High-throughput radiolabeling

Overview

Due to the short radioisotope half-lives, radiopharmaceuticals are prepared frequently (some daily or more often) and at many locations throughout the globe (due to limited delivery timeframe). Preparation is usually performed using automated radiosynthesizers to limit radiation exposure to the chemist. Some radiosynthesizers are operated in research facilities for the safe preparation of a wide variety of different compounds, and some are used commercially for the repeated preparation of large batches of a single radiopharmaceutical that are divided up and shipped to multiple nearby imaging or treatment facilities. Though the cost of specialized equipment, specialized facilities with radiation shielding, reagents, radioisotope, skilled personnel, etc. is very high, the ability to leverage economies of scale in the latter scenario enables the production of high-demand radiopharmaceuticals at a low cost per patient dose. However, for tracers with lower demand such that it is not possible to schedule patients or experiments at the same time to take advantage of cost sharing, conventional systems are not capable of economical production of tracers. For studies that require a large number of batches, e.g. synthesis optimization for novel tracers, the practical result of these costs is to limit the scope, depth, and number of replicates in optimization studies.

In the field of chemistry, high-throughput experimentation (HTE) is increasingly being used to perform reactions screening, catalyst screening, and optimization of reaction conditions. HTE typically leverages automation, miniaturization and/or parallelism, resulting in substantially less effort and reagents per experiment compared to traditional methods. Such approach could provide enormous cost and throughput benefits in the field of radiochemistry.

Based on our recent efforts in droplet-based radiochemistry, we developed a chip with multiple reaction sites to perform up to 16 droplet-based syntheses in parallel, all with the same reaction temperature and time, but with varying volumes or concentrations of reagents or reaction solvent.

Results

As a demonstration, we initially studied the impact on yield of several parameters in the synthesis of [¹⁸F]fallypride, including base amount (used in [¹⁸F]fluoride drying step), as well as precursor concentration and droplet volume used in the fluorination step. Using chips with 4 reaction sites, we studied 20 different reaction conditions (n=2 replicates each) in just 3 days. More recently, using chips with 16 reactions sites, we have been able to perform hundreds of reactions in a few days, allowing a comprehensive exploration of the parameter space.

Current Status / Next Steps

We continue to use this technique for optimizing the synthesis of additional compounds and for studying the properties of droplet reactions in a more high-throughput fashion. We are seeking collaborations with investigators that have libraries of compounds they wish to label for in vitro or in vivo imaging comparisons. Another major direction of this work is the development of a robotic platform to automatically perform and analyze high numbers of reactions using these multi-reaction chips.

Related Publications

• • Alejandra Rios, Jia Wang, Philip H. Chao, R. Michael van Dam. A novel multi-reaction microdroplet platform for rapid radiochemistry optimization. RSC Advances 9: 20370-20374, 2019. DOI: 10.1039/C9RA03639C. (Journal Link)

Team Members and Collaborators

Current

• Alejandra Rios

• Jia Wang

• Jason Jones

• Ksenia Lisova

• Travis Holloway

Former

• Philip Chao

• Christian De Caro