Design, Synthesis and Biological Evaluation of a Novel [¹⁸F]AlF-H₃RESCA-FAPI Radiotracer Targeting Fibroblast Activation Protein.

Abstract: Fibroblast activation protein (FAP) is widely utilized in nuclear medical imaging and cancer diagnosis and treatment. Some small molecule FAP inhibitors (FAPIs) are used to develop diagnostic and therapeutic agents targeting FAP by conjugating the different radionuclides. However, ¹⁸F-labeled FAPIs require further expansion. In this study, We attempted to label FAPI with ¹⁸F by H3RESCA chelator group. The efficacy and pharmacoki- netics of H₃RESCA-FAPI were predicted and evaluated by molecular docking, ADMET properties, affinity test, labeling, positron emission tomography (PET) imaging with U87MG model mice and in vitro biological distribution. The excellent labelling conjugation of H₃RESCA-FAPI and aluminum fluoride ([ ¹⁸F]AlF) in mild conditions, high affinity for FAP, rapid clearance in vivo, effective visualization of tumor tissue and high target and nontarget uptake ratio indicate that [ ¹⁸F]AlF-H₃RESCA-FAPI is a potential PET imaging tracer targeting FAP. However, the extremely high liver and intestine uptake illustrate further structural modifications are nec- essary to optimize its pharmacokinetics and improve imaging quality.