High-throughput technologies for the optimization of radiopharmaceuticals using microfluidics
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High-throughput technologies for the optimization of radiopharmaceuticals using microfluidics


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 automated radiosynthesizers are designed for production of large clinical batches of radiopharmaceuticals. They are not well suited for reaction optimization or novel radiopharmaceutical development, since each data point involves significant reagent consumption, and contamination of the apparatus requires time for radioactive decay before the next use. Though with some radiosynthesizers it is possible to perform a few sequential radiosyntheses in a day, none allow for parallel radiosyntheses. To address these limitations, I developed a new platform for high-throughput experimentation in radiochemistry. This system contains an array of 4 heaters, each used to heat a chip containing an array of 16 reaction sites (hydrophilic patches) on a small Teflon-coated silicon chip, enabling 64 parallel reactions for the rapid optimization of conditions in any stage of a multi-step radiosynthesis process. As example applications, I studied the syntheses of several 18F-labeled radiopharmaceuticals, 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 ~100x less precursor per datapoint. This new method paves the way for more comprehensive optimization studies in radiochemistry and substantially shortening PET tracer development timelines. I also developed new methods and technologies to determine the reaction conversion when optimizing radiosynthesis processes. Radio-thin layer chromatography (radio-TLC) is commonly used to analyze purity of radiopharmaceuticals or to determine the reaction conversion. In applications where there are only a few radioactive species, radio-TLC is preferred over radio-high-performance liquid chromatography (radio-HPLC) due to its simplicity and relatively quick analysis time. However, with current radio-TLC methods, it remains cumbersome to analyze a large number of samples during reaction optimization. In a couple of studies, Cerenkov luminescence imaging (CLI) has been used for high-resolution reading TLC plates spotted with a variety of isotopes. We show that this approach can be extended to develop a high-throughput approach for radio-TLC analysis of many samples by spotting multiple samples in adjacent lanes and then separating and reading out all lanes in parallel. Finally, I worked on techniques to incorporate [19F]fluoride and [18F]fluoride into thioether molecules via electrochemical fluorination. Electrochemical fluorination and radiofluorination was performed under potentiostatic anodic oxidation using various types of electrochemical cells. I incorporated the concept of high throughput experimentation via microfluidics by using 96-ELISA-well plates with printed electrodes for the fast screening of parameters in electrochemistry for the radiofluorination of various thioether molecules, studying variables such as solvents, temperatures and electrolytes for the optimization of electrochemical labeling conditions. The use of high-throughput experimentation in radiochemistry can allow the exploration of various parameters in a fast manner and its combination with microfluidics makes the performance of various experimental parameters possible due to the minimal use of reagents. Both radiochemistry in droplets and electrochemistry for fluoride labeling in well plates showed the screening and optimization of synthesis parameters that could not be possible with conventional methods, moreover the methods presented in this dissertation can help with the exploration of novel PET tracers for preclinical research that otherwise would be expensive at macroscale.

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