Optimization and scale up of production of the PSMA imaging agent [¹⁸F]AlF-P16-093 on a custom automated radiosynthesis platform

Background: Recent advancements in positron emission tomograph (PET) using prostate specific membrane antigen (PSMA)-targeted radiopharmaceuticals have changed the standard of care for prostate cancer patients by providing more accurate information during staging of primary and recurrent disease. [Ga-68]Ga-P16-093 is a new PSMA-PET radiopharmaceutical that demonstrated superior imaging performance in recent head-to-head studies with [Ga-68]Ga-PSMA-11. To improve the availability of this new PSMA PET imaging agent, [F-18]AlF-P16-093 was developed. The F-18-analog [F-18]AlF-P16-093 has been synthesized manually at low activity levels using [F-18]AlF2+ and validated in pre-clinical models. This work reports the optimization of the production of > 15 GBq of [F-18]AlF-P16-093 using a custom automated synthesis platform. Results: The sensitivity of the radiochemical yield of [F-18]AlF-P16-093 to reaction parameters of time, temperature and reagent amounts was investigated using a custom automated system. The automated system is a low-cost, cassette-based system designed for 1-pot syntheses with flow-controlled solid phase extraction (SPE) workup and is based on the Raspberry Pi Zero 2 microcomputer/Python3 ecosystem. The optimized none-decay-corrected yield was 52 +/- 4% (N = 3; 17.5 +/- 2.2 GBq) with a molar activity of 109 +/- 14 GBq/mu mole and a radiochemical purity of 98.6 +/- 0.6%. Run time was 30 min. A two-step sequence was used: SPE-purified [F-18]F- was reacted with 80 nmoles of freeze-dried AlCl36H(2)O at 65 degrees C for 5 min followed by reaction with 160 nmoles of P16-093 ligand at 40 degrees C for 4 min in a 1:1 mixture of ethanol:0.5 M pH 4.5 NaOAc buffer. The mixture was purified by SPE (> 97% recovery). The final product formulation (5 mM pH 7 phosphate buffer with saline) exhibited a rate of decline in radiochemical purity of similar to 1.4%/h which was slowed to similar to 0.4%/h when stored at 4 degrees C. Conclusion: The optimized method using a custom automated system enabled the efficient (> 50% none-decay-corrected yield) production of [F-18]AlF-P16-093 with high radiochemical purity (> 95%). The method and automation system are simple and robust, facilitating further clinical studies with [F-18]AlF-P16-093.