UCLA

Positon emission tomography (PET) is an imaging modality capable of visualizing biomolecules in vivo and can be used to aid in disease diagnosis, staging of disease severity, and monitoring of disease response to treatment. PET relies on the use of tracers (i.e. biomolecules labeled with radionuclides) for imaging. Due to the short half-life of the radionuclides used, PET tracer production is typically performed right before an imaging event. Production of a PET tracer can be broken down into three major parts: production of the radionuclide, radiochemical synthesis of the tracer, and, lastly, purification, formulation and quality control testing of the tracer.

Several groups, including our own, have looked into leveraging the benefits of microfluidics (reduced system size, finer control of reaction parameters, reduced reagent consumption) towards the production of PET tracers. These microfluidic versions of commonly-used PET tracer production equipment enable users to scale up or down the amount of tracer that is produced at a given time. Compared to current commercial systems which are designed to synthesize large batches of PET tracers for clinical applications, these microfluidic systems can offer substantial cost savings by enabling production of smaller batches based on user needs.

Microfluidic approaches have already been applied successfully towards radiochemical synthesis, purification, and quality control testing of tracers. There, however, still exists several steps in tracer production that could benefit from microfluidic technologies. Evaporation of solvent during the concentration and formulation steps following tracer purification is currently performed on slow and bulky rotary evaporators. Microfluidic technology could aid in size reduction while also leveraging microfluidic advantages such as faster heat transfer to increase evaporation rates. Part of this dissertation is focused on applying microfluidic technologies towards the concentration and formulation of PET tracers following purification.

Despite successful design and operation of microfluidic radiosynthesizers, one main limitation that microfluidic radiosynthesizers face is differences between radionuclide volumes (mL) and microfluidic reactor volumes (μL). This disconnect limits the amount of starting radioactivity that can loaded into microscale reactors for radiosyntheses. To address this need, work presented in this dissertation also focuses on the design, fabrication, and testing of an automated microfluidic radionuclide concentrator based on miniaturized anion and cation exchange cartridges enabling the concentration of various types of radionuclides (e.g. fluorine-18 and gallium-68). Concentrated radionuclides in microliter volumes enables microfluidic synthesis of a diverse range of PET tracers in large quantities.

We have also pursued further development of microreactors leading to new advancements to improve the radiosynthesis step during tracer production. Previously our group has demonstrated synthesis of a diverse range of PET tracers using a microfluidic radiosynthesizer based on electrowetting on dielectric (EWOD). Despite advantages of compact size and reduced reagent consumption, a limitation was the cost and complexity of the single-use EWOD chips used during production. In this dissertation, we combat these limitations through the design and fabrication of an automated microfluidic radiosynthesizer based on patterned wettability. This new platform uses reaction chips that are easier to fabricate (compared to EWOD), are a fraction of the cost, and are significantly easier to operate.

Lastly, in this dissertation we demonstrate successful integration of our radionuclide concentrator with our newly design radiosynthesizer. We perform synthesis of [18F]fallypride using high starting activities and demonstrate the ability to produce tracers in high quantities. This integrated platform thus enables both production of low and high quantities of tracer depending on user needs.

The developments presented in this dissertation represent tools for performing portions of the whole PET tracer production process in a more cost effective and efficient manner. Future work will be focused on the successful integration of all components (both microfluidic and conventional) necessary for PET tracer production to enable automated, reliable, high yielding radiosyntheses of clinical grade PET tracers.