Imaging serotonin‐2A (5‐HT_2A) neuroreceptors with positron emission tomography (PET) and [¹⁸F]altanserin has been the focus of a series of PET studies, as [¹⁸F]altanserin is one of the most selective 5‐HT_2A antagonist radiotracers. Previous animal studies showed that radiolabeled metabolites (radiometabolites) of [¹⁸F]altanserin crossed the blood–brain barrier (BBB) to localize nonspecifically in brain, consistent with a constant radioactivity “background.” In this work, we evaluated human bolus injection [¹⁸F]altanserin PET data with detailed consideration of the impact of BBB‐permeable metabolites on the specific binding parameters. Data were quantified using either single (parent radiotracer), dual (parent radiotracer and radiometabolites), or no arterial input function(s) (cerebellum as reference tissue input function). A step‐gradient high‐performance liquid chromatography (HPLC) analysis provided distinct separation of [¹⁸F]altanserin and four radiolabeled components in plasma. After [¹⁸F]altanserin injection, the step‐gradient data showed that the major BBB‐permeable radiometabolites approached constant levels in plasma (>50 min), consistent with a constant metabolite “background.” The single‐input Logan graphical results were highly correlated with the dual‐input results and its bias was fairly constant across regions and subjects, as similarly observed for a nongraphical reference tissue method. The most comprehensive and quantitatively valid analysis for bolus [¹⁸F]altanserin PET data was the dual‐input method that specifically accounted for BBB‐permeable metabolites, although the Logan analysis was preferred because it provided a good compromise between validity, sensitivity, and reliability of implementation. Further study is needed to better understand how the cerebellar kinetics of [¹⁸F]altanserin and its radiometabolites impact the reference tissue measures. Synapse 41:11–21, 2001.

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