Automation; Fluorine-18; Good manufacturing practice; Positron emission tomography; [18F]Flumazenil; Radiology, Nuclear Medicine and Imaging; Pharmacology
Abstract :
[en] ("[en] BACKGROUND: Flumazenil (FMZ) is a functionally silent imidazobenzodiazepine which binds to the benzodiazepine binding site of approximately 75% of the brain γ-aminobutyric acid-A receptors (GABAARs). Positron Emission Tomography (PET) imaging of the GABAARs with [11C]FMZ has been used to evidence alterations in neuronal density, to assess target engagement of novel pharmacological agents, and to study disorders such as epilepsy and Huntington's disease. Despite the potential of FMZ PET imaging the short half-life (t1/2) of carbon-11 (20 min) has limited the more widespread clinical use of [11C]FMZ. The fluorine-18 (18F) isotopologue with a longer t1/2 (110 min) is ideally suited to address this drawback. However, the majority of current radiochemical methods for the synthesis of [18F]FMZ are non-trivial and low yielding. We report a robust, automated protocol that is good manufacturing practice (GMP) compatible, and yields multi-patient doses of [18F]FMZ.
RESULTS: The fully automated synthesis was developed on the Trasis AllinOne (AIO) platform using a single-use cassette. [18F]FMZ was synthesized in a one-step procedure from [18F]fluoride, via a copper-mediated 18F-fluorination of a boronate ester precursor. Purification was performed by semi-preparative radio-HPLC and the collected fraction formulated directly into the final product vial. The overall process from start of synthesis to delivery of product is approximately 55 min. Starting with an initial activity of 23.6 ± 5.8 GBq (n = 3) activity yields of [18F]FMZ were 8.0 ± 1 GBq (n = 3). The synthesis was successfully reproduced at two independent sites, where the product passed quality control release criteria in line with the European Pharmacopoeia standards and ICH Q3D(R1) guidelines to be suitable for human use.
CONCLUSION: Reported is a fully automated cassette-based synthesis of [18F]FMZ that is Good Manufacturing Practice (GMP) compatible and produces multi-patient doses of [18F]FMZ.","[en] ","")
Disciplines :
Chemistry Radiology, nuclear medicine & imaging
Author, co-author :
Gendron, Thibault ; Université de Liège - ULiège > Département de chimie (sciences) > Chimie organique-nucléaire ; Trasis, Rue Gilles Magnée, 90, 4430, Ans, Belgium
Destro, Gianluca; Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK
Straathof, Natan J W; Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK
Sap, Jeroen B I; Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK
Guibbal, Florian; Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK
Vriamont, Charles; Trasis, Rue Gilles Magnée, 90, 4430, Ans, Belgium
Caygill, Claire; Medicines Discovery Institute, Cardiff University, Main Building, Park Place, Cardiff, CF10 3AT, UK
Atack, John R; Medicines Discovery Institute, Cardiff University, Main Building, Park Place, Cardiff, CF10 3AT, UK
Watkins, Andrew J; Wales Research and Diagnostic PET Imaging Centre, Cardiff University, University Hospital of Wales, Heath Park, Cardiff, CF14 4XN, UK
Marshall, Christopher; Wales Research and Diagnostic PET Imaging Centre, Cardiff University, University Hospital of Wales, Heath Park, Cardiff, CF14 4XN, UK
Hueting, Rebekka; Wales Research and Diagnostic PET Imaging Centre, Cardiff University, University Hospital of Wales, Heath Park, Cardiff, CF14 4XN, UK
Warnier, Corentin ; Université de Liège - ULiège > Unités de recherche interfacultaires > GIGA-CRC In vivo Imaging (Centre de Recherche du Cyclotron) ; Trasis, Rue Gilles Magnée, 90, 4430, Ans, Belgium
Gouverneur, Véronique; Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK. veronique.gouverneur@chem.ox.ac.uk
Tredwell, Matthew ; Wales Research and Diagnostic PET Imaging Centre, Cardiff University, University Hospital of Wales, Heath Park, Cardiff, CF14 4XN, UK. tredwellm@cardiff.ac.uk ; School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff, CF10 3AT, UK. tredwellm@cardiff.ac.uk
MRC - Medical Research Council EPSRC - Engineering and Physical Sciences Research Council
Funding number :
EP/R511742/1
Funding text :
This research was supported by MRC Confidence in Concept Scheme (MC_PC_19033) funding (MT, CM) and an EPSRC Impact Accelerator Award (EP/R511742/1) (VG).
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