects on acid-base measurements. Neurology 1982; 32: 451-454.
Ng Y, Moberly SP, Mather KJ, Brown-Proctor C, Hutchins GD, Green MA. Equivalence of arterial and venous blood for [11C]CO2-metabolite analysis following intravenous administration of 1-[11C]acetate and 1-[11C]palmitate. Nucl Med Biol. 2013; 40(3): 361-365. doi: 10.1016/j.nucmedbio.2012.11.011.
Prieto J, García N, Martí-Climent JM, Peñuelas I, Richter JA, Medina JF. Assessment of biliary bicarbonate secretion in humans by position emission tomography. Gastroenterology 1999; 117(1): 167-172.
Raichle ME, Grubb RL Jr, Higgins CS. Measurement of brain tissue carbon dioxide content in vivo by emission tomography. Brain Res. 1979; 166: 413-417.
Raichle ME, Larson KB, Higgins CS, Grubb RL Jr, Eichling JO, Welch MJ, Ter-Pogossian MM. Three-dimensional in vivo mapping of brain metabolism and acid-base status. Acta Neurol Scand Suppl. 1977; 64: 188-189.
Roos A, Boron WF. Intracellular pH. Physiol Rev. 1981; 61: 296-434.
Senda M, Alpert NM, Mackay BC, Buxton RB, Correia JA, Weise SB, Ackerman RH, Dorer D, Buonanno FS. Evaluation of the 11C02 positron emission tomographic method for measuring brain pH. II. Quantitative pH mapping in patients with ischemic cerebrovascular diseases. J Cereb Blood Flow Metab. 1989; 9: 859-873.
Shields AF, Graham MM, Kozawa SM, Kozell LB, Link JM, Swenson ER, Spence AM, Bassingthwaighte JB, Krohn KA. Contribution of labeled carbon dioxide to PET imaging of carbon-11-labeled compounds. J Nucl Med. 1992; 33(4): 581-584.
Zhang X, Lin Y, Gillies RJ. Tumor pH and its measurement. J Nucl Med. 2010; 51: 1167-1170.
Created at: 2009-04-24
Updated at: 2018-07-17
Written by: Vesa Oikonen