Positron emission tomography in serotonergic drug development

Abstract: The serotonin neurotransmission system has a central role in drug treatment of depression and anxiety and is also discussed in relation to treatment of schizophrenia. The benefits of presently available drugs are however limited by partial of poor response and side effects. An additional limitation of antidepressive drugs is the two to three week time required for onset of effect. To overcome these shortcomings there are current developments of new drugs acting on biochemical targets of the serotonin system. Positron emission tomography (PET) is an imaging technique that traces radioactive molecules in the human brain. The principal aim of this thesis was to apply PET to the development of new putative antidepressive and antipsychotic drugs with affinity for the serotonin 5-HT1A and 5-HT2A receptor subtype. Another aim was to examine links between central serotonin receptor occupancy in healthy subjects and drug concentration in plasma as well as pharmacological effects. Initially, two new putative antipsychotic drugs were examined. It could be confirmed that ORG 5222 binds to 5-HT2A- and D2-dopamine receptors in the living human brain. M100907 is the first highly selective 5-HT2A antagonist and thus suitable to examine possible benefits of selective 5-HT2A antagonists in the treatment of schizophrenia. Dose-dependency and saturability of M100907 binding was demonstrated and the results were used to predict the dose regimen required in ensuing clinical studies to induce high 5-HT2A -occupancy. Pindolol is a combined beta1-adrenoreceptor antagonist/partial 5-HT1A agonist, which has been suggested to facilitate the antidepressive effect of selective serotonin reuptake inhibitors (SSRI). It was confirmed that pindolol, at clinically representative plasma concentrations, binds to 5-HT1A receptors in the human brain. This observation supports that the 5-HT1A receptor is a putative target in antidepressive drug development. NAD-299 is the first selective 5-HT1A antagonist in development for the treatment of psychiatric disorders. In an initial study in monkeys and a following study in man NAD-299 bound dosedependently and saturably to central to central 5-HT1A-receptors. The partial 5-HT1A -agonist S 16924 has been suggested for the treatment of schizophrenia. The binding of S 16924, 2.5 -10 mg, was examined in healthy subjects. Importantly, WAY radioligand binding to central 5-HT1A receptors was higher after S 16924. This unexpected finding may represent reduced levels of endogenous serotonin or, alternatively, the first in vivo demonstration of agonist induced receptor recruitment. The reference radioligand [carbonyl-11C]WAY-100635 (WAY) was used to measure 5-HT1A receptor binding by PET. As part of methodological development, the minor radioactive metabolite [carbonyl-11C]Desmethyl-100635 (DWAY) was compared to the mother radioligand. It was demonstrated that DWAY may be advantageous for quantitation of 5-HT1A receptor ligand binding since the radioactivity signal was two-fold higher than for WAY at equipotent doses. Moreover, the contribution from one radioactive metabolite is excluded using DWAY. This thesis corroborates the use of PET in healthy subjects to confirm pharmacological principles in man and to guide the dose regimens selected for clinical studies.