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[68Ga]Ga-HBED-CC-FAPI Derivatives with Improved Radiolabeling and Specific Tumor Uptake

Haiyan Hong,Zhihao Zha,Ruiyue Zhao,Yang Luo,Wenbin Jin,Linlin Li,Ran Wang,Li Yan,Hui Wang,Karl Ploessl,Jinping Qiao,Lin Zhu,Hank F. Kung

Fibroblast activation protein (FAP) is selectively expressed in tumors and highly important for maintaining the microenvironment in malignant tumors. Radioisotope-labeled FAP inhibitors (FAPIs) were proven to be useful for diagnosis and radionuclide therapy of cancer and are under active clinical investigations. Ga-HBED complex displays a higher in vivo stability constant (log KGaL: 38.5), compared to that of Ga-DOTA (log KGaL: 21.3). Such advantage in stability constant suggests that it may be useful for development of alternative FAPI imaging agents. In this study, previously reported [68Ga]Ga-DOTA-FAPI-02 and -04 were converted to the corresponding [68Ga]Ga-HBED-CC-FAPI-02 and -04 derivatives ([68Ga]Ga-4, [68Ga]Ga-5, [68Ga]Ga-6, and [68Ga]Ga-7). It was found that substituting the DOTA chelating group with HBED-CC led to several unique and desirable tumor-targeting properties: (1) robust, fast, and high yield labeling─readily adaptable to a kit formulation; (2) high stabilities in vitro; (3) excellent FAP binding affinities (IC50 ranging between 4 and 7 nM) and improved cell uptake and retention (in HT1080 (FAP+) cells); and (4) excellent selective in vivo tumor uptake in nude mice bearing U87MG tumor. It appeared that Ga(III) chelation with HBED-CC improved the in vivo kinetics favoring higher tumor uptake and retention compared to the corresponding Ga-DOTA complex. Out of the four tested ligands the new [68Ga]Ga-HBED-CC-FAPI dimer, [68Ga]Ga-6, displayed the best tumor localization properties, and further studies are warranted to demonstrate that it is an alternative FAP imaging agent for cancer patients.