Cybulska Klaudia A, Bloemers Vera, Perk Lars R, Laverman Peter
Radboud Translational Medicine B.V., Geert Grooteplein 21, Nijmegen, 6525 EZ, Netherlands.
Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Geert Grooteplein 10, Nijmegen, 6525 GA, Netherlands.
EJNMMI Radiopharm Chem. 2021 May 26;6(1):20. doi: 10.1186/s41181-021-00133-0.
The translocator protein 18 kDa is recognised as an important biomarker for neuroinflammation due to its soaring expression in microglia. This process is common for various neurological disorders. DPA-714 is a potent TSPO-specific ligand which found its use in Positron Emission Tomography following substitution of fluorine-19 with fluorine-18, a positron-emitting radionuclide. [F]DPA-714 enables visualisation of inflammatory processes in vivo non-invasively. Radiolabelling of this tracer is well described in literature, including validation for clinical use. Here, we report significant enhancements to the process which resulted in the design of a fully GMP-compliant robust synthesis of [F]DPA-714 on a popular cassette-based system, Trasis AllinOne, boosting reliability, throughput, and introducing a significant degree of simplicity.
[F]DPA-714 was synthesised using the classic nucleophilic aliphatic substitution on a good leaving group, tosylate, with [F]fluoride using tetraethylammonium bicarbonate in acetonitrile at 100C. The process was fully automated on a Trasis AllinOne synthesiser using an in-house designed cassette and sequence. With a relatively small precursor load of 4 mg, [F]DPA-714 was obtained with consistently high radiochemical yields of 55-71% (n=6) and molar activities of 117-350 GBq/µmol at end of synthesis. With a single production batch, starting with 31-42 GBq of [F]fluoride, between 13-20 GBq of the tracer can be produced, enabling multi-centre studies.
To the best of our knowledge, the process presented herein is the most efficient [F]DPA-714 synthesis, with advantageous GMP compliance. The use of a Trasis AllinOne synthesiser increases reliability and allows rapid training of production staff.
18 kDa转运蛋白因其在小胶质细胞中表达激增而被认为是神经炎症的重要生物标志物。这一过程在各种神经系统疾病中很常见。DPA - 714是一种有效的TSPO特异性配体，在将氟 - 19替换为正电子发射放射性核素氟 - 18后，它被用于正电子发射断层扫描。[F]DPA - 714能够在体内非侵入性地可视化炎症过程。该示踪剂的放射性标记在文献中有详细描述，包括临床应用的验证。在此，我们报告了该过程的显著改进，从而在基于盒式的流行系统Trasis AllinOne上设计出了完全符合GMP标准的[F]DPA - 714稳健合成方法，提高了可靠性、产量，并引入了显著的简便性。
[F]DPA - 714是通过经典的亲核脂肪族取代反应合成的，以对甲苯磺酸酯作为良好的离去基团，在100℃的乙腈中使用碳酸氢四乙铵与[F]氟化物反应。该过程在Trasis AllinOne合成仪上使用内部设计的盒式装置和程序实现了完全自动化。在前体负载量相对较小为4 mg的情况下，合成结束时获得了[F]DPA - 714，其放射化学产率始终保持在55 - 71%（n = 6），摩尔活度为117 - 350 GBq/µmol。从31 - 42 GBq的[F]氟化物开始进行单批次生产，可生产出13 - 20 GBq的示踪剂，能够支持多中心研究。
据我们所知，本文介绍的方法是最有效的[F]DPA - 714合成方法，具有符合GMP标准的优势。使用Trasis AllinOne合成仪提高了可靠性，并便于对生产人员进行快速培训。
