5-Hydroxytryptamine1A Receptor Occupancy by Novel Full Antagonist 2-[4-[4-(7-Chloro-2,3-dihydro-1,4-benzdioxyn-5-yl)- 1-piperazinyl]butyl]-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide: A [C][O-methyl-3H]-N-(2-(4-(2-methoxyphenyl)-1- piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide Trihydrochloride (WAY-100635) Positron Emission Tomography Study in Humans

5-Hydroxytryptamine1A (5-HT1A) receptors have been implicated in the pathophysiology and treatment of anxiety and depression, and are a target for novel drug development. This is the first study examining the human brain in vivo occupancy by a novel, selective, silent 5-HT1A antagonist. 2-[4-[4-(7Chloro-2,3-dihydro-1,4-benzdioxyn-5-yl)-1-piperazinyl]butyl]-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide (DU 125530), a compound in clinical development, has potential applications in the treatment of anxiety and mood disorders. Positron emission tomography (PET) and [C][O-methyl3H]-N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2pyridinyl)cyclohexanecarboxamide trihydrochloride (WAY100635), were used to assess 5-HT1A autoreceptor and postsynaptic receptor occupancy in 12 healthy male volunteers. Over a 10to 40-mg daily dose range, DU 125530 was well tolerated, and exhibited a dose-dependent occupancy from 0 to 72% at 2 h post the last dose. Occupancy correlated significantly with plasma levels of DU 125530, and a fitting of the data to a standard single-site binding model gave a maximum occupancy of 80%, and a half-saturation concentration (ED50) of 7 ng/ml. At 24 h after the last dose 5-HT1A occupancy was 50% of that achieved at 2 h. This study demonstrates that high occupancy of the human brain 5-HT1A receptor can be achieved at doses producing minimal acute side effects. The 5-HT1A receptor is widely distributed in the human brain, with receptor concentration in postmortem human samples varying from 300 fmol/mg tissue in the hippocampus to 230 fmol/mg tissue in the midbrain raphe nuclei (RN) to negligible in the cerebellum (Burnett et al., 1997; Hall et al., 1997). It functions both as a somatodendritic autoreceptor on serotonergic neurons of the RN, and a postsynaptic receptor on neurons in cortical and limbic areas (Peroutka 1985; Pazos et al., 1988). Postsynaptic 5-HT1A receptors mediate some of the effects of 5-HT released from nerve terminals (Sinton and Fallon, 1988; Blier et al., 1990; Chaput et al., 1991; Invernizzi et al., 1991). The 5-HT1A on the RN is an inhibitory autoreceptor, the activation of which leads to decreased 5-HT neuron firing, and hence decreased 5-HT release in terminal synapses (VanderMaelen et al., 1986; Sharp et al., 1989; Adell and Artigas 1991; Invernizzi et al., 1992). The 5-HT1A autoreceptor is therefore an attracThis work was supported by Solvay Pharmaceuticals, Weesp, The Netherlands. ABBREVIATIONS: 5-HT, 5-hydroxytryptamine; RN, raphe nuclei; PET, positron emission tomography; BP, binding potential; ROI, region of interest; ANOVA, analysis of variance; TAC, time activity curve; OCCmax, maximal occupancy; DU 125530, 2-[4-[4-(7-chloro-2,3-dihydro-1,4benzdioxyn-5-yl)-1-piperazinyl]butyl]-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide; WAY-100635, [O-methyl-3H]-N-(2-(4-(2-methoxyphenyl)1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride. 0022-3565/02/3013-1144–1150$7.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 301, No. 3 Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics 4706/987471 JPET 301:1144–1150, 2002 Printed in U.S.A. 1144 at A PE T Jornals on A ril 3, 2017 jpet.asjournals.org D ow nladed from tive site for therapeutic drug action, because it will influence neurotransmission through all 5-HT receptor subtypes. The use of the mixed -adrenergic/5-HT1A weak partial agonist pindolol has been proposed as a novel strategy for augmenting the antidepressant effects of selective serotonin reuptake inhibitors on the basis of its affinity for the 5-HT1A autoreceptor (Artigas et al., 1994). We demonstrated previously that doses of pindolol significantly higher than those used in clinical studies in depression will be needed to achieve a significant occupancy of the 5-HT1A autoreceptor (Rabiner et al., 2000a). A similar conclusion was reached in a subsequent independent study (Martinez et al., 2000). An increased dose of pindolol will raise the risk of -adrenergic side effects, which may limit the usefulness of this strategy in patient populations. Novel compounds with higher selectivity for the 5-HT1A receptor may therefore provide significant advantages in clinical use. 2-[4-[4-(7-Chloro-2,3-dihydro-1,4-benzdioxyn-5-yl)-1piperazinyl]butyl]-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide (DU 125530) was demonstrated to act as a full antagonist on cloned human 5-HT1A receptors (pKi 9.1 nM), as well as in vivo in tests of drug discrimination (Mos et al., 1997), startle potentiation (Joordens et al., 1998), ultrasonic vocalizations (Olivier et al., 1998a), and stress-induced hyperthermia (Olivier et al., 1998b). DU 125530 has a 300-fold higher affinity for the 5-HT1A receptor compared with the other 5-HT receptors, as well as a 7-fold higher affinity compared with the 1-adrenergic receptor, and the D2/D3 receptor (Investigator’s Brochure; Solvay Pharmaceuticals, Marietta, GA). In this study we examined the occupancy of the human 5-HT1A receptor in vivo in 12 healthy volunteers in the dose range of 10 to 40 mg p.o. daily. Materials and Methods