Compartmental models for metabolite correction

Compartmental models can be used to model the appearance of metabolites in the plasma or blood. Huang et al. (1991) introduced general models for metabolite correction, and specific models for [18F]FDOPA and [15O]O2. Compartmental model for metabolite correction of [15O]O2 blood data was simplified by Iida et al. (1993). Several models for [11C]CO2 have been presented, since it is a common metabolite of 11C-labelled radiotracers. Lammertsma et al (1993) used a multi-compartmental model in metabolite analysis of L-[11C]deprenyl, but did not disclose details of the model. Carson et al (1997) used a two-compartmental model in metabolite analysis of [11C]raclopride. In this model, the concentration of metabolites in plasma was calculated from total plasma activity using equation

, where λ1≥0, λ2≥0, t≥0, and λ1λ2. Here, the response function is one form of biexponential,

and its constant, λ1λ2/(λ21) normalises the AUC to unity. If one-compartmental model would suffice, then the biexponential response function can be replaced by surge function, with AUC=1:

Gillings et al (2001) linearised the fitting by applying Patlak plot, using parent plasma concentration as input. Patlak plot has negative curvature if the metabolite(s) are eliminated from the plasma, which was corrected by adding the elimination rate into the Patlak plot when necessary. The method was applied to [11C]NNC112, [11C]NS2214, and [11C]PK11195 in minipigs (Gillings et al., 2001). A different formulation of the linear plot was previously used by the same group for [18F]FDOPA, [11C]deprenyl, [11C]SCH23390, [11C](S)-nicotine, and [11C]raclopride (Cumming et al., 1999).

When the plasma-to-blood ratio and/or the rate of plasma-to-RBC transport is different between the parent tracer and its metabolites, a compartmental model can be used to model both fractions simultaneously, as shown in a 6-[18F]fluoro-L-m-tyrosine study (Asselin et al., 2002). Wu et al. (2007) applied compartmental model for [11C]WAY-100635 when testing the performance of different metabolite correction methods.

Model-based input methods rely on assumption that the input function is common to all tissue regions in the PET image, and can be solved from the data (simultaneous estimation method, SIME). Burger & Buck (1996) have proposed using SIME for metabolite correction, and method has been applied for instance to [11C]flumazenil (Sanabria-Bohórquez et al., 2000).

References

Carson RE, Breier A, de Bartolomeis A, Saunders RC, Su TP, Schmall B, Der MG, Pickar D, Eckelman WC. Quantification of amphetamine-induced changes in [11C]raclopride binding with continuous infusion. J Cereb Blood Flow Metab. 1997; 17(4): 437–447. doi: 10.1097/00004647-199704000-00009.

Lammertsma AA, Hume SP, Bench CJ, Luthra SK, Osman S, Jones T. Measurement of monoamine oxidase B activity using L-[11C]deprenyl: inclusion of compartmental analysis of plasma metabolites and a new model not requiring measurement of plasma metabolites. In: Quantification of brain function: Tracer kinetics and image analysis in brain PET. Uemura K et al., (eds.) 1993, Elsevier, The Netherlands, p. 313-318.

Updated at: 2019-02-03
Created at: 2007-07-18
Written by: Vesa Oikonen