Positron Emission Tomography Quantification of [¹¹C]-Harmine Binding to Monoamine Oxidase-A in the Human Brain

Abstract

This article describes the kinetic modeling of [(11)C]-harmine binding to monoamine oxidase A (MAO-A) binding sites in the human brain using positron emission tomography (PET). Positron emission tomography studies were performed in healthy volunteers at placebo conditions and after treatment with clinical doses of moclobemide. In either condition, a two-tissue compartment model (2CM) provided better fits to the data than a one-tissue model. Estimates of k(3)/k(4) values from an unconstrained 2CM were highly variable. In contrast, estimates of the specifically bound radioligand distribution volume (DV(B)) from an unconstrained 2CM were exceptionally stable, correlated well with the known distribution of MAO-A in the brain (cerebellum <frontal cortex approximately putamen <temporal cortex approximately cingulate <thalamus) and thus provided reliable indices of MAO-A density. Total distribution volume (DV) values were also highly stable and not different from those estimated with the Logan approach. Fixing the DV of free and nonspecifically bound radiotracer (DV(F + NS)) or coupling DV(F + NS) between brain regions enabled more stable estimates of k(3)/k(4) as compared with an unconstrained 2CM. Moclobemide treatment leads to a 64% to 79% MAO-A blockade across brain regions, a result that supports the specificity of [(11)C]-harmine binding to MAO-A. The stability and reliability of DV(B) values obtained from an unconstrained 2CM, together with the computational simplicity associated with this method, support the use of DV(B) as an appropriate outcome measure for [(11)C]-harmine. These results indicate the suitability of using [(11)C]-harmine for quantitative evaluation of MAO-A densities using PET and should enable further studies of potential MAO-A dysregulation in several psychiatric and neurologic illnesses.

Positron Emission Tomography Quantification of [11C]-(+)-PHNO Binding in the Human Brain

“…In contrast, DV T values were estimated with high precision and provided reliable indexes of D 2 -like receptor densities. The difficulty in deriving reliable individual estimates for k 3 /k 4 from a 2CM four parameters configuration while obtaining stable DV T has already been reported for other radioligands (Ginovart et al, 2006b;Koeppe et al, 1996). DV T values obtained with Method B were strongly correlated with those obtained with the invasive Logan approach, a result lending support to the 2CM configuration to describe [ 11 C]-( + )-PHNO binding data.…”

Greater Monoamine Oxidase A Binding in Alcohol Dependence

“…Another limitation is that the main outcome measure of [ 11 C]-harmine PET, MAO-A V T , is an index of MAO-A density and represents total [ 11 C]-harmine in tissue relative to arterial plasma at equilibrium. It is computationally efficient, highly stable, and the least variable measure of [ 11 C]-harmine binding; however, approximately 15% of this measure reflects free and nonspecific binding (37,48). This free and nonspecific component is consistent across individuals, and although tremendous changes in free and nonspecific binding (i.e., 250%) could lead to the changes in MAO-A V T observed, this is unlikely (37).…”

“…Among different groups, K 1 /k 2 is similar [for details, see Ginovart et al (37)]. MAO-A V T can be measured validly and reliably with an unconstrained two-tissue compartment model or the Logan model with arterial sampling; the latter technique was applied in the current study (37).…”

“…Manual samples were obtained at 2.5, 7.5, 15.0, 20.0, 30.0, 45.0, 60.0, and 90.0 minutes. The radioactivity in whole blood and plasma were measured as described previously (37).…”

“…MAO-A V T equals the ratio of tissue to plasma concentration of [ 11 C]-harmine at equilibrium, of which 85% represents radioligand specifically bound to MAO-A (37,48). Hence, changes in MAO-A V T may be interpreted as representing changes in harmine binding to MAO-A.…”