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/β‐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 [3H]WAY‐100635. The binding of [3H]WAY‐100635 was specific and saturable and showed high affinity in the rat dorsal raphe nucleus and hippocampus (KD = 1.5‐1.7 nM). In competition studies, the three compounds had nanomolar affinity and produced monophasic displacement of [3H]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 (Ki = 8.9 ± 1.1 nM) was slightly but significantly higher than that in hippocampus (Ki = 14.4 ± 1.5 nM 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.