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Journal of Pharmacology and Experimental Therapeutics

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Research ArticleNEUROPHARMACOLOGY

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

Eugenii A. Rabiner, Martin R. Wilkins, Federico Turkheimer, Roger N. Gunn, Joanna Udo de Haes, Michiel de Vries and Paul M. Grasby
Journal of Pharmacology and Experimental Therapeutics June 2002, 301 (3) 1144-1150; DOI: https://doi.org/10.1124/jpet.301.3.1144
Eugenii A. Rabiner
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Martin R. Wilkins
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Federico Turkheimer
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Roger N. Gunn
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Joanna Udo de Haes
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Michiel de Vries
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Paul M. Grasby
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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

  • 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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Journal of Pharmacology and Experimental Therapeutics: 301 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 301, Issue 3
1 Jun 2002
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Research ArticleNEUROPHARMACOLOGY

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

Eugenii A. Rabiner, Martin R. Wilkins, Federico Turkheimer, Roger N. Gunn, Joanna Udo de Haes, Michiel de Vries and Paul M. Grasby
Journal of Pharmacology and Experimental Therapeutics June 1, 2002, 301 (3) 1144-1150; DOI: https://doi.org/10.1124/jpet.301.3.1144

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Research ArticleNEUROPHARMACOLOGY

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

Eugenii A. Rabiner, Martin R. Wilkins, Federico Turkheimer, Roger N. Gunn, Joanna Udo de Haes, Michiel de Vries and Paul M. Grasby
Journal of Pharmacology and Experimental Therapeutics June 1, 2002, 301 (3) 1144-1150; DOI: https://doi.org/10.1124/jpet.301.3.1144
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