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

When developing ligands for emission tomography studies, one of the major o bstacles lies in the selection of ligand candidates. A previously unattende d 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 char acteristics of [H-3]-(S)-citalopram and [H-3]-(+)-McN5652 and the receptor- ligand interaction at the serotonin transporter of 17 selective serotonin r euptake inhibitors were compared at 21 degreesC and 37 degreesC, respective ly. Ligand logP values were also calculated. The ratios for K-i at 37 degre esC vs. 21 degreesC varied between 0.2 and 2.2 for the selective serotonin reuptake inhibitors considered in this study, with most of the ligands disp laying an inverse relationship between K-i and temperature. Ten of the 17 s elective serotonin reuptake inhibitors were found to have pK(i) values stat istically significantly different at 21 degreesC compared to 37 degreesC (P < 0.05). The logP values ranged between 3.6 and 4.8, except for DASB, 5-io do-6-nitroquipazine, and paroxetine where logP was 1.9, 2.2, and 5.0, respe ctively. K-d was 0.71 nM at 37<degrees>C and 0.31 nM at 21 degreesC for [H- 3]-(S)-citalopram. For [H-3]-(+)-McN5652 K-d was 0.11 nM at 37 degreesC and 0.08 nM at 21 degreesC. The association and dissociation was much faster f or [H-3]-(S)-citalopram as compared to [H-3]-(+)-McN5652. It is concluded t hat temperature may affect K-d differently and that in vitro dissociation m ay help to predict whether a given ligand may be useful in PET studies. Log P values do not per se predict the potential of a given ligand as an emissi on tomography tracer. Synapse 41: 203-211,2001. (C) 2001 Wiley-Liss, Inc.