An improved fully-automated GMP radiosynthesis of [¹⁸F]fluoro-pivalic acid with solid-phase extraction purification

We previously reported the first-in-human evaluation of 3-[¹⁸F]-fluoro-2,2-dimethylpropionic acid ([¹⁸F]FPIA) for imaging aberrant lipid metabolism and cancer detection. The first-generation semi-automated radiosynthesis of [¹⁸F]FPIA required HPLC purification to provide injection solution devoid of precursor (methyl 2,2-dimethyl-3-[(4-methylbenzenesulfonyl)oxy]propanoate), radioactive intermediate (methyl-3-([18F]fluoro)-2,2-dimethylpropanoate), and potential chemical impurities (tosic acid, 3-hydroxy-2,2-dimethylpropanoic acid and unlabelled FPIA). In readiness for global use of [¹⁸F]FPIA, we report a significant improvement to the GMP production through development of a fully-automated solid-phase extraction (SPE) purification method.

We developed a fully-automated SPE purified radiosynthesis on FASTLab™ for GMP readiness that was translated to and validated on the Trasis AIO™ platform for routine clinical use. Purification of the radiotracer by SPE on both systems was achieved (> 98% radiochemical purity), increasing the radiochemical yield compared to the HPLC-based purification method. Non-decay-corrected radiochemical yields (RCY, n.d.c) were 30.3 ± 2.3% (n = 8) and 25.8 ± 6.6% (n = 46) on GE FASTlab™ and Trasis AIO™, respectively. Non-radioactive FPIA and other analytes determined by HPLC were below the limit of detection (< 1.0 µg/mL) from GE FASTlab™ and ≤ 1.2 µg/mL from Trasis AIO™.

The synthesis of [¹⁸F]FPIA was validated on the Trasis AIO™ platform for GMP production and is currently used to produce clinical doses for phase II clinical trials. Readiness for GMP validation was also demonstrated on GE FASTlab™ and can be adopted on other automated platforms.