TY - JOUR T1 - 5-Hydroxytryptamine<sub>1A</sub> 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-(2<em>H</em>)-one-1,1-dioxide: A [<sup>11</sup>C][<em>O</em>-methyl-3<em>H</em>]-<em>N</em>-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-<em>N</em>-(2-pyridinyl)cyclohexanecarboxamide Trihydrochloride (WAY-100635) Positron Emission Tomography Study in Humans JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 1144 LP - 1150 DO - 10.1124/jpet.301.3.1144 VL - 301 IS - 3 AU - Eugenii A. Rabiner AU - Martin R. Wilkins AU - Federico Turkheimer AU - Roger N. Gunn AU - Joanna Udo de Haes AU - Michiel de Vries AU - Paul M. Grasby Y1 - 2002/06/01 UR - http://jpet.aspetjournals.org/content/301/3/1144.abstract N2 - 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. The American Society for Pharmacology and Experimental Therapeutics ER -