Optimization of [18F]FBPA production for clinical translation through precursor development and manufacturing route evaluation

4-Borono-2-[ 18 F]fluorophenylalanine ([ 18 F]FBPA) is an important imaging agent for identifying suitable candidates for boron neutron capture therapy (BNCT). This study aimed to develop three new precursors for the no-carrier-added synthesis of [ 18 F]FBPA and to establish corresponding automated radiosynthesis protocols suitable for routine production. Following manual optimization, the optimized conditions were successfully translated to automated synthesis, resulting in non-decay-corrected radiochemical yields of 2.6% ± 1.3% for the BNBA-based protocol, 0.3% ± 0.1% for the P-02-based protocol, and 3.1% ± 0.0% for the P-03-based protocol, respectively. MicroPET/MR imaging and biodistribution analyses demonstrated the highest tumor uptake for [ 18 F]FBPA-sorbitol conjugate ([ 18 F]FBPA-Sor), followed by [ 18 F]FBPA and [ 18 F]FBPA-fructose conjugate ([ 18 F]FBPA-Fr). Tumor standardized uptake values obtained from microPET/MR imaging were 1.72 ± 0.25 for [ 18 F]FBPA, 1.29 ± 0.25 for [ 18 F]FBPA-Fr, and 2.57 ± 0.28 for [ 18 F]FBPA-Sor, with corresponding tumor-to-muscle (T/M) ratios of 3.34 ± 1.07, 4.64 ± 0.60, and 9.38 ± 0.88, respectively. Biodistribution studies further confirmed enhanced tumor accumulation of [ 18 F]FBPA-Sor, with tumor uptake values of 10.46 ± 0.61, 11.51 ± 2.75, and 19.32 ± 1.57%ID/g for [ 18 F]FBPA, [ 18 F]FBPA-Fr, and [ 18 F]FBPA-Sor, respectively. In addition, [ 18 F]FBPA-Sor demonstrated the highest tumor-to-muscle and tumor-to-blood ratios, indicating that alditol conjugation significantly influences tracer pharmacokinetics and biodistribution profiles. These findings provide practical insights into precursor design, radiosynthesis optimization, and imaging performance, offering a rational framework to guide future development and clinical translation of [ 18 F]FBPA as a companion diagnostic for BNCT.