Effects of common anesthetic agents on [18F]flumazenil binding to the GABAA receptor

Mikael Palner; Corinne Beinat; Sam Banister; Francesca Zanderigo; Jun Hyung Park; Bin Shen; Trine Hjoernevik; Jae Ho Jung; Byung Chul Lee; Sang Eun Kim; Lawrence Fung; Frederick T Chin

doi:10.1186/s13550-016-0235-2

Effects of common anesthetic agents on [¹⁸F]flumazenil binding to the GABA_A receptor

EJNMMI Res. 2016 Dec;6(1):80. doi: 10.1186/s13550-016-0235-2. Epub 2016 Nov 8.

Authors

Mikael Palner^{1

2}, Corinne Beinat³, Sam Banister³, Francesca Zanderigo^{4

5}, Jun Hyung Park³, Bin Shen³, Trine Hjoernevik^{3

6

7}, Jae Ho Jung⁸, Byung Chul Lee^{9

10}, Sang Eun Kim^{9

10

11}, Lawrence Fung¹², Frederick T Chin^{13

14}

Affiliations

¹ Departments of Radiology, Stanford University School of Medicine, Stanford, CA, USA. mikael.palner@nru.dk.
² Neurobiology Research Unit, Rigshospitalet, Copenhagen, Denmark. mikael.palner@nru.dk.
³ Departments of Radiology, Stanford University School of Medicine, Stanford, CA, USA.
⁴ Department of Molecular Imaging and Neuropathology, New York State Psychiatric Institute, New York, NY, USA.
⁵ Department of Psychiatry, Columbia University, New York, NY, USA.
⁶ The Intervention Centre, Oslo University Hospital, Oslo, Norway.
⁷ The Norwegian Medical Cyclotron Centre, Oslo, Norway.
⁸ Bio Imaging Korea Co., Ltd, Seoul, Republic of Korea.
⁹ Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
¹⁰ Center for Nanomolecular Imaging and Innovative Drug Development, Advanced Institutes of Convergence Technology, Suwon, Republic of Korea.
¹¹ Department of Transdisciplinary Studies, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea.
¹² Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA.
¹³ Departments of Radiology, Stanford University School of Medicine, Stanford, CA, USA. chinf@stanford.edu.
¹⁴ 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.

Abstract

Background: The availability of GABA_A receptor 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 GABA_A receptors 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 (V_T*) 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 V_T* 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 GABA_A receptors involving the use of anesthesia.

Keywords: Anesthesia; Dexmedetomidine; Flumazenil; GABAA receptor; Isoflurane; Ketamine; PET.

Abstract

Grants and funding