[¹¹C](+)McN5652 as a radiotracer for imaging serotonin uptake sites with pet

The in vivo behavior of the stereoisomers of [¹¹C]McN5652, a highly potent serotonin (5-HT) uptake blocker, was determined to evaluate their utility as radiotracers for imaging 5-HT uptake sites by positron emission tomography (PET). After intravenous injection into mice, [¹¹C](+)McN5652 showed markedly higher uptake and longer retention in regions with high density of 5-HT uptake sites than the [¹¹C]-labeled racemic mixture, while [¹¹C](-)McN5652 washed out rapidly. With the [¹¹C](+)-enantiomer, the ratio between hypothalamus and cerebellum reached 6 at 90 minutes. The binding of [¹¹C](+)McN5652 was inhibited by 45-73% by pre-injection of 5 mg/kg of paroxetine, a selective 5-HT uptake blocker, in all regions examined except cerebellum where no significant effect of the drug was observed. [¹¹C](-)McN5652 showed no specific binding in any of the regions. The [¹¹C]-labeled cis isomer, [¹¹C]McN5655, revealed surprisingly low brain penetration and showed no significantly higher uptake in regions of interest than cerebellum. These results suggest that [¹¹C](+)McN5652 is a promising candidate as a PET radiotracer for studying 5-HT uptake sites in vivo.