The monoamine neurotransmitters dopamine, serotonin and norepinephrine are retrieved from the synaptic cleft by transporters, which belong to SLC6 (solute carrier 6). In the brain, serotonergic neurons reside mainly in the raphe nuclei, which project their axons diffusely to essentially all other areas of the brain. Accordingly, serotonin modulates many higher brain functions including mood and motivation. Blockage of the serotonin transporter and the resulting change in serotoninergic neurotransmission has been employed as a therapeutic strategy to treat several psychiatric disorders, in particular depression. Because of its prominent role as a drug target, SERT has a rich pharmacology. The binding site is understood in considerable detail, because crystal structures of SERT are available. However, it is not clear, how the binding site can accommodate very different chemical structures. In the current thesis, the problem was approached by a thermodynamic analysis of the binding reaction: prototypical ligands, i.e. imipramine (a tricyclic antidepressant, TCA), S-citalopram (a selective serotonin reuptake inhibitor, SSRI), noribogaine (a ligand, which traps SERT in the inward facing conformation) and para-chloroamphetamine (PCA, a substrate) were allowed to compete for radioligand binding assays at different temperatures. The thermodynamic driving forces of each binding reaction were calculated by examining the temperature-dependent change of affinities in a vant Hoff plot. The thermodynamic driving forces differed: binding of imipramine and of noribogaine was purely enthalpy-driven and was accompanied by an energetically unfavourable decrease in entropy. Binding of S-citalopram and of PCA had both an enthalpy-driven (60%) and an entropy-driven componnet (40%). The differences can be accounted for by assuming more pronounced conformational changes induced or stabilized by imipramine and noribogaine. These result in a larger entropic penalty compared to the conformational change accompanying binding of S-citalopram and of PCA. For noribogaine, this can be explained through the stabilization of the inward facing conformation. The differences between imipramine and S-Citalopram can be explained by differences in the rigidity of the ligand or of SERT after the binding reaction. The insights obtained in this thesis are of interest to understanding how SERT ligands differ in their ability to act as pharmacochaperones in stabilizing conformational intermediates of SERT and of folding-deficient mutants of SERT and related transporters.