Adenosine A_2A receptors are found on striatal neurones projecting to the external pallidum. KW‐6002 (istradefylline) is a potent and selective antagonist for the adenosine A_2A receptors in the CNS and acts to inhibit the excessive activity of this pathway in the MPTP marmoset model of PD, thus relieving parkinsonism. The objectives of this study were to investigate the regional binding of the novel positron emission tomography tracer [¹¹C]KW‐6002 in the healthy human brain and the rat brain, along with receptor occupancy by cold KW‐6002 at varying doses in human. The highest [¹¹C]KW‐6002 uptake in the rat brain was seen in striatum and lower levels in cortex and cerebellum. Brain [¹¹C]KW‐6002 uptake was well characterized in humans by a two‐tissue compartmental model with a blood volume term, and the ED₅₀ of cold KW‐6002 was 0.5 mg in the striatum. Over 90% receptor occupancy was achieved with daily oral doses of greater than 5 mg. In humans, blockable binding was present in all gray matter structures including the cerebellum, which has not been reported to express A_2A receptors. MRS 1745, an A_2B receptor selective antagonist, had no effect on the cerebellar binding of [¹¹C]KW‐6002 in rats, suggesting that this blockable signal is unlikely to result from an affinity for adenosine A_2B receptors. Synapse 62:671–681, 2008. © 2008 Wiley‐Liss, Inc.