Positron emission tomography quantification of [11C]-harmine binding to monoamine oxidase-A in the human brain.
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.
Ginovart
Nathalie
N
PET Centre, Centre for Addiction and Mental Health, Toronto, Canada. nathalie.ginovart@camhpet.ca
Meyer
Jeffrey H
JH
Boovariwala
Anahita
A
Hussey
Doug
D
Rabiner
Eugenii A
EA
Houle
Sylvain
S
Wilson
Alan A
AA
D000328:Adult; D001665:Binding Sites; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000201:enzymology*; D002250:Carbon Radioisotopes; D006247:Harmine / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D006801:Humans; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D020912:Moclobemide / Q000493:pharmacokinetics; D008954:Models, Biological; D008995:Monoamine Oxidase / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D010919:Placebos; D049268:Positron-Emission Tomography / Q000379:methods*; D012016:Reference Values; D013997:Time Factors
D002250:Carbon Radioisotopes; D010919:Placebos; D006247:Harmine; D008995:Monoamine Oxidase; D020912:Moclobemide