Abstract
ObjectiveThe aim of this study was to establish a reliable and routine method for the preparation of 4-[10B]borono-2-[18F]fluoro-l-phenylalanine (l-[18F]FBPA) for boron neutron capture therapy-oriented diagnosis using positron emission tomography.MethodsTo produce l-[18F]FBPA by electrophilic fluorination of 4-[10B]borono-l-phenylalanine (l-BPA) with [18F]acetylhypofluorite ([18F]AcOF) via [18F]F2 derived from the 20Ne(d,α)18F nuclear reaction, several preparation parameters and characteristics of l-[18F]FBPA were investigated, including: pre-irradiation for [18F]F2 production, the carrier F2 content in the Ne target, l-BPA-to-F2 ratios, separation with high-performance liquid chromatography (HPLC) using 10 different eluents, enantiomeric purity, and residual trifluoroacetic acid used as the reaction solvent by gas chromatography-mass spectrometry.ResultsThe activity yields and molar activities of l-[18F]FBPA (n = 38) were 1200 ± 160 MBq and 46–113 GBq/mmol, respectively, after deuteron-irradiation for 2 h. Two 5 min pre-irradiations prior to [18F]F2 production for 18F-labeling were preferable. For l-[18F]FBPA synthesis, 0.15–0.2% of carrier F2 in Ne and l-BPA-to-F2 ratios > 2 were preferable. HPLC separations with five of the 10 eluents provided injectable l-[18F]FBPA without any further formulation processing, which resulted in a synthesis time of 32 min. Among the five eluents, 1 mM phosphate-buffered saline was the eluent of choice. The l-[18F]FBPA injection was sterile and pyrogen-free, and contained very small amounts of D-enantiomer (< 0.1% of l-[18F]FBPA), l-BPA (< 1% of l-FBPA), and trifluoroacetic acid (< 0.5 ppm).Conclusionsl-[18F]FBPA injection was reliably prepared by the electrophilic fluorination of l-BPA with [18F]AcOF followed by HPLC separation with 1 mM phosphate-buffered saline.
Highlights
L-BPA was purchased from Sigma-Aldrich Chemical (St Louis, MO). l-BPA, l-FBPA, and d-FBPA were kindly supplied by Stella Pharma (Osaka, Japan). 2, 3, and 4-fluoro-d,l-phenylalanine (2, 3, and 4-FPhe, respectively) were purchased from Tokyo Chemical Industry (Tokyo, Japan)
Data are average ± standard deviation a l-[18F]FBPA obtained at the end of synthesis was normalized to that produced by 120-min irradiation b Radiochemical purity (RCP) was determined based on high-performance liquid chromatography (HPLC) analysis c Contamination of 4-[10B]borono-l-phenylalanine (l-BPA) is expressed as a percentage against the mass of l-FBPA. d n = 2
In two l-[18F]FBPA preparations separated with 0.01% AcOH saline and 5 mM phosphate-buffered saline (PBS), the addition of ascorbate injection slightly decreased the RCPs from 98.4% and 97.7–93.2% and 91.3%, respectively, by approximately 4 h
Summary
4-[10B]borono-2-[18F]fluoro-l-phenylalanine (l-[18F]FBPA) was developed in 1991 as a probe for positron emission tomography (PET) to evaluate in vivo 4-[10B]borono-l-phenylalanine (l-BPA) used in boron neutron capture therapy (BNCT) for patients with malignant tumors [1]. The synthesis of l-[18F]FBPA by nucleophilic fluorination using no-carrier-added [ 18F]fluoride will be developed to obtain higher activity yields and higher molar activities of l-[18F]FBPA, as the synthesis of 2-deoxy2-[18F]fluoro-d-glucose has progressed from the method using [18F]F2 to that using no-carrier-added [18F]fluoride At present such radiosynthesis is still under development, a preliminary synthesis was reported recently [29]. We investigated (1) the importance of pre-irradiation for [18F]F2 production with an appropriate F2 carrier, (2) steady production of l-[18F]FBPA in relation to F2 content and l-BPA, (3) HPLC separation methods to provide injectable l-[18F]FBPA without any further formulation processing, (4) the optical purity of l-[18F]FBPA, and (5) analysis of residual trifluoroacetic acid (TFA) used as a solvent in radiosynthetic preparation of l-[18F]FBPA. Labeled compounds and related terms are expressed according to the International Consensus Radiochemistry Nomenclature Guidelines recently recommended by an international Working Group on ‘Nomenclature in Radiopharmaceutical Chemistry and related areas’ [31, 32]
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