Year of Award:
Molecular & Cellular Analysis Technologies
VAN DAM, ROBERT MICHAEL
Other PI or Project Leader:
UNIVERSITY OF CALIFORNIA LOS ANGELES
PROJECT SUMMARY/ABSTRACT Positron emission tomography (PET) is an advanced imaging technique, relying on the injection of radioactive “tracers” to image specific biochemical processes in living subjects. By developing appropriate tracers, PET can provide measurements of the abundance of cell surface markers/receptors, degree of enzyme activity, or the rate of a biological processes. These measurements help understand the biology of cancer, discover and develop new drugs, and provide critical information for clinical trials or clinical decision making. Though basic research has led to the discovery of many new cancer markers and potential therapeutic targets, the development of suitable PET tracers to image these targets typically lags years behind. Beginning with approaches such as library screening to identify candidate tracers, the candidates are ranked based on in vitro criteria (e.g. affinity, selectivity). Due to high costs, only a very tiny number of these candidates are usually labeled for further evaluation. This leads to a slow, incremental tracer development process, exacerbated by the issue that in vitro selection criteria don't correlate well with in vivo performance. This proposal seeks to address this issue by making it practical and affordable to perform in vivo screening of much larger candidate libraries. High-throughput methods already exist for generation of (unlabeled) libraries of candidate tracers, and the potential for high-throughput in vivo imaging has also been reported. However, there does not currently exist a practical approach for performing the middle step in a high-throughput fashion, i.e. rapidly radiolabeling a compound library. This is due not only to the lack of technology for high-throughput radiosynthesis, but also the large volume used in conventional radiosynthesis methods, which leads to high precursor cost and low specific activity. Recent advances in microfluidic radiochemistry, in which reactions are performed in microliter-scale droplets, can overcome all of these limitations. This proposal leverages these advances to create a high-throughput radiolabeling platform. Aim 1 develops a microfluidic reaction array to perform at least 48 simultaneous reactions. In Aim 2, a liquid delivery system is developed to efficiently and rapidly distribute precursor, radiolabeling agent etc. to the reaction sites as needed. An integrated, automated system is developed in Aim 3 and validated using various commonly-used labeling chemistries. Finally, in Aim 4, UPLC chromatography and SPE plates are evaluated as potential means for performing high-throughput purification and formulation so the synthesized tracers are ready for injection. Ultimately, this proposal seeks to make screening a practical, routinely-available tool to accelerate and reduce the cost of novel PET tracer development.