Drying free strategies for sustainable fluorine-18 radiochemistry

IF 3 4区医学 Q1 RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING

Nuclear medicine and biology Pub Date : 2026-03-01 Epub Date: 2026-02-23 DOI:10.1016/j.nucmedbio.2026.109611

Nektarios Pirmettis , Alexandros Pappas , Sevban Doğan Ekici , Abdul Karim Haji Dheere , Charalampos Triantis , Ioannis Pirmettis , Antonio Shegani

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Abstract

Azeotropic removal of water remains a significant limitation in fluorine-18 radiochemistry, often leading to longer synthesis times, variable yields, increased solvent use and operational complexity, and, indirectly, increased resource demand due to decay- and loss-driven activity requirements and incompatibility with base- or heat-sensitive precursors. This review critically evaluates drying-free strategies that mitigate or obviate this step while sustaining high radiochemical performance and compliance with good manufacturing practice. Methods are organized into controlled hydrous fluorination, ionic-liquid media, mixed organic solvent systems, alcohol-assisted elution, copper-mediated aromatic radiofluorination, rhenium-complexation routes, and other advanced approaches. Comparative analysis addresses fluoride recovery, radiochemical yield, substrate scope, including electron-rich arenes and base-sensitive chemotypes, tolerance to residual water/alcohol, cycle time, solvent and waste metrics, and suitability for automation and clinical translation. Copper-mediated protocols currently provide broad aromatic coverage with competitive yields under minimally basic, non-dried conditions; alcohol-assisted and mixed-solvent systems offer rapid, cassette-ready workflows for many aliphatic targets; and rhenium-assisted labeling enables mild conditions for sensitive scaffolds. Remaining challenges include standardized reagent kits and quality control, management of residual metals or additives, harmonized sustainability metrics, and consistent implementation across synthesis platforms. Collectively, drying-free strategies support more robust, streamlined and resource-efficient ¹⁸F tracer synthesis and are poised to facilitate scalable production and wider clinical adoption.

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可持续氟-18放射化学的无干燥策略。

水的共沸去除仍然是氟-18放射化学的一个重大限制，往往导致合成时间延长、产量变化、溶剂使用增加和操作复杂性增加，并且由于衰变和损失驱动的活性要求以及与碱或热敏前体不相容，间接增加了资源需求。本综述批判性地评估了在保持高放射化学性能和符合良好生产规范的同时减轻或避免这一步骤的无干燥策略。方法分为可控水合氟化、离子-液体介质、混合有机溶剂体系、醇辅助洗脱、铜介导的芳族放射性氟化、铼络合路线和其他先进方法。比较分析涉及氟化物回收率、放射化学产率、底物范围（包括富电子芳烃和碱基敏感的化学型）、对残余水/酒精的耐受性、循环时间、溶剂和废物指标，以及自动化和临床转化的适用性。目前，铜介导的方案在最低碱性、非干燥条件下提供了广泛的芳香覆盖和具有竞争力的产量；酒精辅助和混合溶剂系统为许多脂肪族目标提供快速，盒式工作流程；铼辅助标记为敏感支架提供了温和的条件。剩下的挑战包括标准化的试剂盒和质量控制、残余金属或添加剂的管理、统一的可持续性指标以及在合成平台上的一致实施。总的来说，无干燥策略支持更强大，简化和资源高效的18F示踪剂合成，并准备促进可扩展的生产和更广泛的临床应用。

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来源期刊

Nuclear medicine and biology 医学-核医学

CiteScore

6.00

自引率

9.70%

发文量

479

审稿时长

51 days

期刊介绍： Nuclear Medicine and Biology publishes original research addressing all aspects of radiopharmaceutical science: synthesis, in vitro and ex vivo studies, in vivo biodistribution by dissection or imaging, radiopharmacology, radiopharmacy, and translational clinical studies of new targeted radiotracers. The importance of the target to an unmet clinical need should be the first consideration. If the synthesis of a new radiopharmaceutical is submitted without in vitro or in vivo data, then the uniqueness of the chemistry must be emphasized. These multidisciplinary studies should validate the mechanism of localization whether the probe is based on binding to a receptor, enzyme, tumor antigen, or another well-defined target. The studies should be aimed at evaluating how the chemical and radiopharmaceutical properties affect pharmacokinetics, pharmacodynamics, or therapeutic efficacy. Ideally, the study would address the sensitivity of the probe to changes in disease or treatment, although studies validating mechanism alone are acceptable. Radiopharmacy practice, addressing the issues of preparation, automation, quality control, dispensing, and regulations applicable to qualification and administration of radiopharmaceuticals to humans, is an important aspect of the developmental process, but only if the study has a significant impact on the field. Contributions on the subject of therapeutic radiopharmaceuticals also are appropriate provided that the specificity of labeled compound localization and therapeutic effect have been addressed.