High Affinity and FAP-Targeted Radiotracers: A Potential Design Strategy to Improve the Pharmacokinetics and Tumor Uptake for FAP Inhibitors
Yinwen Wang, Hongmei Yuan, Nan Liu, Sufan Tang, Yue Feng, Yang Liu, Ping Cai, Li Xia, Wenlu Zheng, Yue Chen, Zhijun Zhou
Abstract
Fibroblast activation protein (FAP) is overexpressed in cancer-associated fibroblasts, making it an attractive target for both imaging and therapy of malignancy. This study presents a range of novel FAP inhibitors derived from amino derivatives of UAMC1110, incorporating polyethylene glycol and bulky groups containing bifunctional DOTA chelators. The compounds labeled with gallium-68 were developed and characterized to study biodistribution properties and tumor-targeting performance in nude mice bearing U87MG tumor xenografts. Several tracers of interest were screened due to the advantages in imaging and tumor-specific uptake. Positron emission tomography scans revealed that polyethylene glycol-modified 68 Ga-3-3 had a rapid penetration within the neoplastic tissue and excellent tumor-to-background contrast. In a comparative biodistribution study, naphthalene-modified 68 Ga-6-3 exhibited more significant tumor uptake (∼50% ID/g, 1 h p.i.) than 68 Ga-3-3 and 10-fold higher than 68 Ga-FAPI-04 under the same conditions. Remarkably, 68 Ga-8-1, combining the two structural design strategies, obtains superior imaging performance.