Objective: Earlier work has shown markedly lower density of serotonin 2A (5-HT2A) receptors in elderly subjects than in young healthy subjects. In this study the authors used positron emission tomography (PET) and [18F]altanserin, a ligand with high affinity for the 5-HT2A receptor, to examine the relationship between 5-HT2A receptor density and age in more detail. Method: The 22 subjects ranged in age from 21 to 69 years (mean=43.4, SD=13.3) and were healthy comparison subjects in a study of depression. Regions of interest were determined on magnetic resonance images and were transferred to coregistered PET data. The data were derived from dynamic PET scanning and arterial sampling with resulting plasma activity data corrected for labeled metabolites. Compartmental modeling was used to estimate the radioligand distribution volume. By comparing the distribution volume (DV) of different regions to the cerebellum distribution volume, DVratio-1, which is proportional to the binding potential, was calculated. Results: The decrease in 5-HT2A binding was not linear but on average was approximately 17% per decade from age 20. The correlations between age and 5-HT2A DVratio-1 were significant for the global measure and for the medial gyrus rectus, anterior cingulate, posterior medial prefrontal cortex, hippocampus, and occipital cortex. Most of the falloff in receptor binding occurred up through midlife, and there was less decrease in late life. There were no decreases in regional brain volumes of corresponding magnitudes. Conclusions: 5-HT2A receptor binding decreases dramatically in a variety of brain regions up through midlife.