Abstract
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-(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 [11C][O-methyl-3H]-N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride (WAY-100635), were used to assess 5-HT1Aautoreceptor 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 (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.
Footnotes
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This 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-1,4-benzdioxyn-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
- Received October 31, 2001.
- Accepted January 25, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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