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 [11C][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-Hydroxytryptamine(1A) (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-(7-Chloro- 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-11][O-methyl-3H]- N-(2-(4-(2-methoxyphenyl)-1-piperazinyl) ethyl)-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride (WAY-100635), were used to assess 5- HT1A autoreceptor and postsynaptic receptor occupancy in 12 healthy male volunteers. Over a 10- to 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 similar to80%, and a half-saturation concentration (ED50)of similar to7 ng/ml. At 24 h after the last dose 5-HT1A occupancy was similar to50% 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.