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

• Published in: The Journal of pharmacology and experimental therapeutics 2002-06, Vol.301 (3), p.1144-1150
• Main Authors: Rabiner, Eugenii A, Wilkins, Martin R, Turkheimer, Federico, Gunn, Roger N, Udo de Haes, Joanna, de Vries, Michiel, Grasby, Paul M
• Format: Article
• Language: English
• Subjects: Adult; Analysis of Variance; Dose-Response Relationship, Drug; Humans; Male; Middle Aged; Piperazines - metabolism; Pyridines - metabolism; Receptors, Serotonin - metabolism; Receptors, Serotonin, 5-HT1; Serotonin Antagonists - metabolism; Thiazoles - metabolism; Tomography, Emission-Computed - methods; Tomography, Emission-Computed - statistics & numerical data
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.301.3.1144

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-(2 H )-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-3 H ]- 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 ∼80%, and a half-saturation concentration (ED 50 ) of ∼7 ng/ml. At 24 h after the last dose 5-HT 1A occupancy was ∼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.