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

项目总结/摘要 标题：开发用于合成18F基 放射性药物。 在PET示踪剂生产过程中，三苯甲基的脱保护还没有一种方法 在不存在酸的热介导条件下。许多PET示踪剂是在商业上合成的。 可用的放射合成模块，具有良好的放射化学产率，可用于临床前和临床研究。在 18F-标记，前体含有N-三苯甲基（N-Tr）或N-单-（NMTr）或二甲氧基三苯甲基（DMTr）胺，涉及 繁琐的两步反应：（i）N-Tr/DMTr胺保护的前体的18F-NMR，（ii）用HCl处理 用于脱三苯甲基，得到相应的游离胺。一般来说，当使用自动放射合成 系统并遵循现行药品生产质量管理规范（cGMP），Tr/DMTr/MTr保护组 在合成的最后一步用酸（HCl、H2SO 4或乙酸）除去。 然而，酸脱保护 该方法具有许多缺点，主要是因为各种方法之间的非均匀混合。 反应性组分引起部分脱保护，并导致低放射化学产率（RCY）和低放射化学产率。 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 我们开发了这些前体的热介导脱保护途径，而不是N-Boc，因为更长的时间 室温下的寿命稳定性。我们设想所提出的方法操作简单， 方法，有效的放射性示踪剂的放射性合成和纯化，使用商业合成 模块不需要重新配置。PET tau示踪剂和PET报告探针的重要性是公认的， 更广泛的研究调查，以充分探索和验证tau示踪剂-PET的效用是重要的。总的来说， 热介导的N-Tr脱保护有助于缩短总生产时间，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.