Perfluoro-tert-butoxylated Monosaccharides for Metabolic ¹⁹F Magnetic Resonance Imaging in Hepatocellular Carcinoma...

Fluorine-19 magnetic resonance imaging (¹⁹F MRI) holds promise for noninvasive cancer diagnosis due to its negligible background signal, quantitative capability, radiation-free nature, and unlimited tissue penetration. However, its application in tumor imaging has been hindered by low sensitivity and insufficient tumor specificity. Here, we report a new class of perfluoro-tert-butoxylated (PFTB) monosaccharides as high-performance ¹⁹F MRI agents for the detection of hepatocellular carcinoma (HCC). These small molecules, synthesized via a click chemistry strategy, incorporate a PFTB group bearing nine magnetically equivalent ¹⁹F atoms that generates an intense singlet NMR signal, while the monosaccharide scaffold ensures excellent water solubility and biocompatibility. Among them, PFTB-D-galactose exhibits strong binding affinity to hexokinase II, enabling selective uptake and intracellular trapping in HCC cells. Remarkably, intravenous injection allows hot-spot imaging of orthotopic liver tumors without the need for nanocarriers or complex formulations. In contrast to the slow clearance of conventional perfluorocarbons, PFTB-D-galactose is rapidly excreted into the bladder, indicating efficient renal elimination. This work addresses the long-standing challenges of ¹⁹F MRI sensitivity and tumor targeting, providing a versatile design strategy for developing clinically translatable ¹⁹F MRI agents.