Objective The aim of this study was to establish a reliable and routine method for the preparation of 4-[ B]borono-2- 18 18 [ F]fluoro- l -phenylalanine (l -[ F]FBPA) for boron neutron capture therapy-oriented diagnosis using positron emission tomography. 18 10 18 Methods To produce l -[ F]FBPA by electrophilic fluorination of 4-[ B]borono-l -phenylalanine (l -BPA) with [ F]acetyl- 18 18 20 18 hypofluorite ([ F]AcOF) via [ F]F derived from the Ne(d,α) F nuclear reaction, several preparation parameters and 18 18 characteristics of l -[ F]FBPA were investigated, including: pre-irradiation for [ F]F production, the carrier F content in the 2 2 Ne target, l -BPA-to-F ratios, separation with high-performance liquid chromatography (HPLC) using 10 different eluents, enantiomeric purity, and residual triu fl oroacetic acid used as the reaction solvent by gas chromatography-mass spectrometry. Results The activity yields and molar activities of l -[ F]FBPA (n = 38) were 1200 ± 160 MBq and 46–113 GBq/mmol, 18 18 respectively, after deuteron-irradiation for 2 h. Two 5 min pre-irradiations prior to [ F]F production for F-labeling were preferable. For l -[ F]FBPA synthesis, 0.15–0.2% of carrier F in Ne and l -BPA-to-F ratios > 2 were preferable. HPLC 2 2 separations with five of the 10 eluents provided injectable l -[ F]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 18 18 l -[ F]FBPA injection was sterile and pyrogen-free, and contained very small amounts of D-enantiomer (< 0.1% of l -[ F] FBPA), l -BPA (< 1% of l -FBPA), and trifluoroacetic acid (< 0.5 ppm). 18 18 Conclusions l -[ F]FBPA injection was reliably prepared by the electrophilic fluorination of l -BPA with [ F]AcOF followed by HPLC separation with 1 mM phosphate-buffered saline. 18 18 Keywords l -[ F]FBPA · [ F]F production · Quality control · PET · BNCT Introduction 10 18 18 4-[ B]borono-2-[ F]fluoro- l -phenylalanine (l -[ F]FBPA) was developed in 1991 as a probe for positron emission tomography (PET) to evaluate in vivo 4-[ B]borono-l -phe- * Kiichi Ishiwata nylalanine (l -BPA) used in boron neutron capture therapy email@example.com (BNCT) for patients with malignant tumors . Based on several basic studies that verified the usefulness of l -[ F] Institute of Cyclotron and Drug Discovery Research, Southern TOHOKU Research Institute for Neuroscience, FBPA [2–5], l -[ F]FBPA PET has been clinically applied 7-115 Yatsuyamada, Koriyama 963-8052, Japan for this purpose [6–9] and expanded in limited numbers of Department of Biofunctional Imaging, Fukushima Medical PET facilities over the past 20 years [10–13], mainly because University, Fukushima, Japan BNCT is performed using a nuclear reactor for neutron irra- Research Team for Neuroimaging, Tokyo Metropolitan diation. Recently, a cyclotron that acts as an epithermal- Institute of Gerontology, Tokyo, Japan neutron source for BNCT and that can be installed in the Frontier Laboratories, Koriyama, Japan hospitals has been developed [14, 15]. Phase I and II clinical trials of l -BPA BNCT using this cyclotron are in progress SHI Accelerator Service, Tokyo, Japan Vol.:(0123456789) 1 3 464 Annals of Nuclear Medicine (2018) 32:463–473 at two institutes in Japan, including the Southern Tohoku sufficiently in previous reports on the three methods [1 , 8, BNCT Research Center at the Southern TOHOKU Research 24–26, 28]. In the present study, we aimed to elaborate on Institute for Neuroscience. Therefore, the importance of the original method from the viewpoint of routine clinical l -[ F]FBPA PET is increasing, and further basic studies use. 18 18 on the characterization of l -[ F]FBPA have been reported For this purpose, steady production of [ F]F is first in recent years [15–23]. essential. It is well known empirically that a short pre- l -[ F]FBPA has been synthesized by the electrophilic irradiation step is essential before the main irradiation for 18 18 18 18 fluorination of l -BPA with carrier-added [ F]F or [ F] F-labeling; however, systematic studies on [ F]F produc- 2 2 acetylhypofluorite ([ F]AcOF) produced by three different tion have not been reported. A larger amount of carrier F in routes. [ F]F was originally produced by deuteron irradia- Ne target, for example 0.5% F , has a benefit for the steady 2 2 20 18 18 tion of carrier F -containing Ne, termed the Ne(d,α) F production of [ F]F but provides low molar activity, and 2 2 nuclear reaction . However, the activity yields of [ F] the stoichiometric relationship in the fluorination of l -BPA 18 18 18 F and the resultant l -[ F]FBPA were low. For example, with [ F]F /[ F]AcOF should be considered carefully. For 2 2 Wang et al. prepared 444–518 MBq of l -[ F]FBPA from electrophilic fluorination of l -BPA, the original method 18 18 18 5.55 GBq of [ F]F after deuteron irradiation for 2 h . used [ F]AcOF due to its higher selectivity than [ F]F 2 2 18 18 The molar activity of l -[ F]FBPA was also low because of , whereas the second and third methods employed [ F]F carrier F : 30–60 MBq/µmol . The second and third routes probably to avoid activity loss of activity during the conver- 18 18 18 18 18 used the O(p,n) F nuclear reaction for carrier-added [ F] sion process from [ F]F to [ F]AcOF [25–27]. Regarding 18 18 F production. In the former, [ F]F was produced by proton the formulation of l -[ F]FBPA, the most popular prepa- 2 2 irradiation of highly enriched [ O]O gas followed by a sec- ration method is purification by high-performance liquid ond proton irradiation step for the release of [ F]F [25, 26]. chromatography (HPLC) using a reversed-phase column In the latter, [ F]fluoride produced by proton irradiation of with 0.1% aqueous AcOH as the mobile phase followed by 18 18 18 18 [ O]H O was converted to [ F]F via [ F]fluoromethane evaporation of the l -[ F]FBPA fraction and re-dissolution 2 2 18 18 . The O(p,n) F reaction can produce potentially large in physiological saline . To avoid this time-consuming 18 20 18 18 amounts of F compared with the Ne(d,α) F reaction; evaporation process, Vähätalo et al. separated l -[ F]FBPA therefore, the activity yields of l -[ F]FBPA synthesized by HPLC using physiological saline containing 1–2% EtOH via the second route (2 GBq  to 5.3 GBq ), and the and 0.01% AcOH as the eluent, and the l -[ F]FBPA fraction molar activity (257 MBq/µmol ) has been improved. The was used directly for injection in clinical studies ; how- third route was especially devised to give less carrier-added ever, the pH of this injection was not described, although it 18 18 [ F]F . Consequently, the molar activity of l -[ F]FBPA appeared to be below 4. Prior to this, Ishiwata et al. proposed was the highest (3700 MBq/µmol), but the activity yields HPLC separation with physiological saline alone without have not been clearly described . clinical use . In the future, the synthesis of l -[ F]FBPA by nucleo- In the present study, we investigated (1) the importance 18 18 philic fluorination using no-carrier-added [ F]fluoride will of pre-irradiation for [ F]F production with an appropriate be developed to obtain higher activity yields and higher F carrier, (2) steady production of l -[ F]FBPA in relation molar activities of l -[ F]FBPA, as the synthesis of 2-deoxy-to F content and l -BPA, (3) HPLC separation methods to 18 18 2-[ F]fluoro- d -glucose has progressed from the method provide injectable l -[ F]FBPA without any further formula- 18 18 18 using [ F]F to that using no-carrier-added [ F]fluoride. tion processing, (4) the optical purity of l -[ F]FBPA, and However, at present such radiosynthesis is still under devel- (5) analysis of residual trifluoroacetic acid (TFA) used as opment, although a preliminary synthesis was reported a solvent in radiosynthetic preparation of l -[ F]FBPA. To recently . the best of our knowledge, no report on points (4) and (5) At the present stage of l -[ F]FBPA PET for l -BPA has been published previously. Findings for the three other BNCT-oriented diagnosis, l -[ F]FBPA PET is applied to points would also provide useful information for the radio- 18 18 18 18 only a few patients per l -[ F]FBPA preparation and not to synthesis of l -[ F]FBPA using O-derived [ F]F . mass screening; therefore, a steady and reliable synthesis Labeled compounds and related terms are expressed 18 18 of l -[ F]FBPA is required. The molar activity of l -[ F] according to the International Consensus Radiochemistry FBPA is not a critical issue. Among the three methods of Nomenclature Guidelines recently recommended by an l -[ F]FBPA synthesis described previously, Ne-derived international Working Group on ‘Nomenclature in Radiop- [ F]F is produced simply and cost-effectively compared harmaceutical Chemistry and related areas’ [31, 32]. 18 18 with O-derived [ F]F . Therefore, the original method of l -[ F]FBPA synthesis has been adapted clinically to date; however, detailed procedures, the optimization of each process, and technical knowhow have not been described 1 3 Annals of Nuclear Medicine (2018) 32:463–473 465 Materials and methods Synthesis of l ‑[ F]FBPA l -BPA was purchased from Sigma-Aldrich Chemical (St l -[ F]FBPA (total 38 runs) was prepared by electrophilic fluorination with [ F]AcOF using a multipurpose synthe- Louis, MO). l -BPA, l -FBPA, and d -FBPA were kindly supplied by Stella Pharma (Osaka, Japan). 2-, 3-, and sizer (CFN-MPS200, Sumitomo Heavy Industries) using a method that was a slightly modified method from previ- 4-fluoro- d ,l -phenylalanine (2-, 3-, and 4-FPhe, respec- tively) were purchased from Tokyo Chemical Industry ous reports [33, 34]. Two conditioning 5 min irradiations were performed, and a main irradiation for F-labeling (Tokyo, Japan). Normal saline (500 and 1000 mL plas- tic bag), distilled water (20 ml plastic ampule and 500 ml was performed for 90–156 min (123 ± 17 min). In all three irradiations, the content of F in Ne was set at the same plastic bottle) for injection, and sodium phosphate correc- tive injection 0.5 mmol/ml (pH 6.5, 20 ml plastic ampule) percentage of 0.10–0.30% (30–89 µmol: 0.10%, n = 3; 0.15%, n = 8; 0.20%, n = 23; 0.25%, n = 2; and 0.30%, were purchased from Otsuka Pharmaceutical (Tokyo, Japan). Other chemical reagents were obtained from com- n = 2). The [ F]F produced was passed through a column containing sodium acetate trihydrate or sodium acetate mercial sources. anhydrous (4 mm i.d. × 40 mm length), and the resultant [ F]AcOF was bubbled into 4 ml TFA containing l -BPA Production of [ F]F at room temperature with maximal flow rates: 426 ± 68 ml/ min from the target pressure (ca. 380 kPa) to 100 kPa. To An 18 MeV cyclotron (CYPRIS HM-18, 18 MeV protons examine the effect of the l -BPA-to-F ratios on l -[ F] and 9 MeV deuterons, Sumitomo Heavy Industries, Tokyo, FBPA synthesis, the amount of l -BPA was varied in the Japan) was employed. Elemental [ F]F was produced via range 14.2–33.3 mg (68–160 µmol: 14.2–14.8 mg, n = 2; 20 18 the Ne(d,α) F reaction in Ne containing F in a cylin- 18.5 mg, n = 1; 25.1–25.3 mg, n = 3; and 29.3–33.3 mg, drical target chamber [30 mm inner diameter (i.d.) and n = 32). The total (100%) recovered from [ F]F produc- 242 mm length] made of aluminum. The incident deuteron tion was estimated as the summed activities of the sodium energy was 7.9 MeV. All deuteron irradiation processes acetate column and the TFA solution. The radioactivity were performed at a fixed current of 20 µA. sensor using to monitor a reaction vial containing the TFA solution was calibrated according to the standard 18 18 Conditioning production of [ F]F F-activity measured with a dose calibrator (CRC-15 PET, Capintec, Florham Park, NJ, USA). To determine a suitable pre-irradiation protocol before The TFA solution was heated to 120 °C, and the TFA 18 18 the main [ F]F production for F-labeling, three or was removed using a 200 ml/min N flow. The residue was 2 2 four successive 5 min irradiations were conducted within dissolved in 2 ml of the eluent used for preparative HPLC 1–39 day intervals. The content of F in Ne was set in the (described below). The solution was applied to HPLC sep- same range in each experiment: 0.1% (v/v) (n = 7), 0.15% aration, and the fraction with l -[ F]FBPA was obtained. (n = 7), and 0.2% (n = 5) by mixing 5% F -containing Ne The volumes of the l -[ F]FBPA fractions were estimated and pure Ne gases. The final pressure was set at 380 kPa. by weight (1.0 g = 1.0 ml), and the pH was measured using However, the actual F concentrations calculated from the a pH meter (Laqua act, Horiba Scientific, Tokyo, Japan). pressure were determined to have certain ranges. After In four of 38 runs, the l -[ F]FBPA fraction was collected the end of the 5 min irradiation, the [ F]F produced was through a 0.22 µm membrane filter (SLGVJ33RS, Merck recovered with a maximum flow rate by the target pressure Millipore, Darmstadt, Germany) for clinical purposes, and and absorbed into a tandem column of soda lime (No.1, the sterility and apyrogenicity were examined. Filter integ- Wako Pure Chemicals, Osaka, Japan, 9 mm i.d. × 80 mm rity (> 150 kPa) was evaluated using a Millex/Sterivex integ- length) and activated charcoal (Granular, Wako Pure rity tester (Merck Millipore). The activity yields of l -[ F] Chemicals, 9 mm i.d. × 80 mm length). The average flow FBPA at the end of synthesis (EOS) were normalized with rates from maximum pressure (ca. 380 kPa) to 100 kPa respect to those produced by irradiation for 120 min. were in range of 756–845 ml/min. The activity absorbed in the tandem columns was estimated as the total activity HPLC separation of l ‑[ F]FBPA recovered from [ F]F production, and corrected for decay to the end of cyclotron bombardment (EOB). The column used for HPLC separation of l -[ F]FBPA was YMC-Pack ODS-A (S-5 µm, 20 nm, 20 mm i.d. × 150 mm length, YMC, Kyoto, Japan) with a guard cartridge ODS-A (S-5 µm, 12 nm, 20 mm i.d. × 10 mm, YMC). The 10 dif- ferent mobile phases investigated are summarized in Table 1 1 3 466 Annals of Nuclear Medicine (2018) 32:463–473 10 18 18 Table 1 Characteristics of 4-[ B]borono-2-[ F]fluoro- l -phenylalanine (l -[ F]FBPA) preparations separated by high-performance liquid chro- matography using 10 different eluents 18 a b c Eluent n Volume l -[ F]FBPA RCP l -BPA pH mL GBq GBq/mmol % % (1) 0.1% AcOH water 3 16.2 ± 1.8 1.21 ± 0.04 71.4 ± 7.2 97.2 ± 1.1 0.97 ± 0.36 3.3 ± 0.3 (2) 0.01% AcOH water 4 11.9 ± 1.2 1.06 ± 0.20 66.4 ± 6.4 98.5 ± 1.0 0.43 ± 0.17 3.9 ± 0.2 (3) Saline 2 22.3 1.32 66.4 98.7 0.97 6.0 (4) 0.01% AcOH saline 9 24.0 ± 3.0 1.18 ± 0.19 86.6 ± 23.8 98.9 ± 0.8 0.87 ± 0.71 3.8 (5) 1% EtOH, 0.01% AcOH saline 1 20.3 1.35 50.9 98.7 2.08 3.8 (6) 0.01% AcOH, 5 mM phosphate-buffered saline 3 13.8 ± 2.2 0.95 ± 0.05 83.0 ± 24.9 99.6 ± 0.1 0.26 ± 0.23 6.1 ± 0.1 (7) 0.01% AcOH, 1 mM phosphate-buffered saline 3 15.3 ± 0.7 1.22 ± 0.17 60.1 ± 12.3 99.5 ± 0.2 0.72 ± 0.40 4.4 ± 0.1 (8) 10 mM phosphate-buffered saline 2 14.1 1.51 72.5 97.0 0.55 6.8 (9) 5 mM phosphate-buffered saline 3 15.8 ± 1.3 1.14 ± 0.04 71.7 ± 1.3 98.0 ± 0.9 0.32 ± 0.06 6.8 ± 0.0 (10) 1 mM phosphate-buffered saline 8 13.2 ± 3.3 1.12 ± 0.14 92.8 ± 31.4 98.0 ± 0.5 0.41 ± 0.23 6.7 ± 0.0 Data are average ± standard deviation a 18 l -[ F]FBPA obtained at the end of synthesis was normalized to that produced by 120-min irradiation Radiochemical purity (RCP) was determined based on HPLC analysis c 10 Contamination (moles) of 4-[ B]borono-l -phenylalanine (l -BPA) is expressed as a percentage against the mass of l -FBPA. n = 2 (eluents 1–10). Eluents of 10 and 5 mM phosphate-buffered monitor (US-3000, Universal Giken). The retention times of l -BPA and l -FBPA were 6.0 and 8.5 min, 6.1 and 8.7 min, saline (PBS) were prepared by mixing normal saline, sodium phosphate corrective injection 0.5 mmol/ml (pH 6.5), and 5.5 and 7.7 min, and 4.4 and 6.1 min with eluents a, b, c, and d, respectively. The retention times of 2-, 3-, and 4-FPhe distilled water to an isotonic ion strength of 0.15 mEq/ml. Eluent containing 1 mM PBS was prepared by adding 1/500 were 8.5, 12.5, and 12.7 min, and 12.5, 14.1, and 19.9 min with eluents a and d, respectively. volume of sodium phosphate corrective injection 0.5 mmol/ ml (pH 6.5) into normal saline. The flow rate was 10 ml/min, Optical purity of l ‑[ F]FBPA and the elution profile was monitored using an ultraviolet (UV, 260 nm) detector (UV 2715 Plus, Jasco, Tokyo Japan) A Crownpak CR (+) (4.0 mm i.d. × 150 mm length, Daicel, and a radioactivity monitor (UG-PD1A, Universal Giken, Odawara, Japan). First, in the separation with eluent 1, based Tokyo, Japan) column was used with a mobile phase of HClO (pH 2.0) at a flow rate of 1.0 ml/min at 20–21 °C. on previous reports [1, 27], a major radioactive peak, and later other minor radioactive peaks and shoulder compo- The retention times of d -FBPA and l -FBPA were 6.5 and 9.9 min, respectively. nents were fractionated, l -[ F]FBPA and three by-products of 2-, 3-, and 4-[ F]fluoro- l -phenylalanine were identified Measurement of TFA in l ‑[ F]FBPA by comparison of their retention times with those of the authentic compounds (enantiomeric mixtures in the case of Gas chromatography-mass spectrometry (GC-MS) was fluorophenylalanines) in the HPLC analysis described below. applied for the analysis of residual TFA in eight l -[ F] FBPA preparations: eluents 1, n = 1; 4, n = 5; 9, n = 1; and HPLC analysis of l ‑[ F]FBPA 10, n = 1. 0.1 ml of concentrated H SO /MeOH (4/1) was 2 4 added to a 0.5 ml l -[ F]FBPA sample, and the mixture was The column used was YMC-UltraHT Pro C18 S-2 µm (3.0 mm i.d. × 100 mm length, YMC). Four different shaken vigorously for 30 s. 0.4 ml of CH Cl was then added 2 2 to the mixture followed by a 15 s extraction with methyl tri- mobile phases were investigated: (a) 50 mM AcOH/50 mM AcONH (1/1), (b) 50 mM N aH PO , (c) 0.1% AcOH, and fluoroacetate. The CH Cl phase solution (1 µl) was applied 2 2 4 2 4 to GC–MS analysis 1 min after the end of extraction. Stand- (d) 0.8% AcOH containing 1 mM ethylenediaminetetraacetic acid (EDTA) and 1 mM sodium octylsulfate [similar eluents ard aqueous TFA (0.1–100 ppm) was also treated in the same way, and a calibration curve of methyl trifluoroacetate as described in Refs. 1, 23, 25] at a flow rate of 0.5 ml/ min at 20–21 °C, and the elution profiled was monitored was prepared. A quadruple mass spectrometer (5975C, Agilent Tech- using a UV detector at 280 nm (SPD-20A Prominence UV/ VIS detector, Shimadzu, Tokyo, Japan) and a radioactivity nologies, Santa Clara, CA) in conjunction with a gas 1 3 Annals of Nuclear Medicine (2018) 32:463–473 467 chromatograph (5890GC, Agilent Technologies) was used in experiments for the conditioning production of [ F]F with a deactivated metal capillary column (0.25 mm i.d. × together with the yields in each of two conditioning 5 min 30 m) with 1 µm film thickness of Ultra ALLOY-CW (Fron- irradiations for the l -[ F]FBPA synthesis as a function of tier Laboratories, Koriyama, Japan). The oven temperature the intervals of each irradiation day. The calculated actual was maintained at 40 °C for 3 min and then increased to F concentrations for 0.10%, 0.15%, and 0.20% F /Ne targets 2 2 150 °C at 100°C/min and held there for 3 min. The split/ were 0.11 ± 0.01% (range 0.08–0.14%, n = 27), 0.15 ± 0.02% splitless injector and the transfer line were kept at 200 °C. (0.10–0.19%, n = 38), and 0.20 ± 0.02% (0.17–0.25%, The flow rate of He carrier gas was 1.5 ml/min. n = 65), respectively. The activity yields were variable after the first irradiation regardless of the F content or interval days. For 0.10% and 0.15% F /Ne targets, the third irradia- Results and discussion tions produced almost steady-state yields. With 0.20% F / Ne, the yields reached steady state with the second irra- Conditioning production of [ F]F diation. It is noted that steady-state yields are useful from a practical perspective but did not mean the quantitative 18 18 Figure 1 shows a plot of the activity yields of [ F]F recovery of [ F]F produced with each irradiation even if a 2 2 after each of three or four successive 5 min irradiations higher concentration of F was employed. The relationship a-1 a-2 a-3 a-4 1.5 1.5 1.5 1.5 1.0 1.0 1.0 1.0 0.5 0.5 0.5 0.5 0.0 0.0 0.0 0.0 02040 02040 010203040 010203040 b-1 b-2 b-3 b-4 1.5 1.5 1.5 1.5 1.0 1.0 1 1 0.5 0.5 0.5 0.5 0.0 0 0.0 010203040 05 10 15 05 10 15 c-1 c-2 c-3 c-4 1.5 1.5 1.5 1.5 1.0 1.0 1.0 1.0 0.5 0.5 0.5 0.5 0.0 0.0 0.0 0.0 0102030 0102030 05 10 15 05 10 15 Interval (days) Interval(days)Interval(days) Interval (days) Fig. 1 Effect of irradiation times and irradiation interval on the pro- tively, and –(1), -(2), -(3), and (4) indicate the first, second, third, and 18 18 duction of [ F]F . a–c Show the activity yields (GBq) of [ F]F for fourth 5 min irradiations, respectively 2 2 5 min irradiation of Ne containing 0.1%, 0.15%, and 0.2% F , respec- 1 3 18 18 18 [ F]F (GBq)[ F]F (GBq)[ F]F (GBq) 2 2 2 468 Annals of Nuclear Medicine (2018) 32:463–473 a bc d 50 100 1.5 1.0 0.5 0 0.0 0 0 0.00.1 0.20.3 024 050100 0.00.1 0.20.3 F /Ne (%) F /Ne (%) L-BPA/F ratio F /Ne (μmol) 2 2 2 2 18 18 Fig. 2 Effects of reaction conditions on the production of [ F]acetyl- (molar ratio) and radiochemical yield (RCY) of l -[ F]FBPA (%). 18 10 18 hypofluorite ([ F]AcOF) and 4-[ B]borono-2-[ F]fluoro- l -phenyla- d Relationship between F (mole) in Ne and F (mole) recovered 2 2 18 18 18 lanine (l -[ F]FBPA). a Relationship between F content (%) in Ne as [ F]F . The amount (mole) of [ F]F was calculated from the 2 2 2 18 18 and activity yield of [ F]AcOF (GBq). b Relationship between F molar activity of l -[ F]FBPA and the total activity (summed activity content (%) in Ne and activity yield of l -[ F]FBPA (GBq). c Rela- absorbed in a sodium acetate column and recovered in a reaction vial 10 18 tionship between 4-[ B]borono-l -phenylalanine (l -BPA)-to-F ratio as [ F]AcOF) between the molar mass of F set and that of recovered is recovery of [ F]AcOF, and that sodium acetate trihydrate shown later (Fig. 2d). with larger particle sizes would be preferable compared with In an early study on [ F]F production, a carrier con- sodium acetate anhydrous with smaller particle sizes. centration of 0.1% F produced almost 95% of the theoreti- The activity yields of l -[ F]FBPA were variable and did 18 18 cal yield of [ F]F , and a part of [ F]F was adsorbed on not tend to increase with the F percentage in Ne (Fig. 2b). 2 2 2 a stainless steel tube in recovery from the target chamber The averaged activity yield was 1200 ± 160 MBq (n = 38) . The present study demonstrated the clear requirement at 31.6 ± 1.7 min from the EOB. The RCY of l -[ F] of pre-irradiation in a range of 0.1–0.2% F , and suggested FBPA based on [ F]AcOF trapped in the reaction vial was that two pre-conditioning irradiations with these F concen- 33.1 ± 3.8% (n = 38). The RCY increased with increas- trations were preferable for steady [ F]F production. It was ing l -BPA-to-F ratios (Fig. 2c), which suggested that the 2 2 also suggested that mixing 5% F -containg Ne and pure Ne increased [ F]AcOF relative to l -BPA further fluorinated gases made accurate setting of the F concentration difficult. to produce F-difluorinated l -BPA as observed in the elec- trophilic fluorination of l -3-(hydroxy-4-pivaloyloxyphenyl) 18 18 18 18 Synthesis of l ‑[ F]FBPA using [ F]AcOF alanine with [ F]AcOF  and/or degraded l -[ F]FBPA. The preferred l -BPA-to-F ratio is > 2 for the steady produc- 18 18 The total activity of [ F]F (summed activities absorbed tion of l -[ F]FBPA. It is emphasized that the synthesis time in a sodium acetate column and recovered in a reaction vial (32 min) was the shortest compared with those in previous as [ F]AcOF) that was normalized as those produced by reports: 50 min , 72 min , 80 min , 88 min , irradiation for 120 min, was 12.3 ± 1.9 GBq (n = 38). The and 110 min . activity yields of [ F]AcOF trapped in the reaction vial As previously described [1, 27], three by-products of 2-, tended to increase with increasing the F percentage in Ne, 3-, and 4-[ F]fluoro- l -phenylalanine were tentatively iden- and ≥ 0.15% F was preferable (Fig. 2a). The flow rates of tified by comparison with the retention times of authentic 18 18 [ F]F passing through a sodium acetate trihydrate column samples. Although baseline separation of 3- and 4-[ F] were slightly higher than those passing through a sodium fluoro- l -phenylalanine could not be performed in all HPLC acetate anhydrous column: 460 ± 89 ml/min (n = 23) vs. separations investigated, the relative amounts were in the 363 ± 55 ml/min (n = 11, 4 data missing), and the respec- order of 3- > 4- > 2-isomer (Fig. 3), and the summed RCYs tive radiochemical yields (RCYs) of [ F]AcOF were of the three were constant at 11.6 ± 1.3% (n = 37). Electro- 38.8 ± 2.7% (n = 23) and 35.5 ± 1.9% (n = 11, 4 data missing) philic fluorination at the aromatic carbon 4 could explain based on the total activity of [ F]F recovered. The differ - undesired deboronation that leads to the 4-isomer; how- ence in RCYs between the two cases was not large, but two ever, there is no known mechanism that produces the 2- and other experiments using a sodium acetate anhydrous column 3-isomers. Coenen et al. reported that the fluorination of with flow rates of 252 and 319 ml/min produced very low l -phenylalanine in TFA with [ F]F produced 2- (72.5%), 3- 18 18 [ F]AcOF RCYs of 10.9 and 15.9%, respectively. These (13.9%), and 4-[ F]fluoro- l -phenylalanine (13.6%) . It results suggested that low flow rates of [ F]F decreased the is unlikely that l -phenylalanine produced after deboronation 1 3 [ F]AcOF (GBq) L-[ F]FBPA (GBq) RCY of L-[ F]FBPA (%) Recovery of F (μmol) 2 Annals of Nuclear Medicine (2018) 32:463–473 469 c e f g h i 10 18 Fig. 3 HPLC chromatograms of 4-[ B]borono-2-[ F]fluoro- l -phe- 260 nm) absorbance, respectively. The unit of the vertical axis are 18 10 nylalanine (l -[ F]FBPA) separation using 10 different eluents. a–j the millvolt output of the UV detector. Elution positions of 4-[ B] Correspond to the chromatograms with eluents 1–10. Red and blue borono-l -phenylalanine (l -BPA), l -FBPA, and 2-, 3-, and 4-fluoro- lines show the elution profiles of radioactivity and ultraviolet (UV, d ,l -phenylalanine (2-, 3-, and 4-FPhe, respectively) are indicated of l -BPA was fluorinated. We tried further identification of activity of l -[ F]FBPA and the total activity. Large differ - these byproducts by GC-MS as described for the determi- ences observed between the amounts of F set in Ne and nation of TFA using a deactivated metal capillary column the recovered F indicated that the carrier F added could 2 2 (0.25 mm i.d. × 30 m) with 1 µm film thickness of Ultra not be recovered constantly, even after two pre-conditioning ALLOY-1 (polydimethylsiloxane) (Frontier Laboratories), irradiations. but could neither identify nor deny three byproducts to be Discussion of the differences between the present and 18 18 2-, 3-, and 4-[ F]fluoro- l -phenylalanine. previous studies on l -[ F]FBPA synthesis using Ne-derived 18 18 The molar activities of l -[ F]FBPA synthesized using [ F]AcOF is difficult because the detailed reaction condi - 0.1%, 0.15%, 0.2% 0.25%, and 0.3% F were 103.5 ± 9.5 tions were not described in the previous reports. However, (n = 3), 86.1 ± 24.4 (n = 8), 69.0 ± 7.3 (n = 23), 66.0 (n = 2), the present activity yields (1200 ± 160 MBq) were much and 50.3 GBq/mmol (n = 2), respectively. It is reason- higher than in previous reports: 444–518 MBq (n = 10)  able that lower carrier F contents in [ F]F production and 750 ± 250 MBq (n = 8) [33 figures not shown], and the 2 2 resulted in higher molar activities of l -[ F]FBPA; how- molar activities were higher than those in some reports [1, ever, no linear relationship was found between the F con- 23, 24] but lower than that reported in  (130 GBq/mmol). tent and molar activity. Figure 2d shows the molar amounts Fig. 3 shows HPLC separation patterns with 10 different of recovered [ F]F that were calculated from the molar eluents. Eluent 1 0.1% AcOH, a standard mobile phase used 1 3 470 Annals of Nuclear Medicine (2018) 32:463–473 previously, gave a baseline separation (Fig. 3a); however, 98.4 ± 0.6%, respectively. Analyses with eluents (a) and (b) lower 0.01% AcOH (Fig. 3b) was preferable. Physiological were similar, and preferable compared to eluents (c) and saline (Fig. 3c) showed leading peaks of l -BPA and l -[ F] (d). Therefore, all subsequent analyses were conducted with FBPA, but did not show baseline separation. The addition of eluent (a). AcOH to saline (Fig. 3d) improved the separation slightly. The RCPs were over 97% for all 10 l -[ F]FBPA prepara- Further addition of EtOH (Fig. 3e) caused slightly faster tions. The pH was below 4.0 in four of the 10 preparations. elution but without improved separation. The addition of The volumes of l -[ F]FBPA separated with saline with/ sodium phosphate corrective injection 0.5 mmol/ml (pH without 0.01% AcOH were over 20 ml, and the addition of 6.5) to saline with/without AcOH improved the separation sodium phosphate corrective injection reduced the volumes. (Fig. 3f, h, i). Lower sodium phosphate eluted l -BPA more Baseline separation could not be performed using eluents broadly, but l -[ F]FBPA was separated as an apparently 3–5 and 1–2% contamination levels of l -BPA were obtained. single peak (Fig. 3g, j). Contamination levels of l -BPA in five other preparations The characteristics of the 10 l -[ F]FBPA preparations with eluents 6–10 were very low. These five preparations are summarized in Table 1. First, the radiochemical purities were thus considered as acceptable for intravenous injec- (RCPs) of the four eluents for HPLC analysis were com- tion without any further processing. The l -[ F]FBPA eluted pared for five l -[ F]FBPA preparations. In analyses with with 0.1% AcOH (eluent 1) was previously used directly in a eluents (a) 50 mM AcOH/50 mM A cONH (1/1) (Fig. 4a), clinical study after the addition of 25% ascorbic acid injec- (b) 50 mM N aH PO , (c) 0.1% AcOH, and (d) 0.8% AcOH tion and 10% sodium chloride injection to manage the pH 2 4 containing 1 mM EDTA and 1 mM sodium octylsulfate, and ion strength, respectively . Comparison of activity the RCPs were 97.7 ± 1.3%, 97.7 ± 1.4%, 98.6 ± 0.6%, and yields and molar activities in the 10 preparations shown in 300 200 L-FBPA 0 0 0 5 10 15 0 5 10 15 Retention time (min) Retention time (min) 10 18 Fig. 4 HPLC chromatograms of 4-[ B]borono-2-[ F]fluoro- l -phe- output of the UV detector. a In the stability test for 4 h, a radiochemi- nylalanine (l -[ F]FBPA) analysis on a YMC-UltraHT Pro C18 cal impurity appeared at the retention time indicated by the arrow. b S-2 µm and b Crownpak CR (+) columns. Red and blue lines show The inset emphasizes the low levels of the chromatograms and the the elution profiles for radioactivity and ultraviolet (UV, 277 nm) elution position of d -FBPA is indicated by the arrow absorbance, respectively. The units of the vertical axis are millivolt Table 2 Stability of 4-borono-2-[ F]fluoro- l -phenylalanine preparations separated by high-performance liquid chromatography using five dif- ferent eluents Eluent n pH Radiochemical purity (%) 0 h 1 h 2 h 4 h (3) Saline 1 4.9 99.2 98.6 98.3 97.9 (6) 0.01% AcOH, 5 mM phosphate-buffered saline 2 6.1 99.6 97.9 97.6 (7) 0.01% AcOH, 1 mM phosphate-buffered saline 3 4.4 ± 0.1 99.5 ± 0.2 99.3 ± 0.4 99.0 ± 0.5 99.1 ± 0.8 (9) 5 mM phosphate-buffered saline 3 6.8 ± 0.0 98.0 ± 0.9 97.1 ± 1.6 96.7 ± 0.7 (10) 1 mM phosphate-buffered saline 4 6.7 ± 0.0 97.8 ± 0.9 97.4 ± 0.5 97.0 ± 0.5 96.7 ± 0.5 Data are average ± standard deviation The time for the first analysis after the end of synthesis was defined as “0 h”, and then analyses were performed successively at approximately the indicated intervals until approximately 4 h 1 3 Radioactivity/UV response D-FBPA Annals of Nuclear Medicine (2018) 32:463–473 471 Table 2 may not be significant, because the F contents were the peak fraction of l -[ F]FBPA from HPLC separation randomly set. (270–970 MBq/ml), a very small amount of the d -isomer From these results and the stability of l -[ F]FBPA was present (Fig. 4b): < 0.1% (0.09 ± 0.04%, n = 4) com- described later, eluent 10 was selected for routine clinical pared with the l -isomer. The UV peak that corresponds to use because of the small amount of one additive in physi- this activity peak was increased by the addition of small ological saline and ease of eluent preparation. The clini- amounts of standard d -FBPA into the samples. It was noted cal injection volumes of l -[ F]FBPA separated with elu- that a temperature at 20–21 °C was critical in this analysis ent 10 (1120 MBq/13.2 ml, Table 2), were expected to be because d -[ F]FBPA was not separated from the radioactive 2.6–3.9 ml/60 kg when the radioactive injection doses in impurities at higher temperature (25 °C). l -[ F]FBPA PET were 3.7–5.55 MBq/kg [38, 39], and one A UV peak corresponding to d -FBPA was evident and l -[ F]FBPA preparation can be used for 2 subjects with the UV detection sensitivity was higher than that of radio- one PET scanner or 3–4 subjects with two PET scanners. In activity. However, UV signals could not be used to evalu- 18 18 four l -[ F]FBPA preparations separated with eluent 10 and ate d -[ F]FBPA, because the retention times of authentic collected through a 0.22 µm membrane filter, sterility and d -FBPA and l -BPA coincided. No UV peak that corre- apyrogenicity (< 0.0029 EU/ml) of the l -[ F]FBPA injec- sponded to the d -isomer was observed for the starting com- tion and filter integrity (≥ 330 kPa) were confirmed. It is pound l -BPA (both from Sigma-Aldrich and Stella Pharma); 18 18 noted that no radionuclidic impurities were found in l -[ F] therefore, we considered that epimerization of l -[ F]FBPA FBPA prepared using the present method . might occur in TFA solution in the radiosynthesis process, In previous research to improve the activity yields or the as l -amino acids such as l -phenylalanine were epimerized molar activity of l -[ F]FBPA, l -BPA was fluorinated with in acetic acid . 18 18 18 [ F]F produced by the O(p,n) F reaction [25–27]. We 18 18 also fluorinated l -BPA with [ F]F and separated l -[ F] TFA analysis by GC‑MS FBPA by HPLC with eluents 1, 6, and 8; however, the RCPs 18 18 18 (n = 6) were lower than those of [ F]AcOF-derived l -[ F] The residual TFA in l -[ F]FBPA preparations was analyzed FBPA separated using the same eluents. The higher reactiv- by GC-MS after methylation. The retention time of methyl 18 18 ity of [ F]F than [ F]AcOF may result in more side reac- trifluoroacetate in the GC stage was 2.5 min. Three ions tions. Therefore, no further investigation was conducted for were monitored in the SIM-EI mode of operation: m/z 59, the synthesis using [ F]F . 69, and 99. These are the most characteristic ions in the mass spectrum of methyl trifluoroacetate . Because the Stability signal at m/z 69 was much stronger than those at m/z 59 and 99; therefore, only the area of the m/z 69 peak was used for The stabilities of five l -[ F]FBPA preparations are summa- quantitative analysis. Methyl trifluoroacetate was degraded rized in Table 2. The l -[ F]FBPA separated by eluent 7 was gradually by approximately 10% after 20 min from the end the most stable over 4 h after EOS. In the four other prepara- of extraction; therefore, the GC-MS analysis was started tions the RCPs decreased gradually but were maintained at just 1 min after the end of extraction. The detection limit of over 96% for 4 h. Low pH with eluent 7 may contribute to methyl trifluoroacetate was determined to be 0.5 ppm [sig- the stability of l -[ F]FBPA; however, these five prepara- nal-to-nosise ratio (S/N) = 12], and the S/N of the 0.1 ppm tions without stabilizers such as EtOH  and ascorbate standard sample was 8. In eight l -[ F]FBPA preparations  were suitable for routine clinical use for at least 4 h. the residual TFA was less than 0.5 ppm: 0.2 ± 0.1 ppm Preliminarily we found that the ascorbate was not effective (range, 0.0–0.3 ppm) without evaporation processing for 18 18 for stability. In two l -[ F]FBPA preparations separated preparing the l -[ F]FBPA injection. It is noted that the with 0.01% AcOH saline and 5 mM PBS, the addition of LD values are 200 mg/kg in rats (oral administration) and ascorbate injection (final concentration of 10 mg/ml) slightly 1200 mg/kg in mice (intravenous injection) (Hazardous Sub- decreased the RCPs from 98.4% and 97.7–93.2% and 91.3%, stances Data Bank, 2007: https://t oxnet.nlm.nih.go v/cgi-bin/ respectively, by approximately 4 h.sis/searc h2/f?./temp/~TF1xc W:1). Optical purity Conclusion No signal associated with the d -isomer was found in l -[ F] FBPA preparations, probably because of the low activity Two 5 min pre-irradiations enabled the steady production 18 18 concentrations (Table 1, 47–107 MBq/mL) and the sensitiv-of [ F]F for F-labeling by electrophilic fluorination. To ity of the US-3000 radioactivity detector. However, in the achieve a high RCY of l -[ F]FBPA 0.15–0.2% carrier F l -[ F]FBPA samples concentrated by evaporation or only in Ne and an l -BPA-to-F ratio > 2 were preferable. HPLC 1 3 472 Annals of Nuclear Medicine (2018) 32:463–473 11. Evangelista L, Jori G, Martini D, Sotti G. Boron neutron capture separation using 1 mM PBS provided injectable l -[ F] therapy and F-labelled borophenylalanine positron emission FBPA without any further formulation processing, which tomography: A critical and clinical overview of the literature. resulted in a 32-min synthesis period from EOB. The l -[ F] Appl Radiat Isot. 2013;74:91–101. https://doi.or g/10.1016/j.aprad FBPA injection contained small amounts of d -enantiomer iso.2013.01.001. 12. Nariai T, Ishiwata K. Analysis and imaging: PET. In: Sauerwein (< 0.1% of l -[ F]FBPA), l -BPA (< 1% of l -FBPA), and WAG, Wittig A, Moss R, Nakagawa Y, editors. Neutron cap- TFA (< 0.5 ppm). ture therapy, principles and applications. 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