Simpson Spenser R, Jouad Kamal, Clay Allison J, Ghosh Arijit, Wilde Justin H, Dickie Diane A, Vavere Amy L, Neumann Kiel D
Department of Radiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
Department of Radiology and Medical Imaging, University of Virgina, 480 Ray C. Hunt Drive, Charlottesville, VA, 22903, USA.
Appl Radiat Isot. 2025 Nov;225:112076. doi: 10.1016/j.apradiso.2025.112076. Epub 2025 Jul 30.
Bacterial infections remain a significant global health concern, exacerbated by rising antimicrobial resistance and a growing immunocompromised population. Improved diagnostic tools are essential to accurately detect infections, distinguish them from sterile inflammation, and reduce unnecessary antibiotic use that drives resistance. Positron Emission Tomography (PET) has emerged as a powerful non-invasive modality for detecting and monitoring infections in vivo, especially when conventional diagnostics are inconclusive. [F]Fluoromannitol is a novel PET radiopharmaceutical that selectively targets both Gram-positive and Gram-negative bacteria, enabling broad-spectrum imaging and differentiation from sterile inflammation. To support preclinical studies and facilitate broader research use, we report the automated synthesis of [F]fluoromannitol using the ELIXYS FLEX/CHEM radiosynthesizer. The synthesis was adapted from a manual protocol into a fully automated, two-pot, three-step process involving a nucleophilic fluorination, acid deprotection, and sodium borohydride reduction. Reaction conditions were optimized on the ELIXYS FLEX/CHEM platform. The fluorination was optimized for temperature and time to a yield of 78 ± 1.5 %. Acid-catalyzed deprotection yielded an impurity when manual conditions were applied. A large increase in temperature was necessary in order to efficiently produced [F]fluoromannose with >99 % radiochemical purity, which was then reduced to [F]fluoromannitol. The complete synthesis required approximately 136 min, yielding a 15 ± 0.9 % activity yield, a 35 ± 2.0 % radiochemical yield, >99 % radiochemical purity, and a final pH of 5.5 ± 0.5. This automated synthesis protocol supports reliable production of [F]fluoromannitol and its broader adoption in bacterial infection imaging, with the potential to enhance early diagnosis and improve clinical management.
细菌感染仍然是全球重大的健康问题，抗菌药物耐药性的上升和免疫功能低下人群的增加使这一问题更加严重。改进的诊断工具对于准确检测感染、将其与无菌性炎症区分开来以及减少导致耐药性的不必要抗生素使用至关重要。正电子发射断层扫描（PET）已成为一种强大的非侵入性检测和监测体内感染的方法，尤其是在传统诊断尚无定论时。[F]氟甘露糖醇是一种新型PET放射性药物，可选择性地靶向革兰氏阳性菌和革兰氏阴性菌，实现广谱成像并与无菌性炎症相区分。为支持临床前研究并促进更广泛的研究应用，我们报告了使用ELIXYS FLEX/CHEM放射性合成仪自动合成[F]氟甘露糖醇的方法。该合成方法是从手动操作方案改编而来，成为一个全自动的两锅三步过程，包括亲核氟化、酸脱保护和硼氢化钠还原。反应条件在ELIXYS FLEX/CHEM平台上进行了优化。氟化反应的温度和时间经过优化，产率为78±1.5%。应用手动操作条件时，酸催化脱保护产生了杂质。为了高效生成放射化学纯度>99%的[F]氟甘露糖，需要大幅提高温度，然后将其还原为[F]氟甘露糖醇。整个合成过程大约需要136分钟，活性产率为15±0.9%，放射化学产率为35±2.0%，放射化学纯度>99%，最终pH值为5.5±0.5。这种自动合成方案支持可靠地生产[F]氟甘露糖醇，并使其在细菌感染成像中得到更广泛的应用，有可能提高早期诊断水平并改善临床管理。
