Antagonism of 5HT6 receptors is associated with pro-cognitive effects in preclinical species, suggesting a therapeutic potential for this mechanism in Alzheimer's disease (AD) and other cognitive diseases. In a phase 2 dose study, SB742457, a novel 5HT6 antagonist, showed increasing pro-cognitive effects in patients with AD as the dose increased, with a pro-cognitive signal in AD patients at a dose of 35mg/day superior to the other doses tested (5 and 15mg/day). In this paper, we describe the quantification and pharmacological selectivity of a new 5HT6 PET ligand ((11)C-GSK215083) in healthy volunteers, and its use to measure occupancies achieved at various doses of SB742457. RESULTS: Kinetic analysis of (11)C-GSK215083 uptake in human brain demonstrated the multilinear model, MA2, to represent the method of choice when a blood input was available and the full tissue reference method when no input was available. Pharmacological dissection of the in vivo (11)C-GSK215083 specific binding showed the ligand bound mostly the 5HT6 in the striatum (blocked by SB742457, but not by the selective 5HT2A antagonist ketanserin) and to 5HT2A in the frontal cortex (blocked by both ketanserin and SB742457). Repeated administration of SB742457 (3, 15 and 35mg/day) saturated the 5HT6 receptors at all doses. In cortex, 5HT2A receptors occupancy was 24±6% (3mg/day), 35±4% (15mg/day) and 58±19% (35mg/day; mean±SD), suggesting a progressive engagement of 5HT2A as the dose increased. CONCLUSION: Collectively, these data support the use of (11)C-GSK215083 as a 5HT6 clinical imaging tool, and suggest that blocking both the 5HT6 and 5HT2A receptors may be required for the optimal therapeutic action of SB742457 in AD.