Description: Serotonin receptor 6 (5-hydroxytrypamine-6, or 5-HT 6 ) is a potential therapeutic target given its distribution in brain regions that are important in depression, anxiety, and cognition. This study sought to investigate the effects of age on 5-HT 6 receptor availability using 11 C-GSK215083, a PET ligand with affinity for 5-HT 6 in the striatum and 5-HT 2A in the cortex. Methods: Twenty-eight healthy male volunteers (age range, 23–52 y) were scanned with 11 C-GSK215083 PET. Time–activity curves in regions of interest were fitted using a multilinear analysis method. Nondisplaceable binding potential ( BP ND ) was calculated using the cerebellum as the reference region and corrected for partial-volume effects. Results: In 5-HT 6 –rich areas, regional 11 C-GSK215083 showed a negative correlation between BP ND and age in the caudate ( r = –0.41, P = 0.03) (14% change per decade) and putamen ( r = –0.30, P = 0.04) (11% change per decade) but not in the ventral striatum or pallidum. A negative correlation with age was also seen in cortical regions ( r = –0.41, P = 0.03) (7% change per decade), consistent with the literature on 5-HT 2A availability. Conclusion: To our knowledge, this was the first in vivo study on humans to examine the effect of age on 5-HT 6 receptor availability. The study demonstrated a significant age-related decline in 5-HT 6 availability ( BP ND ) in the caudate and putamen.