Research of Al 18F-Labeled Novel Cyclic Peptide Probe Al 18F-FAP-NOX in Tumor-Targeted Molecular Imaging

Objective:To develop a novel fibroblast activation protein (FAP) cyclic peptide imaging agent, Al 18F-FAP-NOX, evaluate its in vitro and in vivo properties, and explore its feasibility of PET/CT imaging in tumors with FAP positive expression. Methods:Al 18F-FAP-NOX was manually synthesized. The in vitro stability of Al 18F-FAP-NOX was determined using radio high performance liquid chromatography (HPLC). The lipid water partition coefficient log P, in vitro cell uptake experiments, microPET/CT imaging and biodistribution in 293T-FAP tumor-bearing mice were conducted to preliminarily evaluate the pharmacokinetics and biological efficacy of Al 18F-FAP-NOX. Afterwards, a patient (male, 65 years old) with lung cancer underwent Al 18F-FAP-NOX PET/CT imaging. Results:Al 18F-FAP-NOX was successfully synthesized with a yield of (26.28±2.31)% without attenuation correction ( n=4), and the radiochemical purity was more than 95%. Al 18F-FAP-NOX exhibited good stability and hydrophilicity (log P=-3.02±0.08, n=5). In cell assays, the uptake of Al 18F-FAP-NOX in HT1080-FAP cells reached the plateau phase at 15 min ((7.31±0.53) percentage activity of injection dose per million cells (%ID/mio cells)), exhibiting high cellular uptake. The uptake of Al 18F-FAP-NOX could be significantly inhibited by 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid (DOTA)-FAP-2286. The microPET/CT results of 293T-FAP tumor-bearing mice in vivo showed that Al 18F-FAP-NOX was highly uptaken in FAP-positive tumor tissues (60 min: (12.47±1.66) percentage activity of injection dose per gram of tissue (%ID/g)), while the uptake was very low in FAP-negative tumors. The biodistribution results were similar to the microPET/CT imaging results of tumor-bearing mice. The human clinical imaging showed an abnormal increase in Al 18F-FAP-NOX uptake (SUV max 5.5) of the lung cancer lesions. Conclusions:A novel cyclic peptide radiopharmaceutical, Al 18F-FAP-NOX, demonstrates good stability and hydrophilicity. It can be quickly distributed to tumor tissue in vivo. The human clinical PET/CT imaging shows certain diagnostic ability of Al 18F-FAP-NOX for lung cancer lesions. It is a promising cyclic peptide agent for PET imaging.