Automated radiosynthesis of [18F]fluoromannitol on the Sofie Biosciences ELIXYS FLEX/CHEM system

Abstract

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. [¹⁸F]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 [¹⁸F]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 [¹⁸F]fluoromannose with >99 % radiochemical purity, which was then reduced to [¹⁸F]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 [¹⁸F]fluoromannitol and its broader adoption in bacterial infection imaging, with the potential to enhance early diagnosis and improve clinical management.

Keywords: Automation; Bacteria; Fluorine-18; Infectious disease; PET imaging; Pre-clinical; Radiochemistry.