Synthesis Of 4-Borono-2-F-18-Fluoro-Phenylalanine Using Copper Mediated Nudeophilic Radiofluorination

1606 Objectives: Boron neutron capture therapy (BNCT) is a radiotherapy based on nuclear reaction between 10B and low energy thermal neutrons. A boron carrier which is clinically used is 10B-4-borono-L-phenylalanine (BPA). We have previously reported that 4-borono-2-18F-fluoro-phenylalanine (18F-FBPA) PET would estimate BPA concentration (Yoshimoto M, et al., Cancer Sci, 2018). In clinical use, 18F-FBPA is currently produced from 18F-acetyl hypofluorite, which is a conventional method with a low yield. In this study, we tried to synthesize 18F-FBPA from n.c.a. 18F- using copper mediated oxidative aromatic radiofluorination. Methods: For fluorination, 18F- was activated by K2CO3 and Kryptofix222 (Reagent Set F) in a reaction vial. The boron ester precursor 1 (10mg) and [Cu(OTf)2(py)4] (12.5 mg) were dissolved in DMF (500 µL)/AcCN (50 µL), and the solution was poured into the reaction vial. The reaction vial was heated at 110 °C for 20 min. The reaction mixture was passed through Sep-Pak silica cartridge, and 3.5 ml of 1,4-dioxane was passed through the cartridge. For borylation, Pd2(dba)3 (4.5 mg), P(Cy)3 (2.8 mg) was dissolved in the eluted 1,4-dioxane solution. After leaving for 10 min, (Bpin)2 (44.4 mg) /1,4-dioxane (100µL) was added. Subsequently AcOK (25.7 mg)/H2O (100 µL) was added and heated at 110 °C for 15 min. After removing the reaction solvent, 48% HBr (1 mL) was added to the reaction vial and heated to hydrolyze the compound 3 at 150 °C for 20 min. After neutralization with NaOH, 18F-FBPA was purified using HPLC. [TLC] Silica-gel plate, eluent 1: hexane/AcOEt = 9/1, eluent 2: n-BuOH/AcOH/H2O = 12/3/5. [HPLC] 5C18-MS-II, 10 ID x 250 mm, eluent: 0.1 % AcOH, flow rate: 4 mL/min. Results: The TLC analysis revealed that the fluorination, bolylation and hydrolysis was succsessfully carried out with labelling yields of 52-58% (compound 2), 43-55% (compound 3) and 64-90% (18F-FBPA), respectively. The total yield of 18F-FBPA was 20-24% (decay corrected). Conclusions: We have successfully synthesized 18F-FBPA from n.c.a. 18F- using copper mediated nucleophilic radiofluorination. This three-step synthesis would improve the labeling yield of 18F-FBPA and be applied to an automated synthetic devise. Grant support: Grant of Practical Research for Innovative Cancer Control in Japan Agency for Medical Research and Development. (15Ack0106026h0102)