Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Identification of Hepatic Metabolites of [18F]Flumazenil and Evaluation of its Application in Neuroimaging

Wei-Hsi Chen
,
Chuang-Hsin Chiu
ORCID logo ,
Shiou-Shiow Farn
,
Kai-Hung Cheng
,
Yuan-Ruei Huang
,
SHIH-YING LEE
,
Yao-Ching Fang
,
Yu-Hua Lin
,
Kang-Wei Chang
* ORCID logo
Version 1 : Received: 18 April 2023 / Approved: 18 April 2023 / Online: 18 April 2023 (10:29:26 CEST)

A peer-reviewed article of this Preprint also exists.

Chen, W.-H.; Chiu, C.-H.; Farn, S.-S.; Cheng, K.-H.; Huang, Y.-R.; Lee, S.-Y.; Fang, Y.-C.; Lin, Y.-H.; Chang, K.-W. Identification of the Hepatic Metabolites of Flumazenil and their Kinetic Application in Neuroimaging. Pharmaceuticals 2023, 16, 764. Chen, W.-H.; Chiu, C.-H.; Farn, S.-S.; Cheng, K.-H.; Huang, Y.-R.; Lee, S.-Y.; Fang, Y.-C.; Lin, Y.-H.; Chang, K.-W. Identification of the Hepatic Metabolites of Flumazenil and their Kinetic Application in Neuroimaging. Pharmaceuticals 2023, 16, 764.

Abstract

Studies on the neurobiological causes of anxiety disorders suggest that the GABA system in-creases synaptic concentration and enhances the affinity of GABAA (type A) receptors for ben-zo-diazepine ligands. Flumazenil antagonizes the benzodiazepine binding site of the GABA (γ-aminobutyric acid) type /benzodiazepine receptor (BZR) complex in the central nervous sys-tem (CNS). The integration of the metabolites of flumazenil by LC-tandem mass spectrometry will complete understanding of the in vivo metabolism of flumazenil and accelerate radio-pharmaceutical inspection and registration. The main goal of our study was to investigate using reversed-phase HPLC (PR-HPLC) coupled with electrospray ionization triple quadrupole tan-dem mass spectrometry (ESI-QqQ MS) for the identification of flumazenil and its metabolites in a hepatic matrix. And a carrier-free nucleophilic fluorination with automatic synthesizer for [18F]flumazenil which applied to in vivo nano-positron emission tomography (Nano-PET)/computed tomography (CT) imaging and ex vivo bio-distribution used to analyze in normal rats. The study showed that 50% of the flumazenil was bio-transformed at 60 min by the rat liver homogenate, while one metabolite (M1) was a methyl transesterification product of flumazenil. In a rat liver microsomes system, two metabolites were identified (M2 and M3) as its carboxylic acid and hydroxylated ethylester forms, respectively. [18F]flumazenil in vivo nanoPET/CT imag-ing and ex vivo bio-distribution assay also showed significant effects on GABAA receptor availa-bility in the amygdala, prefrontal cortex, cortex, and hippocampus in the rat brain, worriless about the formation of metabolites. We showed completion of the bio-transformed course of flumazenil by the hepatic system; and [18F]flumazenil can be a good ligand and serve as a PET agent for determination of GABAA/BZR complex for multiplex neurological syndromes in the clinical stage.

Keywords

Flumazenil; LC-QqQ MS; Metabolism; r-aminobutyric acid receptor antagonist; benzodiazepine receptors

Subject

Medicine and Pharmacology, Medicine and Pharmacology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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