Binding characteristics of selective serotonin reuptake inhibitors with relation to emission tomography studies

When developing ligands for emission tomography studies, one of the major obstacles lies in the selection of ligand candidates. A previously unattended factor such as the influence of temperature on candidate ligand affinity is likely to play a role. By use of rat brain homogenates, the binding characteristics of [ 3 H]‐(S)‐citalopram and [ 3 H]‐(+)‐McN5652 and the receptor‐ligand interaction at the serotonin transporter of 17 selective serotonin reuptake inhibitors were compared at 21°C and 37°C, respectively. Ligand logP values were also calculated. The ratios for K i at 37°C vs. 21°C varied between 0.2 and 2.2 for the selective serotonin reuptake inhibitors considered in this study, with most of the ligands displaying an inverse relationship between K i and temperature. Ten of the 17 selective serotonin reuptake inhibitors were found to have pK i values statistically significantly different at 21°C compared to 37°C ( P < 0.05). The logP values ranged between 3.6 and 4.8, except for DASB, 5‐iodo‐6‐nitroquipazine, and paroxetine where logP was 1.9, 2.2, and 5.0, respectively. K d was 0.71 nM at 37°C and 0.31 nM at 21°C for [ 3 H]‐(S)‐citalopram. For [ 3 H]‐(+)‐McN5652 K d was 0.11 nM at 37°C and 0.08 nM at 21°C. The association and dissociation was much faster for [ 3 H]‐(S)‐citalopram as compared to [ 3 H]‐(+)‐McN5652. It is concluded that temperature may affect K d differently and that in vitro dissociation may help to predict whether a given ligand may be useful in PET studies. LogP values do not per se predict the potential of a given ligand as an emission tomography tracer. Synapse 41:203–211, 2001. © 2001 Wiley‐Liss, Inc.