Establishment of a radiosynthesis method of 4-[18F]fluorophenylalanine using pinacol borane ester

Introduction: Recently, radiotherapy using α-rays, which damages tumor cells, is attracting attention. The antitumor effect of 4-[²¹¹At]astatophenylalanine labeled with ²¹¹At at the 4-position of phenylalanine (Phe), which highly selective for the amino acid transportor-1 overexpressed in tumors, has been reported . We focused on 4-[¹⁸F]fluorophenylalanine ([¹⁸F]4FPhe) as a companion drug of 4-[²¹¹At]astatophenylalanine. Synthesis of [¹⁸F]4FPhe has been reported, however, the synthesis method was used 12 M hydrochloric acid for deprotection of fluorinated precursor, which is considered to give a load on the synthesizer . In this study, we studied the alternative synthesis method of [¹⁸F]4FPhe using a precursor with pinacol borane ester introduced at the 4-position of Phe for a high labeling rate and easy deprotection with a weaker acid , which can be suitably transferred to a synthesizer for clinical use .

Methods: [¹⁸F]fluoride produced by the cyclotron was collected to an anion exchange column (QMA) pre-conditioned with 10 mL of 1 M potassium carbonate and recovered into reactor using various solvents. The [¹⁸F]fluoride solution was dried then the [¹⁸F]fluoride was reacted with precursor for 20 min. For the fluorination, parameters examined were solvent dissolving the precursor (dimethylformamide, dimethylacetamide, a mixture of n-butanol and N,N-dimethylacetamide), the amounts of precursor and the catalyst [tetrakis pyridine copper (II) triflate (Cu(OTf)₂(py)₄) with/without pyridine], and the reaction temperature. Then, several deprotecting agents were added to the reaction solution after fluorination and the solution was heated at 110℃ for 10 min. The ¹⁸F-labeling and deprotection rates were measured using TLC and HPLC, respectively.

Results: The best condition determined for fluorination was use of [¹⁸F]fluoride recovered from QMA with tetraethylammonium bicarbonate, a mixture of n-butanol and N,N-dimethylacetamide as solvent, 20 µmol of precursor, and 100 µmol of Cu(OTf)₂(py)₄ without pyridine at 140°C of the reaction temperature, and the labeling rate was approximately 80%. In the deprotection step, it was confirmed that 4 M hydrochloric acid was sufficient to proceed.

Conclusions: We have established a new synthesis method of [¹⁸F]4FPhe with high labeling rate using a novel pinacol borane ester precursor and deprotection by weaker acid. The method can be suitably applied to an automated synthesizer for clinical use.