MAO-A INHIBITION IN BRAIN AFTER DOSING WITH ESUPRONE, MOCLOBEMIDE ANDPLACEBO IN HEALTHY-VOLUNTEERS - IN-VIVO STUDIES WITH POSITRON EMISSION TOMOGRAPHY

Objective: The aim of the study was to investigate whether or not esup rone binds substantially to MAO-A in the human brain. Methods: In a ra ndomised double-blind placebo-controlled study 16 male healthy volunte ers were examined with positron emission tomography (PET) with [C-11]h armine. Eight of the volunteers were given daily doses of 800 mg esupr one, four were given bi-daily doses of 300 mg moclobemide, and four vo lunteers were given placebo tablets. PET was performed before initiati on of a 7-day treatment period. On day 7, one investigation was made i mmediately before administration of the drug, representing 23 h after the previous day's treatment for esuprone and 11 h after the last tabl ets of moclobemide. Further investigations were made 4 h and 8 h after the morning dose on day 7. Results: PET showed a high degree of bindi ng of [C-11]harmine, a high-affinity ligand for MAO-A, before the star t of treatment, and a marked and similar reduction after treatment wit h esuprone and moclobemide. A slight tendency for normalisation of enz yme binding was observed at the last time point. In the placebo group no change was observed. Plasma kinetics of esuprone showed a rapid eli mination with a half-life of about 4 h. Conclusion: The study demonstr ates that esuprone was comparable to moclobemide in its effect on MAO- A inhibition in the brain at the doses given. This is an illustration of the potential of PET to monitor drug effects directly on target bio chemical systems in the brain in human volunteers: and the possibility of using these data, rather than pharmacokinetic data, for the determ ination of dosing intervals.