The potential usefulness of 18F-labelled setoperone, a high-affinity antagonist of the serotonin-2 (S2) receptors, to study the S2 receptors in vivo with positron emission tomography (PET) was investigated in four baboons. In the control state, there was a rapid wash-out of intravenously injected tracer from the cerebellum, a structure essentially devoid of S2, receptors, and marked retention in both the cerebral cortex and the striatum (region/cerebellum ratios up to 3 and 3.5 after 60 min in cortex and striatum, respectively). The retention of radioligand in the cerebral cortex was abolished after pretreatment with spiperone or ketanserin at saturating doses. In striatum, however, radioligand retention was fully prevented by spiperone but only partly by ketanserin. These results demonstrate that [18F]setoperone was bound to the S2 receptors in the cerebral cortex, whereas the radioligand was bound to both the S2 and the dopamine D2 receptors in the striatum. The high cortex/cerebellum ratio achieved indicates that [18F]setoperone should be a useful radiotracer for PET studies of the S2 receptors.