Positron Emission Tomography Imaging of Cathepsin B in Tumors with Activable Small Molecule Tracers

• Published in: Journal of medicinal chemistry 2024-12, Vol.67 (23), p.21292-21302
• Main Authors: Li, Huirong, Li, Yuelin, Li, Ke, Wang, Qianhui, Yang, Jichen, Qiu, Ling, Lin, Jianguo
• Format: Article
• Language: English
• Subjects: Animals; Cathepsin B - metabolism; Cell Line, Tumor; Gallium Radioisotopes - chemistry; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Positron-Emission Tomography - methods; Radiopharmaceuticals - chemistry; Small Molecule Libraries - chemistry; Tissue Distribution
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.4c02178

Cathepsin B (CTB) is overexpressed in several types of tumors, and precise evaluation of the CTB activity can offer a promising method for the early diagnosis of tumors. In this study, two CTB-activated positron emission tomography (PET) tracers, [ 68 Ga]­NOTA-SFCVM and [ 68 Ga]­NOTA-SFCVHEM, were developed for sensitive and specific detection of CTB. Both tracers undergo a click condensation between 2-cyano-6-aminobenzothiazole (CBT) and cysteine (Cys) to form a cyclization product, thereby enhancing and prolonging the PET signal in tumors. In vitro cellular experiments showed that the tracers could differentiate tumor cells with different expression levels of CTB. In vivo PET imaging further revealed that the tracers selectively accumulated in the CTB-positive tumors. Compared with [ 68 Ga]­NOTA-SFCVM, [ 68 Ga]­NOTA-SFCVHEM containing a morpholine group and a histidine–glutamate–histidine–glutamate–histidine–glutamate sequence exhibited faster catalytic efficiency toward CTB, higher tumor uptake, and reduced liver uptake. These findings suggest that [ 68 Ga]­NOTA-SFCVHEM holds potential for clinical use in the early diagnosis of CTB-related tumors.