Proof-of-concept optimization of a copper-mediated 18F-radiosynthesis of a novel MAGL PET tracer on a high-throughput microdroplet platform and its macroscale translation

Copper-mediated radiofluorination has demonstrated remarkable potential in forming aromatic C-F-18 bonds of radioligands for positron emission tomography (PET). Achieving optimal results often requires optimization efforts, requiring a substantial amount of radiolabeling precursor and time, severely limiting the experimental throughput. Recently, we successfully showcased the feasibility of performing and optimizing Cu-mediated radiosynthesis on a high-throughput microdroplet platform using the well-known and clinically used radioligand [F-18]FDOPA as an illustrative example. In our current work, we optimized the Cu-mediated synthesis of a novel monoacylglycerol lipase (MAGL) PET tracer ([F-18]YH149), showing the versatility of droplet-based techniques for early stage tracer development. Across 5 days, we conducted a total of 117 experiments, studying 36 distinct conditions, while utilizing <15 mg of total organoboron precursor. Compared to the original report in which the radiochemical yield (RCY) was 4.4 +/- 0.5% (n = 5), the optimized droplet condition provided a substantial improvement in RCY (52 +/- 8%, n = 4) and showed excellent radiochemical purity (100%) and molar activity (77-854 GBq mu mol(-1)), using a starting activity of 0.2-1.45 GBq. Furthermore, we showed for the first time a translation of the optimized microscale conditions to a vial-based method. With similar starting activity (0.2-1.44 GBq), the translated synthesis exhibited a comparable RCY of 50 +/- 10% (n = 4) while maintaining excellent radiochemical purity (100%) and acceptable molar activity (20-46 GBq mu mol(-1)). The successful translation to vial-based reactions ensures wider applicability of the optimized synthesis by leveraging widely available commercial vial-based synthesis modules.

Automated summary

Copper-mediated radiofluorination has great potential in the synthesis of PET radioligands. We demonstrated the feasibility of Cu-mediated radiosynthesis on a high-throughput microdroplet platform and optimized the reaction conditions. By utilizing microscale conditions, we achieved higher radiochemical yield and excellent radiochemical purity and molar activity. We also successfully translated these optimized conditions to a vial-based method, expanding the applicability of the synthesis approach.