Affinity of (±)-pindolol, (-)-penbutolol, and (-)-tertatolol for pre- and postsynaptic serotonin 5-HT1A receptors in human and rat brain

There is considerable interest in the use of drugs that selectively block presynaptic (somatodendritic) serotonin 5-HT1A receptors for the adjunctive treatment of major depressive disorder. The 5-HT1A/beta-adrenoceptor ligands (+/-)-pindolol, (-)-tertatolol, and (-)-penbutolol are currently under clinical investigation, and knowledge of their affinity at different populations of central 5-HT1A receptors is needed. Here we have determined the affinity of these drugs for presynaptic and postsynaptic 5-HT1A receptors in postmortem human and rat brain using receptor autoradiography and the selective 5-HT1A radioligand [H-3]WAY-100635. The binding of [H-3]WAY-100635 was specific and saturable and showed high affinity in the rat dorsal raphe nucleus and hippocampus (K-D = 1.5-1.7 nM). In competition studies, the three compounds had nanomolar affinity and produced monophasic displacement of [H-3]WAY-100635 binding in all regions of both species. (-)-Penbutolol and (-)-tertatolol had similar affinity for pre- and postsynaptic 5-HT1A receptors in both rat and human brain. However, in the human, but not the rat, the affinity of (+/-)-pindolol in dorsal raphe nucleus (K-i = 8.9 +/- 1.1 nM) was slightly but significantly higher than that in hippocampus (K-i = 14.4 +/- 1.5 n/M in CA1). In summary, our data show that (+/-)-pindolol, (-)-tertatolol, and (-)-penbutolol are all high-affinity ligands at native human and rat 5-HT1A receptors. (-)-Penbutolol and (-)-tertatolol do not discriminate between the pre- and postsynaptic 5-HT1A sites tested in either species, but (+/-)-pindolol showed a slightly higher affinity for the presynaptic site in human brain. Further work is needed to establish whether the latter difference is clinically relevant.