Optimizing the synthesis of[18F]FTMP for commercial distribution

Abstract The development of genetic medicines such as gene and cell therapies like Chimeric Antigen Receptor (CAR) T cells has necessitated new technologies that can monitor the biodistribution of these therapies in human patients. Imaging is particularly well suited to provide such quantitative measurements of a genetic medicine over time. Vellum Biosciences is a platform imaging company geared to fill this void in technology, providing repeatable, robust, sensitive measures of a genetic medicine in situ with clear applications in new drug development, clinical research, and eventually clinical practice. Vellum’s technology is based on positron emission tomography (PET) radiotracer derivatives of the synthetic antibiotic trimethoprim (TMP) and its protein target dihydrofolate reductase (DHFR). When DHFR is expressed in a genetically delivered medicine (e.g. mRNA, lentiviral or adenoviral vectors), TMP radiotracers can be used to measure the expression of the protein products in any tissue within the body. This strategy has been used to monitor the trafficking of CAR T cells targeting several solid tumors in animals. In this STTR phase 1, we propose the development of a commercially viable radiosynthetic route for broad, widespread distribution of TMP radiotracers. In AIM1, we will develop a two-step radiosynthetic process which shall decrease the need for HPLC purification and co-develop a single vessel synthesis which will be applicable to many commercial radiosynthesis modules. In AIM2, we focus on a cartridge-based, solid-phase workup of the radiochemical products. Taken together these short-term goals provide both the feasibility and tractability for commercial radiopharmacy production of TMP radiotracers. More broadly, imaging is expected to be particularly important in the coming decades to validate and prioritize new genetic medicine therapies. We have already formed relationships with global pharmaceutical companies to use these technologies and envision that these approaches are critical to the advancement of next-generation medicines for the continued improvement of human health.