Noninvasive Imaging of Early Venous Thrombosis by 19F Magnetic Resonance Imaging With Targeted Perfluorocarbon Nanoemulsions

Background-Noninvasive detection of deep venous thrombi and subsequent pulmonary thromboembolism is a serious medical challenge, since both incidences are difficult to identify by conventional ultrasound techniques. Methods and Results-Here, we report a novel technique for the sensitive and specific identification of developing thrombi using background-free F-19 magnetic resonance imaging, together with alpha 2-antiplasmin peptide (alpha 2(AP))-targeted perfluorocarbon nanoemulsions (PFCs) as contrast agent, which is cross-linked to fibrin by active factor XIII. Ligand functionality was ensured by mild coupling conditions using the sterol-based postinsertion technique. Developing thrombi with a diameter <0.8 mm could be visualized unequivocally in the murine inferior vena cava as hot spots in vivo by simultaneous acquisition of anatomic matching H-1 and F-19 magnetic resonance images at 9.4 T with both excellent signal-to-noise and contrast-to-noise ratios (71 +/- 22 and 17 +/- 5, respectively). Furthermore, alpha 2(AP)-PFCs could be successfully applied for the diagnosis of experimentally induced pulmonary thromboembolism. In line with the reported half-life of factor XIIIa, application of a2AP-PFCs >60 minutes after thrombus induction no longer resulted in detectable F-19 magnetic resonance imaging signals. Corresponding results were obtained in ex vivo generated human clots. Thus, alpha 2(AP)-PFCs can visualize freshly developed thrombi that might still be susceptible to pharmacological intervention. Conclusions-Our results demonstrate that H-1/F-19 magnetic resonance imaging, together with alpha 2(AP)-PFCs, is a sensitive, noninvasive technique for the diagnosis of acute deep venous thrombi and pulmonary thromboemboli. Furthermore, ligand coupling by the sterol-based postinsertion technique represents a unique platform for the specific targeting of PFCs for in vivo F-19 magnetic resonance imaging.