Enabling translation of cancer cell proliferation PET imaging via droplet radiochemistry technology

PROJECT SUMMARY Despite the widespread use and success of [18F]FDG-PET imaging in oncology, there are many situations where [18F]FDG cannot be used for diagnosis or treatment monitoring, especially for cancers where there is high background uptake, low tissue density, or slow-growing tumors. Infection or inflammation frequently leads to false positives. Many tracers are being developed that provide improved contrast, sensitivity, and accuracy compared to [18F]FDG. Of particular interest is the nucleoside analog [18F]FMAU, which is incorporated into DNA when tumor cells divide, thus directly measuring increased cell proliferation, a universal hallmark of cancer. Promising clinical data of [11C]FMAU and preclinical data of [18F]FMAU have led to initial clinical studies of [18F]FMAU in cancer patients, and there is high interest in clinical studies of [18F]FMAU PET as a means to assess treatment response in diverse cancer types. However, the radiosynthesis of [18F]FMAU is very challenging, hindering translational efforts such as multicenter clinical trials that are needed to ensure sufficient recruitment of patient populations. Over many years, Dr. Chen’s lab at USC has improved the [18F]FMAU synthesis using a 1-pot process, but it still involves lengthy reaction steps (~3 h synthesis), uses corrosive and unstable reagents that are not compatible with automated synthesis modules, and has a relatively low activity yield (~5%), making adoption of this approach extremely difficult. To widely enable clinical studies, this proposal leverages an innovative droplet-radiochemistry approach developed in Dr. van Dam’s lab at UCLA, and now being commercialized by DropletPharm, in which reactions are performed in 10 µL volumes instead of 1 mL volumes, enabling higher isotope concentration, higher reaction yields and much shorter synthesis time. A preliminary study showed [18F]FMAU could be produced in <1 h. Our central hypotheses in this project are that cell proliferation imaging can provide a superior assessment of treatment response (e.g. earlier response detection and higher specificity to tumor growth) than other tracers, and that droplet technology can facilitate widespread access to [18F]FMAU for clinical translation. Leveraging synergistic academic and industry expertise and capabilities, our multi-PI team will advance the clinical translation of [18F]FMAU via four complementary aims: (1) Develop an optimized droplet radiosynthesis of [18F]FMAU at multi-dose scale; (2) Customize a droplet radiosynthesizer for [18F]FMAU production, then automate and validate the synthesis; (3) Pursue preclinical studies to evaluate [18F]FMAU for assessing treatment response (compared to [18F]FDG and [18F]FLT) to support future clinical trials; (4) Enable wide availability of [18F]FMAU by providing a low-cost self-shielded synthesizer, developing reagent/consumable kits, establishing a user training program, and compiling an IND amendment that can be referenced in future trials. We believe that quantitative [18F]FMAU-PET imaging will provide early and accurate assessment of cancer treatment leading to individually tailored therapeutic plans with improved patient outcomes.