Gendron Thibault, Destro Gianluca, Straathof Natan J W, Sap Jeroen B I, Guibbal Florian, Vriamont Charles, Caygill Claire, Atack John R, Watkins Andrew J, Marshall Christopher, Hueting Rebekka, Warnier Corentin, Gouverneur Véronique, Tredwell Matthew
Trasis, Rue Gilles Magnée, 90, 4430, Ans, Belgium.
Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK.
EJNMMI Radiopharm Chem. 2022 Mar 20;7(1):5. doi: 10.1186/s41181-022-00158-z.
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 (GABARs). Positron Emission Tomography (PET) imaging of the GABAARs with [C]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) of carbon-11 (20 min) has limited the more widespread clinical use of [C]FMZ. The fluorine-18 (F) isotopologue with a longer t (110 min) is ideally suited to address this drawback. However, the majority of current radiochemical methods for the synthesis of [F]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 [F]FMZ.
The fully automated synthesis was developed on the Trasis AllinOne (AIO) platform using a single-use cassette. [F]FMZ was synthesized in a one-step procedure from [F]fluoride, via a copper-mediated F-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 [F]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.
Reported is a fully automated cassette-based synthesis of [F]FMZ that is Good Manufacturing Practice (GMP) compatible and produces multi-patient doses of [F]FMZ.
氟马西尼（FMZ）是一种无功能活性的咪唑并苯二氮䓬类药物，它与约75%的脑γ-氨基丁酸-A受体（GABARs）的苯二氮䓬结合位点相结合。用[C]FMZ对GABAARs进行正电子发射断层扫描（PET）成像已被用于证明神经元密度的改变、评估新型药物的靶点结合情况以及研究癫痫和亨廷顿舞蹈病等疾病。尽管FMZ PET成像具有潜力，但碳-11的短半衰期（t，20分钟）限制了[C]FMZ在临床上更广泛的应用。具有较长半衰期（110分钟）的氟-18（F）同位素类似物非常适合解决这一缺点。然而，目前大多数用于合成[F]FMZ的放射化学方法都很复杂且产率较低。我们报告了一种稳健的、自动化的方案，该方案符合药品生产质量管理规范（GMP），并能生产多患者剂量的[F]FMZ。
在Trasis AllinOne（AIO）平台上使用一次性试剂盒开发了全自动合成方法。[F]FMZ通过一步法从[F]氟化物合成，经由铜介导的硼酸酯前体的F-氟化反应。通过半制备放射性高效液相色谱法进行纯化，并将收集的馏分直接配制成最终产品小瓶。从合成开始到产品交付的整个过程约为55分钟。以初始活度23.6±5.8 GBq（n = 3）开始，[F]FMZ的活度产率为8.0±1 GBq（n = 3）。该合成方法在两个独立的地点成功重现，产品通过了符合欧洲药典标准和ICH Q3D(R1)指南的质量控制放行标准，适合用于人体。
本文报道了一种基于一次性试剂盒的[F]FMZ全自动合成方法，该方法符合药品生产质量管理规范（GMP），并能生产多患者剂量的[F]FMZ。
