The brain binding kinetics and distribution of the antidepressant venlafaxine, labelled with 11C in the O-methyl position, was studied by PET after intravenous injection in anesthetized pigs. In addition, venlafaxine's action on serotonin (5-HT) uptake was studied in vitro in blood platelets obtain from humans or pigs. Venlafaxine resembled imipramine, paroxetine and citalopram in causing a dose-dependent inhibition of 5-HT uptake in blood platelets from pigs and humans. Venlafaxine-derived radioactivity entered the living brain readily and showed higher binding potentials in diencephalic and telencephalic regions than in cerebellum. Acute administration of an antidepressant drug (i.e. imipramine, citalopram or paroxetine) enhanced the distribution and altered the binding of venlafaxine in certain brain regions. The findings show that [11C]venlafaxine is not an ideal PET radiotracer mainly because of its relatively low binding potentials and its lack of specificity for the 5-HT transporter in living brain.