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Tritiated sertraline, a radiolabeled form of a potent and selective inhibitor of serotonin uptake, was found to bind with high affinity to rat whole brain membranes. Characterization studies showed that [H] sertraline binding occurred at a single site with the following parameters: K 0.57 nM, B 821 fmol/mg protein, n 1.06. This binding was reversible; the dissociation constant calculated from kinetic measurements ( K 0.81 nM) agreed with that determined by saturation binding experiments. [H] Sertraline binding in the presence of serotonin, paroxetine, fluoxetine or imipramine suggested competitive inhibition of binding (large increase in K with little change in B). The rank order of potency of inhibition of [H] sertraline binding was similar to that of inhibition of serotonin uptake for known uptake inhibitors and the 1-amino-4-phenyltetralin uptake blockers. A marked decrease in ex vivo [H] sertraline binding in the brain of rats 7 days after treatment with p-chloroamphetamine was consistent with the loss of serotonin uptake sites induced by this agent. The results of our study indicated that [H] sertraline labels serotonin uptake sites in rat brain. [ABSTRACT FROM AUTHOR]