Abstract
Cancer-associated fibroblasts (CAFs) are essential components of the tumor microenvironment. Fibroblast activation protein (FAP) is overexpressed in CAFs. FAP-targeted molecular imaging agents, including the FAP inhibitors (FAPIs), have shown promising results in tumor diagnosis. We aimed to design a Gd-labeled FAPI Dimer, Gd-DOTA-Suc-Lys-(FAPI04)2, to optimize the pharmacokinetics and evaluate its potential capacity for targeting FAP-positive solid tumors in vivo. The Gd-labeled FAPI Dimer was successfully synthesized with exceeding 98% purity. Preclinical pharmacokinetics were determined in assessed FAP-positive U87 cell-derived xenografts and FAP-negative C6-derived xenografts using small-animal T1-weighted 7.0T MR imaging. The longitudinal correlation coefficient (r1) of the agent was 3.813 mM-1·S-1. The administration of the Gd-FAPI04 Dimer probe showed a notable enhancement of tumor contrast on T1-weighted whole-body MRI. At 10 and 30 minutes post-injection, the U87 subcutaneous tumor demonstrated significantly greater contrast enhancement than the C6 subcutaneous tumor (P <0.05). In vivo, the safety of the Gd-FAPI-04 Dimer probe was evaluated, which showed no tissue damage in vital organs like the heart, liver, spleen, lung, and kidneys, as indicated by unchanged morphology compared to a normal saline control group. The novel Gd-FAPI04 Dimer molecular probe, Gd-DOTA-Suc-Lys-(FAPI-04)2 specifically targeting FAP may serve as a safe and promising tool for the diagnostic imaging of solid tumors.