A new series of serotonin uptake inhibitors is described. Compounds 2c,f,g,o and r exhibit potent and selective activities in a binding assay for the 5-HT uptake site. Compounds 2c, 2f and 2g behave like strong in vivo serotonin uptake inhibitors. The last decade has witnessed a growing interest in receptors for serotonin (5-hydroxytryptamine, 5-HT), and to date at least seven subtypes of these 5-HT receptors have been identified. In addition to the search for 5-HT receptor antagonists, the quest for potent and specific 5-HT uptake inhibitors has been important in attempts to discover new antidepressant drugs. Several 5-HT uptake inhibitors are known, including fluoxetine, indalpine and zimelidine. In our previous papers, we described indole derivatives as potential antidepressant drugs. One of them, 1-[2-[4-((5-fluoro-1H-indol-3-yl)-methyl)-1-piperidinyl]-ethyl]-5,6-dihydro-1H,4H-1,2,5-thiadiazolo[4,3-a]quinoline-2,2-dioxide 1 (RP 68303) displayed strong activity as serotonin uptake inhibitor (IC50=1.2nM), and was found in vivo to be as active as fluoxetine in potentiating head shakes induced by 5-HTP. As already mentioned, the presence of the 2-[4-((5-fluoro-1H-indol-3-yl)-methyl)-1-piperidinyl]-ethyl moiety seems to be critical for 5-HT uptake inhibitor activity. We therefore decided to keep this constant, and to replace the thiadiazoloquinoline-2,2-dioxide ring of 1 by other heterocyclic moieties, in order to find new potent 5-HT uptake inhibitors, and in addition to obtain more information about structure-activity relationships in this family. The present paper reports on the synthesis of novel compounds 2a-r (Table 1), on their inhibition of 5-HT uptake, and on their in vivo activities.