PROJECT SUMMARY Despite the enormous value of radiopharmaceuticals for imaging and therapy in clinical nuclear medicine, and for research and drug development, the production of these compounds remains very expensive because of the need for complex, capital-intensive equipment and infrastructure (i.e., hot cells, stack monitor, radiosynthesizer, and a suite of QC testing equipment) at each site. For the most widely used PET radiopharmaceutical, [18F]FDG, multiple patients can be scheduled on the same day, enabling the batch production costs to be divided among many individual doses. However, for most other PET tracers, such cost-sharing opportunities are rare or non-existent, meaning that each production run is effectively dedicated to a single patient, resulting in a high cost per patient dose. These challenges discourage manufacturers from investing in the production of valuable but less-used radiopharmaceuticals, which severely limits their availability. Additionally, the high price of many radiopharmaceuticals discourages their use in research (e.g. pre-clinical), and hampers the development and validation of novel radiopharmaceuticals. In addition to limited demand, some radiopharmaceuticals are constrained by supply-side issues (e.g. limited output of Ga-68 generators) that inherently limits the number of patient doses that can be made in a single batch. Instead of relying on cost reductions through increased demand for radiopharmaceuticals and increase size of batches produced, which will be impossible for many cases, our strategy is to lower the batch production cost itself. New microfluidic methods of PET tracer manufacture have emerged in recent years with the potential to revolutionize tracer production via dramatic reductions in cost and complexity. The droplet-based approach developed by the van Dam laboratory at UCLA enables the production of numerous 18F-radiopharmaceuticals with ~100x reagent reduction, 2-3x reduction in synthesis and purification time, and high molar activity, all in a system the size of a coffee cup. Droplet reactions were scaled to clinically-relevant amounts (one to many patient doses) by using an upstream radioisotope concentrator. DropletPharm, Inc. is commercializing a benchtop radiopharmacy platform based on this technology that will enable a transformation to low-cost production of a broad range of radiopharmaceuticals. Though most of the prior development of droplet radiochemistry has focused on 18F-radiopharmaceuticals, there is intense interest in radiometal isotopes for imaging and therapy, with a large number of Ga-68 compounds in pre-clinical development, clinical trials and a few with FDA-approval for routine use. In this Phase I STTR project, we aim to expand the applications of DropletPharm’s droplet radiochemistry approach beyond F-18 radiotracers by building a metal-free droplet reactor and establishing the feasibility of radiometal labeling. We will develop radioisotope concentration methods for Ga-68, Cu-64, and Zr-89 (Aim 1), develop droplet labeling methods for example radiotracers (Aim 2), and demonstrate production of [68Ga]Ga-PSMA-11 in a cGMP setting (Aim 3).

RELEVANCE Radiopharmaceuticals play a profound role in medicine as diagnostic imaging agents and therapeutics, but their high production cost limits access and availability and slows the pace of discovery, development, and clinical translation of new radiopharmaceuticals. The production cost is high because of the specialized facilities and equipment required, and because the short half life necessitates establishing manufacturing facilities (radiopharmacies) close to each point of use. The proposed novel microscale radiochemistry technology will directly address this current shortcoming by dramatically shrinking the size, cost, and complexity of radiopharmacies.