Radiochemistry and Biomarker Development Unit, Division of Nuclear Medicine, Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Austria; Department of Inorganic Chemistry, University of Vienna, Austria.
Nucl Med Biol. 2013 Nov;40(8):1049-54. doi: 10.1016/j.nucmedbio.2013.08.007. Epub 2013 Oct 5.
In neurodegenerative diseases and neuropsychiatric disorders dysregulation of the norepinephrine transporter (NET) has been reported. For visualization of NET availability and occupancy in the human brain PET imaging can be used. Therefore, selective NET-PET tracers with high affinity are required. Amongst these, [(18)F]FMeNER-D2 is showing the best results so far. Furthermore, a reliable fully automated radiosynthesis is a prerequisite for successful application of PET-tracers. The aim of this work was the automation of [(18)F]FMeNER-D2 radiolabelling for subsequent clinical use. The presented study comprises 25 automated large-scale syntheses, which were directly applied to healthy volunteers and adult patients suffering from attention deficit hyperactivity disorder (ADHD).
Synthesis of [(18)F]FMeNER-D2 was automated within a Nuclear Interface Module. Starting from 20-30 GBq [(18)F]fluoride, azeotropic drying, reaction with Br2CD2, distillation of 1-bromo-2-[(18)F]fluoromethane-D2 ([(18)F]BFM) and reaction of the pure [(18)F]BFM with unprotected precursor NER were optimized and completely automated. HPLC purification and SPE procedure were completed, formulation and sterile filtration were achieved on-line and full quality control was performed.
Purified product was obtained in a fully automated synthesis in clinical scale allowing maximum radiation safety and routine production under GMP-like manner. So far, more than 25 fully automated syntheses were successfully performed, yielding 1.0-2.5 GBq of formulated [(18)F]FMeNER-D2 with specific activities between 430 and 1707 GBq/μmol within 95 min total preparation time.
A first fully automated [(18)F]FMeNER-D2 synthesis was established, allowing routine production of this NET-PET tracer under maximum radiation safety and standardization.
在神经退行性疾病和神经精神障碍中，去甲肾上腺素转运体（NET）的调节已被报道。为了可视化人脑中 NET 的可用性和占有率，可以使用 PET 成像。因此，需要具有高亲和力的选择性 NET-PET 示踪剂。在这些示踪剂中，[(18)F]FMeNER-D2 迄今为止显示出最佳结果。此外，可靠的全自动放射性合成是成功应用 PET 示踪剂的前提。这项工作的目的是自动化 [(18)F]FMeNER-D2 的放射性标记，以便随后在临床中应用。本研究包括 25 次全自动大规模合成，这些合成直接应用于健康志愿者和患有注意力缺陷多动障碍（ADHD）的成年患者。
[(18)F]FMeNER-D2 的合成在核接口模块内自动化进行。从 20-30GBq [(18)F] 氟化物开始，进行共沸干燥、与 Br2CD2 反应、1-溴-2-[(18)F] 氟代甲烷-D2 ([(18)F]BFM)的蒸馏以及纯 [(18)F]BFM 与未保护前体 NER 的反应都进行了优化和完全自动化。HPLC 纯化和 SPE 程序完成，制剂和无菌过滤在线完成，全面进行质量控制。
在临床规模的全自动合成中获得了纯化产物，允许最大限度的辐射安全，并以类似 GMP 的方式进行常规生产。迄今为止，已经成功地进行了 25 次以上的全自动合成，在 95 分钟的总制备时间内，以 1.0-2.5GBq 的形式得到了[(18)F]FMeNER-D2，其比活度在 430 至 1707GBq/μmol 之间。
建立了首个全自动 [(18)F]FMeNER-D2 合成方法，允许在最大辐射安全和标准化条件下常规生产这种 NET-PET 示踪剂。
