A novel method for synthesis of 4-Borono-2-[¹⁸F]fluoro-L-phenylalanine

Objectives 4-Borono-2-[¹⁸F]fluoro-L-phenylalanine ([¹⁸F]FBPA) has been generally prepared according to the method described by Ishiwata et al. (Appl Radiat Isot 1991), in order to study tissue accumulation before boron neutron capture therapy where 4-borono-L-phenylalanine (BPA) is given intravenously as a carrier of ¹⁰B to tumor tissue. However, fluorination of BPA with [¹⁸F]acetylhypofluorite ([¹⁸F]AcOF) in trifluoroacetic acid (TFA), is insufficient for clinical use because of low radiochemical yield (RCY) (20-35%; decay corrected on the based on [¹⁸F]AcOF). We devised a novel synthesis of [¹⁸F]FBPA in order to improve the RCY.

Methods [¹⁸F]AcOF was bubbled into CHCl₃ (2 mL) containing N-tert-butoxycarbonyl-BPA tert-butyl ester (N-Boc-BPA(OBu^t) (42 mg) for 5 min at room temperature (rt). After removal of CHCl₃, the residue was dissolved in TFA (1 mL) and stirred for 5 min at rt. The RCY of [¹⁸F]FBPA were measured by thin layer chromatography with CHCl₃/MeOH/AcOH (3/2/1) as eluent.

Results The protic solvents such as TFA have been generally used as reaction field for the directly aromatic fluorination with [¹⁸F]AcOF. However, it is known that the solvents provide significantly [¹⁸F]labeled byproducts in fluorination with [¹⁸F]AcOF. Whereas, the aprotic solvent has been hardly used in the aromatic fluorination with [¹⁸F]AcOF. We selected CHCl₃ which is an aprotic solvent as reaction field and N-Boc-BPA(OBu^t) as a novel precursor. [¹⁸F]FBPA was prepared by fluorination of N-Boc-BPA(OBu^t) with [¹⁸F]AcOF in CHCl₃, followed by removal of Boc and Bu^t groups with TFA. The RCY based on [¹⁸F]AcOF was approximately 80% and was 2-4 times higher than that (20-35%) by the method previously employed.

Conclusions The present finding suggested that a novel synthesis of [¹⁸F]FBPA may enable increment of the number of cases examined in [¹⁸F]FBPA-PET.