UCLA

Positron emission tomography (PET) is a widely-used nuclear medicine imaging technique for assessing biodistribution of drugs, diagnosing diseases, and monitoring therapy response. The rapid development of new PET tracers in both research and clinical applications (to image new targets) demands new advances in radiolabeling techniques to facilitate the frequent production of diverse tracers. Recent developments in droplet-based radiochemistry have shrunk reaction volumes 100x (i.e. to <10 µL), offering advantages like minimal reagent use, rapid synthesis, high yields, and increased molar activity; they also enable high-throughput optimization and scalable production, with great potential to revolutionize radiopharmaceutical production. While our group has successfully utilized microdroplet reactors (a small Teflon-coated silicon chip containing hydrophilic reaction sites) for multiple different radiopharmaceuticals, exploration into metal-mediated radiosynthesis remains limited, primarily due to concerns about the sensitivity of metal reagents to environmental moisture in droplet-based reactors. As a proof-of-concept, I conducted the first microscale copper (Cu)-mediated synthesis of [18F]FDOPA (a clinical PET probe used for imaging dopaminergic function). Substantial enhancement in yield and time was achieved while utilizing only nanomole quantities of precursors and other reagents. Later, I explored the versatility of this method in optimizing additional tracers employing similar Cu-mediated 18F-radiolabeling routes on a high-throughput microdroplet reactor. For example, across 5 days, I conducted 117 reactions, exploring 36 conditions with <15 mg of precursor, and achieved 12x yield improvement for a novel monoacylglycerol lipase (MAGL) probe ([18F]YH149). Leveraging an automated robotic platform for high-throughput studies, we optimized the production of [18F]FBnTP, a potentiometric radiopharmaceutical, with 64 simultaneous droplet reactions in one morning. In addition, on the technology side, many researchers have wondered whether the droplet-based optimized conditions can guide reaction conditions in conventional vial-based reactors, and I demonstrated for the first time that this indeed can be done. This suggests a rapid and economical approach for novel tracer development, i.e., optimizing radiochemistry on a high-throughput microdroplet platform (rapidly, with minimal reagents) and then performing straightforward translation to vial-based systems to enable wider applicability to the existing install base of radiosynthesizer technology. Furthermore, to assess the adaptability of droplet-based radiochemistry in handling exceptionally complex syntheses, I undertook the investigation of a highly intricate three-step radiosynthesis of [18F]FMAU (imaging cell proliferation), encompassing radiofluorination, coupling, and deprotection reactions all within a microdroplet reactor. Compared the lengthy (~150 min) and low-yielding conventional production, the microdroplet-based radiosynthesis of [18F]FMAU provided significant improvement, completing the production in <60 min and achieving >2x higher radiochemical yield and >3x activity yield, while consuming 34-200x less reagents. Moreover, to establish the clinical relevance of droplet-based radiochemistry, we developed various droplet-based scale-up approaches including (i) iteratively loading and evaporating [18F]fluoride aliquots in a single droplet reaction, (ii) pre-concentrating [18F]fluoride in a miniature cartridge compatible with a single reaction site, and (iii) pooling multiple droplet reactions for on-demand dose. These methods, validated for reliability and versatility, successfully delivered clinically-relevant doses of [18F]FET (an amino acid tracer), [18F]Florbetaben (an amyloid imaging agent), [18F]FBnTP, isotopic exchange fluorinated compounds, and aluminum-[18F]fluoride probes. Apart from droplet-based radiosynthesis techniques, I also pursued other novel radiochemistry systems. I helped to develop a platform for microvolume reactions, featuring a pipettor on an XYZ motion gantry and a disposable cassette with integrated micro-vial. The versatile setup performs operations like trapping/releasing [18F]fluoride, liquid transfers, and lid installation/removal for reactor. Comprehensive experiments have been conducted to characterize the system and demonstrate the radiosynthesis feasibility, using [18F]Fallypride as an example. I also helped develop a novel electrochemical radiofluorination (ECRF) technique using a spilt bipolar electrode (s-BPE) for electron-rich compounds such as thioether derivatives. Unlike traditional ECRF which requires high salt concentration, this s-BPE system, with its dual conductive materials, facilitates anodic and cathodic reactions at lower salt concentrations. We achieved a 5x increase in molar activity for [18F]fluoromethyl (methylthio)acetate compared to conventional ECRF approaches, mainly attributed to reduced [19F]F- contamination from less salt. Radiochemistry in droplets and electrochemistry for [18F]fluoride labeling showcased an innovative optimization approach and scalable method for clinically-relevant production, surpassing conventional methods. The methodologies outlined in this dissertation provide a comprehensive pathway to speed up the transition of both established and novel PET tracers from the laboratory to clinical application swiftly and cost-effectively.