Microliter-scale reaction arrays for economical high-throughput experimentation in radiochemistry

Abstract

Abstract The increasing number of positron-emission tomography (PET) tracers being developed to aid drug development and create new diagnostics has led to an increased need for radiosynthesis development and optimization. Current radiosynthesis instruments are designed to produce large-scale clinical batches and are often limited to performing a single synthesis before they must be decontaminated by waiting for radionuclide decay, followed by thorough cleaning or disposal of synthesizer components. Though with some radiosynthesizers it is possible to perform a few sequential radiosyntheses in a day, none allow for parallel radiosyntheses. Throughput of one or a few experiments per day is not well suited for rapid optimization experiments. To combat these limitations, we leverage the advantages of droplet-radiochemistry to create a new platform for high-throughput experimentation in radiochemistry. This system contains an array of 4 heaters, each used to heat a set of 16 reactions on a small chip, enabling 64 parallel reactions for the rapid optimization of conditions in any stage of a multi-step radiosynthesis process. As examples, we study the syntheses of several 18F-labeled radiopharmaceuticals ([18F]Flumazenil, [18F]PBR06, [18F]Fallypride, and [18F]FEPPA), performing > 800 experiments to explore the influence of parameters including base type, base amount, precursor amount, solvent, reaction temperature, and reaction time. The experiments were carried out within only 15 experiment days, and the small volume (~ 10 μL compared to the ~ 1 mL scale of conventional instruments) consumed ~ 100 × less precursor per datapoint. This new method paves the way for more comprehensive optimization studies in radiochemistry and substantially shortening PET tracer development timelines.