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. 2022 Sep 13;27(18):5931.
doi: 10.3390/molecules27185931.

Effective Preparation of [18F]Flumazenil Using Copper-Mediated Late-Stage Radiofluorination of a Stannyl Precursor

Mohammad B Haskali  1   2 , Peter D Roselt  2 , Terence J O'Brien  3 , Craig A Hutton  4   5 , Idrish Ali  3 , Lucy Vivash  3 , Bianca Jupp  3
Affiliations

Effective Preparation of [18F]Flumazenil Using Copper-Mediated Late-Stage Radiofluorination of a Stannyl Precursor

Mohammad B Haskali et al. Molecules. .

Abstract

(1) Background: [18F]Flumazenil 1 ([18F]FMZ) is an established positron emission tomography (PET) radiotracer for the imaging of the gamma-aminobutyric acid (GABA) receptor subtype, GABAA in the brain. The production of [18F]FMZ 1 for its clinical use has proven to be challenging, requiring harsh radiochemical conditions, while affording low radiochemical yields. Fully characterized, new methods for the improved production of [18F]FMZ 1 are needed. (2) Methods: We investigate the use of late-stage copper-mediated radiofluorination of aryl stannanes to improve the production of [18F]FMZ 1 that is suitable for clinical use. Mass spectrometry was used to identify the chemical by-products that were produced under the reaction conditions. (3) Results: The radiosynthesis of [18F]FMZ 1 was fully automated using the iPhase FlexLab radiochemistry module, affording a 22.2 ± 2.7% (n = 5) decay-corrected yield after 80 min. [18F]FMZ 1 was obtained with a high radiochemical purity (>98%) and molar activity (247.9 ± 25.9 GBq/µmol). (4) Conclusions: The copper-mediated radiofluorination of the stannyl precursor is an effective strategy for the production of clinically suitable [18F]FMZ 1.

Keywords: Flumazenil 1; GABAA; PET imaging; benzodiazepine; radiochemistry; radiofluorination; stannane; stannyl.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Nucleophilic radiofluorination methods for the preparation of [18F]flumazenil 1.
Figure 2
Figure 2
Synthesis of stannyl precursor 3.
Figure 3
Figure 3
Cu-catalyzed radiosynthesis of [18F]FMZ 1.
Figure 4
Figure 4
LC-MS/MS analysis of major by-products that were formed in the crude reaction mixture of [18F]FMZ 1 at 120 °C after 10 min reaction time.
Figure 5
Figure 5
Representative image of [18F]flumazenil 1 uptake.
Figure 6
Figure 6
Box and whisker plots of hippocampal Bmax and 1/KD values and average time activity curves (TAC) from hippocampal and pons volumes of interest.
See this image and copyright information in PMC

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