2008-12-01 V Oikonen, T Tolvanen, K Liukko, P Virsu, A Roivainen

• TPC
• Data analysis
• Blood analysis
• Blood and plasma data
• Metabolite correction
• Software
• Vocabulary

This page is obsolete: please read the new version.

Converting blood TAC to plasma TAC

Background

Most PET tracers equilibriate relatively slowly between plasma and red blood cells. In these cases, only the tracer in plasma is available to tissue extraction during the about 1 sec passage through the capillary. Thus, for most tracers, the blood TAC measured using on-line detector ("blood pump"), or extracted from the PET image, must be converted to plasma TAC before it can be used as the input function in a quantitative analysis.

Plasma and blood TACs are usually not similar; even if the equlibrium between blood cells and plasma is reached instantly, the water space is smaller inside the cells than in the plasma.

Certain analysis methods require that the impact of vascular radioactivity must be considered. However, if only plasma TAC is measured, then the blood TAC must be calculated from it, e.g. using p2blood.

Tracer persists in plasma

If PET tracer, or any radioactive metabolite in plasma, can not penetrate the red blood cell (RBC) membrane, the concentrations in plasma and blood are related by the equation
CB(t)=(1-HCT)*CP(t),
where HCT is the hematocrit, the volume fraction of red blood cells in the blood.

These PET tracers include [¹¹C]raclopride, [¹⁸F]FTHA, and [carbonyl-¹¹C]WAY-100635.

Radioactive metabolite penetrates RBC membrane

[¹¹C]palmitate and most of its radioactive metabolites stay in plasma, but the first appearing metabolite, [¹¹C]CO₂ (or [¹¹C]HCO₃^-) permeates the RBCs readily:

Parent tracers [¹¹C]-R-PK11195 and [¹¹C]Carfentanil persist in plasma, but their radioactive metabolites equilibrate between RBC and plasma water spaces:

Tracer persists in red blood cells

These tracers inlcude [¹⁵O]O₂ and [¹⁵O]CO. Note that the concentration of metabolite of [¹⁵O]O₂, [¹⁵O]H₂O, is in equlibrium between blood and plasma.

Tracer penetrates RBC membrane instantly

These tracers include [¹⁵O]H₂O, [¹⁸F]EF5, [¹¹C]FETNIM, [¹¹C]HED ([¹¹C]hydroxyephedrine), [¹¹C]metomidate, [¹¹C]MP4A and [¹¹C]MP4B, [¹¹C]FLB-457, [¹⁸F]CFT ([¹⁸F]WIN-35428).

Note that some radioactive metabolites may persist in the plasma, or are trapped in blood cells, and that the ratio at equilibrium may be very different from 1. In these cases, the blood-to-plasma ratio may have to measured at several time points (for example [¹¹C]L-deprenyl-D2), fitted to an appropriate function (for example a sigmoidal function), and thereafter blood-to-plasma conversion is done using the individual or population average function.

[¹¹C]Metomidate is an example of tracer which, along with its radioactive metabolites, stays in the blood water spaces; the blood-to-plasma ratio is only dependent on blood hematocrit and water contents of blood cells (63%) and plasma (94%).

Tracer penetrates RBC membrane slowly

These PET tracers include [¹⁸F]FDOPA, [¹¹C]DOPA, [¹⁸F]FBPA, [¹¹C]MeAIB, and [¹¹C]methionine, and probably also most other amino acid tracers. [¹⁸F]FDG equilibrates between RBC and plasma water spaces rapidly (less than one minute), but continues to be slowly accumulated in the RBCs.

Also with these tracers, plasma-to-blood ratio often starts to increase during the scan. This is indicative of the appearance of labelled metabolites which do not penetrate the RBC membrane and therefore accumulate in plasma.

New PET tracers

When a new tracer is introduced, radioactivity concentrations in both plasma and blood have to be measured. Based on those a decision can be made whether a conversion can be applied, e.g. based on hematocrit or measured one-point blood-to-plasma ratio, or whether both plasma and blood samples need to be measured also in future. Note that hematocrit in small vessels in tissue is usually lower than in large venous vessels, from where the sample for hematocrit determination is collected.

Software for converting blood to plasma and plasma to blood

For at least the following tracers, b2plasma and p2blood can be used to make the conversions from blood to plasma or from plasma to blood:

• [¹⁸F]FBPA
• [¹⁸F]FTHA
• [¹⁸F]FDG
• [¹⁸F]FDOPA
• [¹⁸F]Flumazenil
• [¹¹C]Carfentanil
• [¹¹C]MeAIB
• [¹¹C]Metomidate ([¹¹C]MTO)
• [¹¹C]PK11195
• [¹¹C]PIB
• [¹¹C]Palmitate
• [¹¹C]PE2I

Notice that (arterial) blood TAC calculated this way does not represent the average TAC of blood in tissue, which consists of arterial and venous blood in unknown proportion, and also the local venous blood TAC is unknown.

Concentration in blood cells

Radioactivity concentration in red blood cells (RBC) can not be measured directly from centrifuged blood samples, because RBC preparations always contain some plasma. If plasma is washed away, then part of the radioactivity inside the cells is also removed.

However, if the TACs of whole blood and plasma, and hematocrit (HCT) are measured, then the TAC of RBC can be calculated using program b2rbc. Blood-to-plasma ratio curve can be converted to RBC-to-plasma with bpr2cpr.

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References:

Hinz R, Bhagwagar Z, Cowen PJ, Cunningham VJ, Grasby PM. Validation of a tracer kinetic model for the quantification of 5-HT_2A receptors in human brain with [¹¹C]MDL 100,907. J Cereb Blood Flow Metab 2007; 27: 161-172.

Koeppe RA. Quantitative functional imaging using positron computed tomography and rapid parameter estimation techniques. Thesis (Ph.D.), The Univeristy of Wisconsin, Madison, 1984.

Lee J-S, Su K-H, Lin J-C, Chuang Y-T, Chueh H-S, Liu R-S, Wang S-J, Chen J-C. A novel blood-cell-two-compartment model for transferring a whole blood time activity curve to plasma in rodents. Comput Methods Programs Biomed. 2008; 92(3): 299-304.

Lubberink M, Boellaard R, Greuter HNJM, Lammertsma AA. Effect of uncertainty in plasma metabolite levels on kinetic analysis of [¹¹C]flumazenil and [¹¹C](R)-PK11195 PET studies. Neuroimage 2004; 22: T119-T120.

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