Schopf Eric, Waldmann Christopher M, Collins Jeffrey, Drake Christopher, Slavik Roger, van Dam R Michael
SOFIE.
Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles (UCLA); Ahmanson Translational Imaging Division, University of California, Los Angeles (UCLA).
J Vis Exp. 2018 Oct 26(140):58428. doi: 10.3791/58428.
The development of new positron-emission tomography (PET) tracers is enabling researchers and clinicians to image an increasingly wide array of biological targets and processes. However, the increasing number of different tracers creates challenges for their production at radiopharmacies. While historically it has been practical to dedicate a custom-configured radiosynthesizer and hot cell for the repeated production of each individual tracer, it is becoming necessary to change this workflow. Recent commercial radiosynthesizers based on disposable cassettes/kits for each tracer simplify the production of multiple tracers with one set of equipment by eliminating the need for custom tracer-specific modifications. Furthermore, some of these radiosynthesizers enable the operator to develop and optimize their own synthesis protocols in addition to purchasing commercially-available kits. In this protocol, we describe the general procedure for how the manual synthesis of a new PET tracer can be automated on one of these radiosynthesizers and validated for the production of clinical-grade tracers. As an example, we use the ELIXYS radiosynthesizer, a flexible cassette-based radiochemistry tool that can support both PET tracer development efforts, as well as routine clinical probe manufacturing on the same system, to produce [F]Clofarabine ([F]CFA), a PET tracer to measure in vivo deoxycytidine kinase (dCK) enzyme activity. Translating a manual synthesis involves breaking down the synthetic protocol into basic radiochemistry processes that are then translated into intuitive chemistry "unit operations" supported by the synthesizer software. These operations can then rapidly be converted into an automated synthesis program by assembling them using the drag-and-drop interface. After basic testing, the synthesis and purification procedure may require optimization to achieve the desired yield and purity. Once the desired performance is achieved, a validation of the synthesis is carried out to determine its suitability for the production of the radiotracer for clinical use.
新型正电子发射断层扫描（PET）示踪剂的开发使研究人员和临床医生能够对越来越多的生物靶点和过程进行成像。然而，不同示踪剂数量的增加给放射性药物药房的生产带来了挑战。从历史上看，为每种示踪剂的重复生产专门配备定制配置的放射性合成仪和热室是可行的，但改变这种工作流程变得很有必要。最近基于一次性盒式/试剂盒的商用放射性合成仪，通过消除针对特定示踪剂的定制修改需求，简化了使用一套设备生产多种示踪剂的过程。此外，其中一些放射性合成仪除了购买商用试剂盒外，还使操作人员能够开发和优化自己的合成方案。在本方案中，我们描述了如何在其中一台此类放射性合成仪上实现新PET示踪剂的手动合成自动化，并验证其用于生产临床级示踪剂的一般程序。例如，我们使用ELIXYS放射性合成仪，这是一种灵活的基于盒式的放射化学工具，可在同一系统上支持PET示踪剂的开发工作以及常规临床探针的制造，以生产[F]氯法拉滨（[F]CFA），一种用于测量体内脱氧胞苷激酶（dCK）酶活性的PET示踪剂。将手动合成转化为自动化合成，需要将合成方案分解为基本的放射化学过程，然后转化为由合成仪软件支持的直观化学“单元操作”。然后，通过使用拖放界面将这些操作组装起来，可迅速将其转换为自动化合成程序。在进行基本测试后，合成和纯化程序可能需要优化以达到所需的产率和纯度。一旦达到所需性能，就对合成进行验证，以确定其是否适合生产用于临床的放射性示踪剂。
