PROJECT SUMMARY/ABSTRACT
The continuous discovery of new biological targets presents opportunities to dramatically improve our
understanding of diseases and normal function and provides new avenues for treatment. In vivo imaging of these
targets via positron-emission tomography (PET) is an especially powerful tool to understand the initiation and
progression of disease and to aid in the development of novel therapeutics. The major benefits of PET are the
very high sensitivity (enabling imaging of rare targets such as neuroreceptors without saturating them), and the
ability to image deep tissues (which provides translatability from preclinical research to later clinical use).
But the development of useful and validated tracers can take years or decades. A significant limiting factor is the
complexity and cost of radiochemistry, and the difficulty in using current technologies to optimize synthesis
conditions – a key step toward achieving reliable production with sufficient yield to support initial imaging studies.
Slow throughput and high reagent and isotope consumption mean that optimization studies are very expensive
and time-consuming, and thus such studies tend to be very limited and are unlikely to find globally optimal
conditions. These limitations also create pressures in other aspects of new probe development, e.g., significant
efforts are made to reduce the number of “hits” so only a very small number of compounds are labeled and
studied via in vitro and ex vivo assays and in vivo imaging. However, this selection process is imperfect as it
sometimes leads to the pursuit of dead-ends while it excludes promising candidates.
To more rapidly leverage preclinical and clinical imaging of new biological targets, the radiochemistry field is in
urgent need of new tools to improve the tracer discovery and development process. Our proposed solution is
the development of high-throughput radiochemistry methods. Arrays of droplet reactions have recently been
introduced as a way to rapidly perform dozens of reactions in parallel from a single batch of radioisotope, with
total reagent consumption of those reactions similar to a single batch on a conventional system. Furthermore,
the droplet reactions can readily be scaled to quantities for preclinical or even clinical imaging. These methods
could be used to efficiently explore a vast reaction parameter space in a matter of days (instead of weeks to
months), or they could be used to label dozens of candidate compounds in parallel to perform screening based
on the most relevant metric: in vivo properties. While these reaction arrays, operated using manual pipetting,
have revealed the benefits and potential of high-throughput radiochemistry, this new technology requires
significant further development and automation to increase safety and speed, and reduce the chance for human
error. We propose to (1) integrate in situ radiation detectors to quantify the radioactivity at various stages of each
reaction, (2) integrate a method to automatically sample the reactions for analysis (radio-TLC or radio-UPLC),
and (3) use high-throughput methods to optimize the synthesis of 5 neurotracers that currently have low yield,
develop at least one novel tracer, and develop best practices for high-throughput optimization in radiochemistry.
