Abstract
[(11)C]Cimbi-36, a 5-HT(2A) receptor agonist PET radioligand, contains three methoxy groups amenable to [(11)C]-labeling. In pigs, [(11)C]Cimbi-36 yields a polar (M1) and a less polar (M2) radiometabolite fraction, while changing the labeling to [(11)C]Cimbi-36_5 yields only the M1 fraction. We investigate whether changing the labeling position of [(11)C]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 [(11)C]Cimbi-36, both the M1 and M2 fraction appeared in plasma, whereas only the M1 appeared after [(11)C]Cimbi-36_5 injection. [(11)C]Cimbi-36_5 generated higher uptake than [(11)C]Cimbi-36 in both neocortex and cerebellum. With the simplified reference tissue model mean neocortical non-displaceable binding potential for [(11)C]Cimbi-36 was 1.38 ± 0.07, whereas for [(11)C]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 [(11)C]formaldehyde and/or [(11)C]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 [(11)C]Cimbi-36 has a better signal-to-background ratio than [(11)C]Cimbi-36_5, and thus will be more sensitive to changes in 5-HT(2A) receptor levels in the brain.