Abstract
BACKGROUND: Boron neutron capture therapy relies on the selective accumulation of boron-containing compounds in tumor tissue, making accurate quantification of boron distribution essential for effective treatment planning. The amino acid analog boronophenylalanine is widely used as a boron delivery agent, yet direct assessment of its biodistribution remains challenging. A fluorine-18 labeled analog, 2-fluoro-boronophenylalanine, offers the potential to visualize and quantify uptake through positron emission tomography. However, reported radiosynthetic methods often suffer from low radiochemical yield, complex workflows, and limited compatibility with automated production platforms. The aim of this study was to design a stable precursor suitable for nucleophilic fluorination, develop a fully automated single-reactor radiosynthesis, and characterize the resulting tracer to support both preclinical use and future clinical translation. RESULTS: A rationally protected precursor incorporating tert-butyloxycarbonyl and pinacol ester groups was synthesized and isolated with high chemical and enantiomeric purity. Using this precursor, an automated single-pot radiosynthesis was implemented on a commercial synthesis module employing copper-mediated nucleophilic fluorination followed by acidic hydrolysis. Across eight production runs, the method yielded 2-fluoro-boronophenylalanine with non-decay-corrected radiochemical yields of 3-5% and a total synthesis time of approximately 60-70 min. Radiochemical purity consistently exceeded 98%, and the molar activity at the end of synthesis ranged from 85 to 120 GBq per micromole. The final formulation remained chemically and radiochemically stable for at least four hours at room temperature. Analytical and chiral chromatographic assessments confirmed product identity, purity, and retention of stereochemical configuration. CONCLUSIONS: This study establishes a practical and fully automated radiosynthetic approach for producing 2-fluoro-boronophenylalanine using a single-reactor nucleophilic fluorination strategy. The method overcomes key limitations of electrophilic fluorination and multi-pot workflows, provides high radiochemical purity and suitable molar activity, and is compatible with commercially available synthesis equipment. These features support routine preclinical application and position the method for future current good manufacturing practice adaptation to enable clinical use in boron neutron capture therapy planning.