Improved Stability and Practicality for Synthesis of 4-Borono-2-[18F]fluoro-l-phenylalanine by Combination of [18O]O2 Single-Use and [18F]CH3COOF Labeling Agents

Abstract

Purpose: 4-Borono-2-[¹⁸F]fluoro-l-phenylalanine ([¹⁸F]FBPA) synthesized with [¹⁸F]F₂, produced using the ¹⁸O(p, n)¹⁸F reaction, has been reported for increasing radioactivity. However, a dedicated system and complex procedure is required to reuse the costly [¹⁸O]O₂ gas; also, the use of [¹⁸F]F₂ as a labeling agent reduces the labeling rate and radiochemical purity. We developed a stable and practical method for [¹⁸F]FBPA synthesis by combining [¹⁸F]F₂, produced using a [¹⁸O]O₂ single-use system, and a [¹⁸F]CH₃COOF labeling agent.

Methods: The produced [¹⁸F]F₂ was optimized, and then [¹⁸F]FBPA was synthesized. For passivation of the target box, 0.5% F₂ was pre-irradiated in argon. Gaseous products were discarded; the target box was filled with [¹⁸O]O₂ gas, and then irradiated (first irradiation). Then, the [¹⁸O]O₂ gas was discarded, 0.05-0.08% F₂ in argon was fed into the target box, and it was again irradiated (second irradiation). The [¹⁸F]F₂ obtained after this was passed through a CH₃COONa column, converting it into the [¹⁸F]CH₃COOF labeling agent, which was then used for [¹⁸F]FBPA synthesis.

Results: The mean amount of as-obtained [¹⁸F]F₂ was 55.0 ± 3.3 GBq and that of as-obtained [¹⁸F]CH₃COOF was 21.6 ± 1.4 GBq after the bombardment. The radioactivity and the radiochemical yield based on [¹⁸F]F₂ of [¹⁸F]FBPA were 4.72 ± 0.34 GBq and 12.2 ± 0.1%, respectively. The radiochemical purity and molar activity were 99.3 ± 0.1% and 231 ± 22 GBq/mmol, respectively.

Conclusion: We developed a method for [¹⁸F]FBPA production, which is more stable and practical compared with the method using [¹⁸O]O₂ gas-recycling and [¹⁸F]F₂ labeling agent.

Keywords: Boron neutron capture therapy; Single-use; [18F]CH3COOF; [18F]F2; [18F]FBPA; [18O]O2 gas.

Fig. 1

Schematic representation of target system with single-use of [¹⁸O]O₂ gas for [¹⁸F]F₂ gas production; valve-switching alone is performed manually while all other systems are controlled by cupid system

Fig. 2

[¹⁸F]FBPA synthesis scheme; after conversion to [¹⁸F]CH₃COOF using the CH₃COONa column, [¹⁸F]FBPA was synthesized and allowed to react with [¹⁸F]CH₃COOF and BPA in TFA solution at ambient temperature

Fig. 3

Radioactivity of [¹⁸F]F₂ under each condition: a second irradiation time at 17 μA for 2 (n=2), 10 (n=5), and 20 min (n=2). Radioactivity was 3723 ± 132, 6891 ± 218, and 7598 ± 276 MBq, respectively; b beam current of cyclotron was set to 5 (n=2) or 17 μA (n=5) for 10 min. Radioactivity was 4369 ± 116, 6891 ± 218 MBq, respectively. Radioactivity (decay-correct to EOB) of [¹⁸F]F₂ was depicted after second irradiation with 0.05–0.08% fluorine in target gas.

Fig. 4

Radioactivity of [¹⁸F]F₂ at each fluorine concentration in the target (0–0.9%); radioactivity (decay-correct to EOB) of [¹⁸F]F₂ after second irradiation at 17 μA for 10 min

Fig. 5

Radio-chromatograms of [¹⁸F]FBPA with analysis HPLC: a typical radio-chromatogram of [¹⁸F]FBPA solution at EOS; b typical radio-chromatogram of [¹⁸F]FBPA solution after 6 h of EOS

Fig. 6

Chromatograms of [¹⁸F]FBPA with Chiral HPLC: a typical radio-chromatogram of [¹⁸F]FBPA solution; b typical UV-chromatogram of [¹⁸F]FBPA solution; c typical UV-chromatogram of the d-FBPA and l-FBPA reference standard mixed solution. Final concentration of the reference standard mixed solution was 0.25 mg/mL

Fig. 7.

Typical separation HPLC chromatogram of [¹⁸F]FBPA solution; red line indicates the radioactivity peak while blue line indicates the UV (280 nm) peak