Design, Synthesis, and Evaluation of 18 F-Labeled Tracers Targeting Fibroblast Activation Protein for Brain Imaging.

Fibroblast activation protein (FAP) is closely related to central nervous system diseases such as stroke and brain tumors, but PET tracers that can be used for brain imaging have not been reported. Here, we designed, synthesized, and evaluated 18 F-labeled UAMC1110 derivatives suitable for brain imaging targeting FAP. By substituting the F atom for the H atom on the aromatic ring of compound UAMC1110, 1a - c were designed and prepared. 1a - c were confirmed to have a high affinity for FAP through molecular docking and enzyme assay. [ 18 F] 1a - c were successfully prepared and confirmed to have high affinity. The stability in vivo indicates that no obvious metabolites of [ 18 F]1a , b were found in the plasma 1 h after injection, which is beneficial for brain imaging. In vitro cell uptake experiments showed that [ 18 F]1a , b and [ 68 Ga]FAPI04 exhibited similar uptake and internalization rates. PET imaging of U87MG subcutaneous tumor showed that [ 18 F]1a , b could penetrate the blood-brain barrier with higher uptake and longer retention time than [ 68 Ga]FAPI04 (uptake at 62.5 min, 1.06 ± 0.23, 1.09 ± 0.25% ID/g vs 0.21 ± 0.10% ID/g, respectively). The brain-to-blood ratios of [ 18 F]1a , b were better than [ 68 Ga]FAPI04. Biodistribution and PET imaging showed that [ 18 F]1a had better uptake on tumors and a higher tumor-to-muscle ratio than [ 18 F]1b and [ 68 Ga]FAPI04. Further imaging of U87MG intracranial glioma showed that [ 18 F]1a outlined high-contrast gliomas in a short period of time compared to [ 18 F]1b . Therefore, [ 18 F]1a is expected to be useful in the diagnosis of FAP-related brain diseases.