The logic of total synthesis transformed a stagnant state of chemistry when there was a paucity of methods and reagents to synthesize pharmaceuticals. Molecular imaging by positron emission tomography (PET) is now experiencing a renaissance in the way radiopharmaceuticals are synthesized; however, a paradigm shift is desperately needed in the radiotracer discovery pipeline to accelerate drug development. As with most drugs, most radiotracers also fail, therefore expeditious evaluation of tracers in preclinical models before optimization or derivatization of the lead molecules is necessary. Furthermore the exact position of the ¹¹C and ¹⁸F radionuclide in tracers is often critical for metabolic considerations, and flexible methodologies to introduce radionuclides are needed. A challenge in PET radiochemistry is the limited choice of labelled building blocks available with carbon-11 (¹¹C; half-life ~20 min) and fluorine-18 (¹⁸F; half-life ~2 h). In fact, most drugs cannot be labelled with ¹¹C or ¹⁸F owing to a lack of efficient and diverse radiosynthetic methods. Routine radiopharmaceutical production generally relies on the incorporation of the isotope at the last or penultimate step of synthesis. Such reactions are conducted within the constraints of an automated synthesis unit (‘box’), which has further stifled the exploration of multistep reactions with short-lived radionuclides. Radiopharmaceutical synthesis can be transformed by considering logic of total synthesis to develop novel approaches for ¹¹C- and ¹⁸F-radiolabelling complex molecules via retrosynthetic analysis and multistep reactions. As a result of such exploration, new methods, reagents, and radiopharmaceuticals for in vivo imaging studies are discovered and are critical to work towards our ultimate, albeit impossible goal – a concept we term as total radiosynthesis – to radiolabel virtually any molecule. In this account, we show how multistep radiochemical reactions have impacted our radiochemistry program, with prominent examples from others, focusing on impact towards human imaging studies. As the goal of total synthesis is to be concise, we strive to simplify the syntheses of radiopharmaceuticals. New clinically useful strategies, including [¹¹C]CO₂ fixation, which has enabled library radiosynthesis, as well as radiofluorination of non-activated arenes via iodonium ylides are highlighted. We also showcase state-of-the-art automation technologies, including microfluidic flow chemistry for radiopharmaceutical production.

当合成药物的方法和试剂匮乏时，全合成的逻辑改变了化学的停滞状态。正电子发射断层扫描（PET）分子成像现在正在经历放射性药物合成方式的复兴；然而，放射性示踪剂发现管道迫切需要进行范式转变，以加速药物开发。与大多数药物一样，大多数放射性示踪剂也会失败，因此在先导分子的优化或衍生化之前，有必要在临床前模型中快速评估示踪剂。此外，示踪剂中¹¹ C 和¹⁸ F 放射性核素的确切位置对于代谢考虑通常至关重要，并且需要灵活的方法来引入放射性核素。PET 放射化学的一个挑战是碳 11（¹¹ C；半衰期约 20 分钟）和氟 18（¹⁸ F；半衰期约 2 小时）标记构建模块的选择有限。事实上，由于缺乏高效且多样化的放射合成方法，大多数药物无法用¹¹ C 或¹⁸ F 标记。常规放射性药物生产通常依赖于在合成的最后或倒数第二步骤中掺入同位素。此类反应是在自动合成单元（“盒子”）的限制下进行的，这进一步抑制了对短寿命放射性核素多步反应的探索。放射性药物合成可以通过考虑全合成逻辑来转变，通过逆向合成分析和多步反应开发¹¹ C-和¹⁸ F-放射性标记复杂分子的新方法。这些探索的结果是，发现了用于体内成像研究的新方法、试剂和放射性药物，它们对于实现我们最终的、尽管不可能的目标（我们称之为全放射合成的概念）来放射性标记几乎任何分子至关重要。在这篇文章中，我们展示了多步放射化学反应如何影响我们的放射化学计划，并结合其他人的突出例子，重点关注对人类成像研究的影响。由于全合成的目标是简洁，因此我们努力简化放射性药物的合成。强调了新的临床有用的策略，包括[ ¹¹ C]CO ₂固定，这使得文库放射合成成为可能，以及通过碘叶立德对非活化芳烃进行放射性氟化。我们还展示最先进的自动化技术，包括用于放射性药物生产的微流体化学。