Automated Synthesis Method to Produce the Pet Tracer [68Ga]ga-Fapi-46 for Clinical Applications: Development, Optimization and Validation

Fibroblast Activation Protein (FAP) is a serine protease selectively expressed in many disorders associated with fibrotic dysregulation. FAP expression in healthy tissues is low, but significantly elevated in sites of tissue remodelling and repair. This specific pattern of expression makes FAP an ideal target for imaging and therapy and then FAP-Specific Small-Molecule Inhibitors (FAPIs) have been developed. The most promising molecule has been found FAPI-46, functionalized with DOTA to obtain a PET probe. Our goal was to develop, optimize and validate a new automated synthesis method to label DOTA-FAPI-46 with Ga-68 and a new quality control system to make the radiopharmaceutical available. The radiopharmaceutical production was optimized scaling down the amount of DOTA-FAPI-46 (50 - 10 μg). The synthesis of [68Ga]Ga-FAPI-46 was done using the Scintomics GRP® module with the already estabilished synthesis template for [68Ga]Ga-DOTATOC/[68Ga]Ga-PSMA. Synthesis efficiency and relevant quality control parameters were evaluated for each produced batch in accordance with the European Pharmacopeia. Best results were yielded with 20 μg DOTA-FAPI-46 and three different batches of validation were obtained with optimal radiochemical yield (67.75%) as well radiochemical purity (99.76%) and molar activity (26.23 GBq/µmol). [68Ga]Ga-FAPI-46 was successfully synthesized and it is available for multi-dose application in clinical settings.