Positron emission tomography (PET) is a real-time, in vivo 3D imaging technique with unparalleled specificity and sensitivity for visualizing biochemical processes. These properties lend it enormous value in drug discovery and understanding the biology of diverse diseases (e.g. in oncology, neurology, cardiology, etc.) Thousands of different PET tracers have been synthesized to measure: (i) density of receptors or cell-surface markers, (ii) enzyme activity, (iii) metabolism, (iv) pharmacokinetics and pharmacodynamics of drugs (by radiolabeling the drug), and (v) response to therapy. PET will play a critical role in the emerging era of precision medicine by providing a more complete picture of disease than is possible via biopsy and in vitro assays. Though several PET tracers have been advanced to the clinic, the development and translation of others is hindered by limited availability and high production cost of these short-lived compounds. The emerging technique of micro-droplet radiochemistry can remove this bottleneck by minimizing reagent costs and eliminating the need for large scale radiochemistry infrastructure. Furthermore, such devices can routinely produce tracers with high molar activity (AM) ? a critical quality when imaging rare biological targets (e.g. neuroreceptors) or small animals ? across a wide range of synthesis scales. In contrast, with macroscale apparatus, high AM can typically only be achieved by using very high starting radioactivity, increasing safety concerns, risk of radiolysis, and radioisotope cost. Micro-droplet radiochemistry is ideally suited to produce small batches for novel tracer development, while also being capable with up-scaling by pre-concentrating the isotope. While significant development of microfluidics for production of PET tracers has occurred in the last few years, there has been relatively little progress in advancing microscale purification techniques for radiochemistry, aside from miniaturization of solid-phase extraction, a technique that does not have sufficient separating power for most tracers. Instead, microfluidic radiochemistry chips are often coupled to conventional instruments (e.g. HPLC), undermining many of the advantages of microfluidics. In this proposal, the feasibility of using capillary electrophoresis (CE) as a radiotracer purification method to replace HPLC is explored. CE has comparable separating power and flexibility as HPLC, but can be readily miniaturized into low-cost microfluidic chips. In previous work, analytical-scale CE has successfully been used to separate the tracers 3'-deoxy-3'- [18F]fluorothymidine ([18F]FLT) and 1-(2'-deoxy-2'-[18F]fluoro-?-D-arabino-furanosyl) cytosine ([18F]FAC) from their impurities at the analytical scale (~5-50 nL samples); however, it is not known whether this technique can be scaled up (Aim 1) to purify the much larger (~1 L) volume from the microdroplet synthesis chip, how best to integrated miniature radiation and chemical detectors (Aim 2), nor how to implement a high-efficiency microfluidic fraction collector (Aim 3). It is anticipated that microscale synthesizers with integrated microscale purification will be an enabling technology in driving increased availability and lower cost of diverse PET tracers.
Due to compact size and small reagent volumes, microscale methods promise to enable high molar activity radiotracers for positron emission tomography (PET) imaging to be produced at lower cost than conventional methods. The proposed research will develop the last critical missing piece of microscale radiochemistry technology, namely a microscale purification system. By enabling routine, low-cost access to diverse tracers, the combination of microscale synthesis and purification technologies will facilitate and accelerate the development and clinical translation of emerging and novel PET tracers.
