Quantification of serotonin 5‐HT 1A receptors in humans with [ 11 C]( R )‐(−)‐RWAY: Radiometabolite(s) likely confound brain measurements

[ 11 C]( R )‐(−)‐RWAY has been shown to be a promising radioligand for imaging brain 5‐HT 1A receptors with positron emission tomography in rodents and nonhuman primates. We now report the first use of [ 11 C]( R )‐(−)‐RWAY in six healthy human subjects, using kinetic brain imaging and serial arterial measurements of plasma parent radiotracer. At 80 min after radiotracer injection, activity ratios were about three for brain receptor‐rich regions compared with cerebellum. However, the washout from brain was unexpectedly slow relative to plasma clearance of the parent radiotracer. This disparity between brain and plasma activity was quantified with distribution volume calculated from increasingly truncated brain imaging data. In both receptor‐rich regions and cerebellum, distribution volumes were unstable and increased continuously from 90 to 150 min by about 30%. This increasing distribution volume was unlikely due to the variations or errors of plasma input at later time points, since a similar truncation of plasma time points from 150 to 90 min did not significantly affect the analysis of the brain data. When the metabolites of [ 11 C]( R )‐(−)‐RWAY in human and monkey were compared, a moderate lipophilic radiometabolite was present at a significantly higher percentage of total plasma radioactivity in human than in monkey. The relatively slow washout of activity from brain and the temporal instability of distribution volume likely reflect the accumulation of radiometabolite(s) in human brain. Although prior studies in rodents and nonhuman primates showed [ 11 C]( R )‐(−)‐RWAY to be a promising radiotracer, we suspect that a species difference in metabolism caused this serious deficiency in humans. Synapse 61:469–477, 2007. Published 2007 Wiley‐Liss, Inc.