Automated Radiosynthesis of High-Molar-Activity 4-Borono-2-[18F]Fluorophenylalanine: Validation in Rodent Tumor Models and Nonhuman Primates.

Abstract

The clinical efficacy of [10B]borono-l-phenylalanine ([10B]BPA)-mediated Boron Neutron Capture Therapy (BNCT) relies heavily on accurate patient stratification using the companion diagnostic tracer 4-borono-2-[18F]fluorophenylalanine ([18F]FBPA). However, widespread clinical deployment is currently hindered by the limited production capacity and low molar activity of traditional electrophilic synthesis. To address this unmet need, we established a fully automated, GMP-compliant radiosynthesis of [18F]FBPA using a spirocyclic iodonium ylide (SCIDY) precursor on a commercial module. This optimized protocol delivered clinical-grade [18F]FBPA with a decay-corrected radiochemical yield of 15.5% ± 6.3% and a high molar activity of 75.9 ± 20.0 GBq/μmol. In vivo evaluation in subcutaneous xenografts showed high specificity for LAT1-positive tumors. Furthermore, in orthotopic C6 glioma and CAL27 tongue squamous cell carcinoma models, the tracer demonstrated effective blood-brain barrier penetration and good contrast, achieving Tumor-to-Normal (T/N) ratios of ∼ 3.3. Translational pharmacokinetic studies in nonhuman primates revealed rapid renal clearance and low background accumulation in critical head-and-neck organs, with a favorable effective dose of 0.012 mSv/MBq. This study presents a robust, clinical-ready strategy for producing high-molar-activity [18F]FBPA, bridging the gap between advanced radiochemistry and precise BNCT treatment planning.