BLOOD CEREBROSPINAL-FLUID AND BLOOD-BRAIN BARRIERS IMAGED BY F-18 LABELED METABOLITES OF F-18 SETOPERONE STUDIED IN HUMANS USING POSITRON EMISSION TOMOGRAPHY

F-18-Setoperone, a sensitive radioligand for brain serotonin 5-HT2 receptor positron emission tomography studies, is metabolized into F-18-labeled metabolites, which participate in blood F-18 radioactivity. Its main metabolite, identified as reduced F-18-setoperone, was synthesized and studied in humans to determine if F-18-labeled metabolites of F-18-setoperone (a) enter into the brain, (b) bind to the 5-HT2 receptor, and (c) explain the increase of F-18 radioactivity in the free fraction in blood measured following F-18-setoperone injection. After reduced F-18-setoperone injection, the brain-to-blood F-18 radioactivity concentration ratio (a) was low, at the beginning, indicating that this metabolite did not cross the blood-brain barrier; (b) was increased thereafter, with a higher radioactivity level in the choroid plexus than in brain tissue, suggesting a blood-CSF barrier crossing due to radioligand hydrophilicity; and (c) showed similar kinetics for cerebellum and frontal cortex, indicating that radioactive metabolites of F-18-setoperone did not bind to the 5-HT2 receptor. Because hydrophilic F-18-labeled metabolites of F-18-setoperone increased F-18 radioactivity in the free fraction in blood, we quantified the relation between F-18-setoperone metabolism and free fraction kinetics in blood. A significant negative correlation was found between metabolism and free fraction rate constants in blood, showing it was possible to predict the F-18-setoperone metabolism rate using free fraction kinetics in blood. This will allow us to avoid the use of radio-TLC, a reference method that is difficult to use when multiple samples must be analyzed. A hydrophilic positron-emitter radioligand could also be used to study the blood-CSF barrier.