Effects of common anesthetic agents on [18F]flumazenil binding to the GABAAreceptor.
BACKGROUND
The availability of GABAAreceptor binding sites in the brain can be assessed by positron emission tomography (PET) using the radioligand, [18F]flumazenil. However, the brain uptake and binding of this PET radioligand are influenced by anesthetic drugs, which are typically needed in preclinical imaging studies and clinical imaging studies involving patient populations that do not tolerate relatively longer scan times. The objective of this study was to examine the effects of anesthesia on the binding of [18F]flumazenil to GABAAreceptors in mice.


METHODS
Brain and whole blood radioactivity concentrations were measured ex vivo by scintillation counting or in vivo by PET in four groups of mice following administration of [18F]flumazenil: awake mice and mice anesthetized with isoflurane, dexmedetomidine, or ketamine/dexmedetomidine. Dynamic PET recordings were obtained for 60 min in mice anesthetized by either isoflurane or ketamine/dexmedetomidine. Static PET recordings were obtained at 25 or 55 min after [18F]flumazenil injection in awake or dexmedetomidine-treated mice acutely anesthetized with isoflurane. The apparent distribution volume (VT*) was calculated for the hippocampus and frontal cortex from either the full dynamic PET scans using an image-derived input function or from a series of ex vivo experiments using whole blood as the input function.


RESULTS
PET images showed persistence of high [18F]flumazenil uptake (up to 20 % ID/g) in the brains of mice scanned under isoflurane or ketamine/dexmedetomidine anesthesia, whereas uptake was almost indiscernible in late samples or static scans from awake or dexmedetomidine-treated animals. The steady-state VT* was twofold higher in hippocampus of isoflurane-treated mice and dexmedetomidine-treated mice than in awake mice.


CONCLUSIONS
Anesthesia has pronounced effects on the binding and blood-brain distribution of [18F]flumazenil. Consequently, considerable caution must be exercised in the interpretation of preclinical and clinical PET studies of GABAAreceptors involving the use of anesthesia.
Departments of Radiology, Stanford University School of Medicine, Stanford, CA, USA. mikael.palner@nru.dk.|Neurobiology Research Unit, Rigshospitalet, Copenhagen, Denmark. mikael.palner@nru.dk.
Mikael
M
Palner
Departments of Radiology, Stanford University School of Medicine, Stanford, CA, USA.
Corinne
C
Beinat
Departments of Radiology, Stanford University School of Medicine, Stanford, CA, USA.
Sam
S
Banister
Department of Molecular Imaging and Neuropathology, New York State Psychiatric Institute, New York, NY, USA.|Department of Psychiatry, Columbia University, New York, NY, USA.
Francesca
F
Zanderigo
Departments of Radiology, Stanford University School of Medicine, Stanford, CA, USA.
Jun Hyung
JH
Park
Departments of Radiology, Stanford University School of Medicine, Stanford, CA, USA.
Bin
B
Shen
Departments of Radiology, Stanford University School of Medicine, Stanford, CA, USA.|The Intervention Centre, Oslo University Hospital, Oslo, Norway.|The Norwegian Medical Cyclotron Centre, Oslo, Norway.
Trine
T
Hjoernevik
Bio Imaging Korea Co., Ltd, Seoul, Republic of Korea.
Jae Ho
JH
Jung
Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.|Center for Nanomolecular Imaging and Innovative Drug Development, Advanced Institutes of Convergence Technology, Suwon, Republic of Korea.
Byung Chul
BC
Lee
Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.|Center for Nanomolecular Imaging and Innovative Drug Development, Advanced Institutes of Convergence Technology, Suwon, Republic of Korea.|Department of Transdisciplinary Studies, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea.
Sang Eun
SE
Kim
Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA.
Lawrence
L
Fung
Departments of Radiology, Stanford University School of Medicine, Stanford, CA, USA. chinf@stanford.edu.|Department of Radiology, Cyclotron Radiochemistry, Molecular Imaging Program at Stanford, Stanford University School of Medicine, 1201 Welch Road, Rm PS049, Stanford, CA, 94305-5484, USA. chinf@stanford.edu.
Frederick T
FT
Chin
Anesthesia; Dexmedetomidine; Flumazenil; GABAA receptor; Isoflurane; Ketamine; PET