Background: The availability of GABAA receptor binding sites in the brain can be assessed by positron\nemission tomography (PET) using the radioligand, [18F]flumazenil. However, the brain uptake and binding\nof this PET radioligand are influenced by anesthetic drugs, which are typically needed in preclinical imaging\nstudies and clinical imaging studies involving patient populations that do not tolerate relatively longer scan\ntimes. The objective of this study was to examine the effects of anesthesia on the binding of [18F]flumazenil\nto GABAA receptors in mice.\nMethods: Brain and whole blood radioactivity concentrations were measured ex vivo by scintillation counting\nor in vivo by PET in four groups of mice following administration of [18F]flumazenil: awake mice and mice\nanesthetized with isoflurane, dexmedetomidine, or ketamine/dexmedetomidine. Dynamic PET recordings were\nobtained for 60 min in mice anesthetized by either isoflurane or ketamine/dexmedetomidine. Static PET\nrecordings were obtained at 25 or 55 min after [18F]flumazenil injection in awake or dexmedetomidine-treated\nmice acutely anesthetized with isoflurane. The apparent distribution volume (VT*) was calculated for the\nhippocampus and frontal cortex from either the full dynamic PET scans using an image-derived input\nfunction or from a series of ex vivo experiments using whole blood as the input function.\nResults: PET images showed persistence of high [18F]flumazenil uptake (up to 20 % ID/g) in the brains of\nmice scanned under isoflurane or ketamine/dexmedetomidine anesthesia, whereas uptake was almost indiscernible\nin late samples or static scans from awake or dexmedetomidine-treated animals. The steady-state VT* was twofold\nhigher in hippocampus of isoflurane-treated mice and dexmedetomidine-treated mice than in awake mice.\nConclusions: Anesthesia has pronounced effects on the binding and blood-brain distribution of [18F]flumazenil.\nConsequently, considerable caution must be exercised in the interpretation of preclinical and clinical PET studies\nof GABAA receptors involving the use of anesthesia.
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