Substance P (SP) is a neurotransmitter and neuromodulator that mediates its effects in the brain predominantly via the neurokinin-1 receptors (NK1Rs). NK1Rs and SP have been shown clinically to be involved in nausea and emesis after chemotherapy (CINV) and have been implicated preclinically in a range of neuropsychiatric disorders but unlike CINV their blockade in these conditions does not have proven clinical value. We investigated whether age and gender affects NK1R binding potential (NK1R-BP; an index of receptor availability) in the living human brain using PET and [18F]SPA-RQ, a highly specific NK1R antagonist. Forty-five healthy volunteers (35 male and 10 female), aged between 19 and 55 years were studied. NK1R-BP was estimated using the simplified reference tissue model with cerebellum as a reference region. A regression analysis indicated that that a loss of NK1R is associated with normal ageing as shown by decreased NK1R-BP (average rate 7% per decade). Statistically significant negative associations between age and NK1R-BP were observed in temporal, parietal and frontal cortex, hippocampus and parahippocampal formation. In addition preliminary data were obtained suggesting possible gender differences in NK1R-BP in the cortex and putamen with females having a lower NK1R-BP. The exact physiological significance of these results remains to be elucidated but conceptually they could be involved in age-related CNS disorders or those with gender differences in prevalence.