1. ¹PET Centre, Centre for Addiction and Mental Health, Toronto, Canada
2. ²Department of Psychiatry, University of Toronto, Toronto, Canada
3. ³PET Psychiatry, Translational Medicine and Genetics, GlaxoSmithKline, Cambridge, UK

Correspondence: Dr N Ginovart, PET Centre, CAMH, 250 College Street, Toronto, Ontario, Canada M5T 1R8. E-mail: nathalie.ginovart@camhpet.ca

Received 25 January 2005; Revised 23 June 2005; Accepted 24 June 2005; Published online 3 August 2005.

Abstract

This article describes the kinetic modeling of [¹¹C]-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 k₃/k₄ 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 cortexputamen <temporal cortexcingulate <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 k₃/k₄ 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 [¹¹C]-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 [¹¹C]-harmine. These results indicate the suitability of using [¹¹C]-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.