multi-patient dose synthesis of [18F]Flumazenil via a copper-mediated 18F-fluorination

Thibault Gendron; Gianluca Destro; Natan J.W. Straathof; Jeroen B.I. Sap; Florian Guibbal; Charles Vriamont; Claire Caygill; John R. Atack; Andrew J. Watkins; Christopher Marshall; Rebekka Hueting; Corentin Warnier; Véronique Gouverneur; Matthew Tredwell

doi:10.1186/s41181-022-00158-z

multi-patient dose synthesis of [18F]Flumazenil via a copper-mediated ¹⁸F-fluorination

Thibault Gendron
, Gianluca Destro
, Natan J.W. Straathof
, Jeroen B.I. Sap
, Florian Guibbal
, Charles Vriamont
, Claire Caygill
, John R. Atack
, Andrew J. Watkins
, Christopher Marshall
, Rebekka Hueting
, Corentin Warnier
, Véronique Gouverneur
, Matthew Tredwell

Trasis
University of Oxford
Cardiff University
Cardiff University School of Medicine

Research output: Contribution to journal › Article › peer-review

17 Scopus citations

Abstract

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 (GABA_ARs). 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 (t_1/2) of carbon-11 (20 min) has limited the more widespread clinical use of [¹¹C]FMZ. The fluorine-18 (¹⁸F) isotopologue with a longer t_1/2 (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.

Original language	English
Article number	5
Journal	EJNMMI Radiopharmacy and Chemistry
Volume	7
Issue number	1
DOIs	https://doi.org/10.1186/s41181-022-00158-z
State	Published - Dec 2022
Externally published	Yes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 9 Industry, Innovation, and Infrastructure

Keywords

Automation
Fluorine-18
Good manufacturing practice
Positron emission tomography
[F]Flumazenil

Access to Document

10.1186/s41181-022-00158-z

Cite this

Gendron, T., Destro, G., Straathof, N. J. W., Sap, J. B. I., Guibbal, F., Vriamont, C., Caygill, C., Atack, J. R., Watkins, A. J., Marshall, C., Hueting, R., Warnier, C., Gouverneur, V., & Tredwell, M. (2022). multi-patient dose synthesis of [18F]Flumazenil via a copper-mediated ¹⁸F-fluorination. EJNMMI Radiopharmacy and Chemistry, 7(1), Article 5. https://doi.org/10.1186/s41181-022-00158-z

@article{5480fce232674e4fb03b26d1a5090d74,

title = "multi-patient dose synthesis of [18F]Flumazenil via a copper-mediated 18F-fluorination",

abstract = "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{\textquoteright}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.",

keywords = "Automation, Fluorine-18, Good manufacturing practice, Positron emission tomography, [F]Flumazenil",

author = "Thibault Gendron and Gianluca Destro and Straathof, \{Natan J.W.\} and Sap, \{Jeroen B.I.\} and Florian Guibbal and Charles Vriamont and Claire Caygill and Atack, \{John R.\} and Watkins, \{Andrew J.\} and Christopher Marshall and Rebekka Hueting and Corentin Warnier and V{\'e}ronique Gouverneur and Matthew Tredwell",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1186/s41181-022-00158-z",

language = "English",

volume = "7",

journal = "EJNMMI Radiopharmacy and Chemistry",

issn = "2365-421X",

publisher = "Springer Science and Business Media Deutschland GmbH",

number = "1",

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TY - JOUR

T1 - multi-patient dose synthesis of [18F]Flumazenil via a copper-mediated 18F-fluorination

AU - Gendron, Thibault

AU - Destro, Gianluca

AU - Straathof, Natan J.W.

AU - Sap, Jeroen B.I.

AU - Guibbal, Florian

AU - Vriamont, Charles

AU - Caygill, Claire

AU - Atack, John R.

AU - Watkins, Andrew J.

AU - Marshall, Christopher

AU - Hueting, Rebekka

AU - Warnier, Corentin

AU - Gouverneur, Véronique

AU - Tredwell, Matthew

PY - 2022/12

Y1 - 2022/12

N2 - 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.

AB - 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.

KW - Automation

KW - Fluorine-18

KW - Good manufacturing practice

KW - Positron emission tomography

KW - [F]Flumazenil

UR - https://www.scopus.com/pages/publications/85126773146

U2 - 10.1186/s41181-022-00158-z

DO - 10.1186/s41181-022-00158-z

M3 - Article

AN - SCOPUS:85126773146

SN - 2365-421X

VL - 7

JO - EJNMMI Radiopharmacy and Chemistry

JF - EJNMMI Radiopharmacy and Chemistry

IS - 1

M1 - 5

ER -