Blood-cerebrospinal fluid and blood-brain barriers imaged by 18F-labeled metabolites of 18F-setoperone studied in humans using positron emission tomography.
18F-Setoperone, a sensitive radioligand for brain serotonin 5-HT2 receptor positron emission tomography studies, is metabolized into 18F-labeled metabolites, which participate in blood 18F radioactivity. Its main metabolite, identified as reduced 18F-setoperone, was synthesized and studied in humans to determine if 18F-labeled metabolites of 18F-setoperone (a) enter into the brain, (b) bind to the 5-HT2 receptor, and (c) explain the increase of 18F radioactivity in the free fraction in blood measured following 18F-setoperone injection. After reduced 18F-setoperone injection, the brain-to-blood 18F 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 18F-setoperone did not bind to the 5-HT2 receptor. Because hydrophilic 18F-labeled metabolites of 18F-setoperone increased 18F radioactivity in the free fraction in blood, we quantified the relation between 18F-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 18F-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.
Blin
J
J
Service Hospitalier Frédéric Joliot, Département de Recherche en Imagerie Médicale, Pharmacologie et Physiologie, Hôpital d'Orsay, France.
Crouzel
C
C
D000328:Adult; D001812:Blood-Brain Barrier / Q000502:physiology*; D001921:Brain / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism / Q000502:physiology / Q000648:ultrastructure; D002540:Cerebral Cortex / Q000378:metabolism / Q000502:physiology / Q000648:ultrastructure; D005462:Fluorine Radioisotopes; D006801:Humans; D011744:Pyrimidinones / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D011869:Radioligand Assay; D011985:Receptors, Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D014055:Tomography, Emission-Computed
D005462:Fluorine Radioisotopes; D011744:Pyrimidinones; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C045359:setoperone