Visualizing enterohepatic circulation in vivo by sensitive ¹⁹F MRI with a fluorinated ferrous chelate-based small...

Enterohepatic circulation (EHC) is a critical biological process for the normal regulation of many endogenous biomolecules and the increased retention of various exogenous substances. The status of EHC is closely related to the ordinary functioning of several digestive organs. However, it remains a challenge to achieve in vivo real-time visualization of this process. Herein, we rationally design and synthesize a ferrous chelate, DO3A-Fe(II)-9F, with high fluorine content and favorable water solubility for visualizing EHC via¹⁹F magnetic resonance imaging (MRI). The assessments on imaging performance reveal an 18-time increase in signal intensity compared to the fluorinated ligand alone. This probe's capability of entering EHC via the mediation of organic anion transporting polypeptides (OATPs) is validated with ex vivo bio-distribution analysis and in vivo uptake-blocking imaging experiments, which allows short-time sensitive ¹⁹F MRI of EHC in healthy mice. Additionally, we illustrate its capacity for clearly imaging tampered EHC in the mice with inflammatory bowel diseases (IBD), drug-induced liver injury (DILI) or orthotopic hepatocellular carcinoma (HCC). These results illustrate the promising potential of this probe for in vivo visualization of EHC under different conditions, especially disease conditions, which is beneficial for the study, diagnosis, or even stratification of various diseases.