Structural Optimization of Fibroblast Activation Protein Inhibitors Through Zwitterionic and PEG Modification Strategy: Impact on Pharmacokinetics and Tumor Imaging

Fibroblast activation protein (FAP), highly overexpressed in cancer-associated fibroblasts (CAFs), is crucial in tumor pathogenesis and progression, making it an important target for diagnosis and therapy. This study presents the design of a series of FAP inhibitors (FAPIs) derived from UAMC-1110 derivative, modified with zwitterions and polyethylene glycol (PEG). The novel 68Ga-labeled tracers show improved pharmacokinetics compared to 68Ga-FAPI-04. Small animal positron emission tomography/computed tomography (micro-PET/CT) on U87MG tumor-bearing nude mice revealed that 68Ga-FAPI-BN-1, incorporating boron trifluoride zwitterion, and 68Ga-FAPI-P8PN, with phosphate zwitterion and PEG8 modifications, demonstrated high tumor uptake and minimal normal tissue uptake. Biodistribution studies confirmed their excellent tumor accumulation and tumor-to-normal tissue ratios (T/NT). Specifically, 68Ga-FAPI-BN-1 exhibited a tumor uptake of 49.31 ± 2.76%ID/g at 1 h, with a tumor/muscle ratio of 24, while 68Ga-FAPI-P8PN showed a tumor uptake of 42.19 ± 3.21% ID/g at 0.5 h, with a tumor/muscle ratio of 23. These results indicate that these tracers hold promise as effective molecular imaging agents targeting FAP.

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