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: Eugenii A Rabiner, Martin R Wilkins, Federico Turkheimer, Roger N Gunn, Joanna Udo de Haes, Michiel de Vries, Paul M Grasby
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 301 Issue 3 Pg. 1144-50 (Jun 2002) ISSN: 0022-3565 [Print] United States
• PMID: 12023549 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Piperazines
• Pyridines
• Receptors, Serotonin
• Receptors, Serotonin, 5-HT1
• Serotonin Antagonists
• Thiazoles
• N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide
• 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

Topics

• 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, statistics & numerical data)