Development of an Optimized Thermal Deprotection Method for the Synthesis of 18F-based Radiopharmaceuticals

项目摘要/摘要 18F基化合物最佳热脱保护合成方法的研究 放射性药物。 到目前为止，在聚酯示踪剂生产过程中，还没有一种有效的方法来去除三苯基的保护 在无酸的热介质条件下。许多PET示踪剂是在商业上合成的 可用于临床前和临床研究的放射合成模块，具有良好的放射化学产率。在 18F-标记，前体含有N-三丁基(N-Tr)或N-单-(NMTr)或二甲氧基三丁基(DMTr)胺 繁琐的两步反应：(I)N-Tr/DMTR胺保护前驱体的18F-氟化，(Ii)用盐酸处理 用于去硝基反应以提供相应的游离胺。一般来说，当使用自动放射合成时 根据当前的良好制造规范(CGMP)、Tr/DMTR/MTR保护组 在合成的最后一步用酸(HCl、H_2SO_4或醋酸)除去。 然而，酸脱保护 这种方法有一些缺点，主要是因为不均匀的混合之间的各种 反应性成分会导致部分去保护，导致低放化产额(RCY)和低 放射化学纯度(RCP)。 考虑到N-Tr/DMTR保护前体的商业可用性，我们选择了 为这些前体开发我们的热中介去保护路线，而不是N-Boc，因为 室温下的寿命稳定性。我们设想建议的方法在操作上简单、更环保 用于放射性合成和提纯使用商业合成的放射性示踪剂的有效方法 模块，无需重新配置。PET tau示踪剂和PET报告探针的重要性得到了充分的认识， 而更广泛的研究调查，以充分探索和验证tau示踪剂-PET的用途是重要的。总的来说， 热介导的N-Tr去保护有助于缩短总体生产时间，它可能会增加 示踪剂的RCY。

Project Summary/Abstract Title: Development of an Optimized Thermal Deprotection Method for the Synthesis of 18F-based Radiopharmaceuticals. To date, in the process of PET tracer production, there is no method available for deprotection of trityl group under thermal mediated conditions in the absence of acid. Many PET tracers are synthesized on commercially available radiosynthesis modules in good radiochemical yield for preclinical and clinical research studies. In the 18F-labeling, the precursor contains N-trityl (N-Tr) or N-mono-(NMTr) or dimethoxytrityl (DMTr) amine involves a cumbersome, two-step reaction: (i) 18F-fluorination of N-Tr/DMTr amine protected precursor, (ii) treated with HCl for detritylation to afford the corresponding free amine. Generally speaking, when using automated radiosynthetic systems and following current Good Manufacturing Practices (cGMP), Tr/DMTr/MTr protection groups are removed by acid (HCl, H2SO4, or acetic acid) at the last step of synthesis. However, the acid deprotection approach has a number of drawbacks, primarily because of non-homogeneous mixture between various reactive components cause partial deprotection and leads to the low radiochemical yield (RCY) and low radiochemical purity (RCP). Given the commercial availability of N-Tr/DMTr protected precursors, we opted to develop our thermal mediated deprotection route for these precursors, rather than N-Boc because of the longer life-time stability at room temperature. We envision the proposed method to be operationally simple, greener method, effective for the radiosynthesis and purification of the radiotracer that uses a commercial synthesis module without reconfiguration. The importance of PET tau tracers and PET reporter probes are well recognized, and broader research investigation to fully explore and validate the utility of tau tracer-PET is important. Overall, thermal mediated N-Tr deprotection helped to shorten the overall production time, it potentially could increase RCY of the tracers.