[¹¹C]Cimbi-36, a 5-HT_2A receptor agonist PET radioligand, contains three methoxy groups amenable to [¹¹C]-labeling. In pigs, [¹¹C]Cimbi-36 yields a polar (M1) and a less polar (M2) radiometabolite fraction, while changing the labeling to [¹¹C]Cimbi-36_5 yields only the M1 fraction. We investigate whether changing the labeling position of [¹¹C]Cimbi-36 eliminates M2 in humans, and if this changes the signal-to-background ratio. Six healthy volunteers each underwent two dynamic PET scans; after injection of [¹¹C]Cimbi-36, both the M1 and M2 fraction appeared in plasma, whereas only the M1 appeared after [¹¹C]Cimbi-36_5 injection. [¹¹C]Cimbi-36_5 generated higher uptake than [¹¹C]Cimbi-36 in both neocortex and cerebellum. With the simplified reference tissue model mean neocortical non-displaceable binding potential for [¹¹C]Cimbi-36 was 1.38 ± 0.07, whereas for [¹¹C]Cimbi-36_5, it was 1.18 ± 0.14. This significant difference can be explained by higher non-displaceable binding caused by demethylation products in the M1 fraction such as [¹¹C]formaldehyde and/or [¹¹C]carbon dioxide/bicarbonate. Although often considered without any impact on binding measures, we show that small polar radiometabolites can substantially decrease the signal-to-background ratio of PET radioligands for neuroimaging. Further, we find that [¹¹C]Cimbi-36 has a better signal-to-background ratio than [¹¹C]Cimbi-36_5, and thus will be more sensitive to changes in 5-HT_2A receptor levels in the brain.