title: 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.
abstract: 5-Hydroxytryptamine(1A) (5-HT(1A)) 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-HT(1A) 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 [(11)C][O-methyl-3H]-N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride (WAY-100635), were used to assess 5-HT(1A) 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 approximately 80%, and a half-saturation concentration (ED(50)) of approximately 7 ng/ml. At 24 h after the last dose 5-HT(1A) occupancy was approximately 50% of that achieved at 2 h. This study demonstrates that high occupancy of the human brain 5-HT(1A) receptor can be achieved at doses producing minimal acute side effects.
authors.affiliation: Medical Research Council Cyclotron Unit, Hammersmith Hospital, Imperial College School of Medicine, London, UK. Eugenii_A_Rabiner@gsk.com
authors.forename: Eugenii A
authors.initials: EA
authors.lastname: Rabiner
authors.forename: Martin R
authors.initials: MR
authors.lastname: Wilkins
authors.forename: Federico
authors.initials: F
authors.lastname: Turkheimer
authors.forename: Roger N
authors.initials: RN
authors.lastname: Gunn
authors.forename: Joanna
authors.initials: J
authors.lastname: Udo de Haes
authors.forename: Michiel
authors.initials: M
authors.lastname: de Vries
authors.forename: Paul M
authors.initials: PM
authors.lastname: Grasby
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000378:metabolism*; D011725:Pyridines / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists / Q000378:metabolism*; D013844:Thiazoles / Q000378:metabolism*; D014055:Tomography, Emission-Computed / Q000379:methods* / Q000706:statistics & numerical data
chemical_list: D010879:Piperazines; D011725:Pyridines; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D013844:Thiazoles; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; C106973:1,2-benzisothiazol-3(2H)-one, 2-(4-(4-(7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-1-piperazinyl)butyl)-, 1,1-dioxide