β-Diketonate-Iron(III) Complex: A Versatile Fluorine-19 MRI Signal Enhancement Agent

Abstract

Fluorine-19 magnetic resonance imaging (MRI) has gained considerable momentum as a promising imaging modality for in vivo tracking of cellular therapies and as a diagnostic for inflammatory disease. To further the utility of this technique, we increase imaging probe sensitivity by merging paramagnetic metal chelates with aqueous perfluorocarbon (PFC) nanoemulsions. We prepared a highly fluorinated ferric tris(<i>β</i>-diketonate) chelate (MW = 1265.2 g/mol) at gram scale. This iron chelate is soluble in multiple PFC oils used for MRI and readily reduces the ¹⁹F longitudinal relaxation time (<i>T</i> ₁) to <100 ms with modest line broadening and displays superior properties for ¹⁹F MRI applications. The sensitivity enhancement by Fe(III) laden PFC nanoemulsion was confirmed in MRI phantom studies, where reduced <i>T</i> ₁ speeds data acquisition thereby increasing the ¹⁹F image sensitivity per time via signal averaging. Additionally, ¹⁹F relaxivity of nanoemulsions incorporating other metal ions, including Gd, Er, Ho, Dy, Mn, Cr, and Ni, were evaluated. High-moment lanthanide ions, such as Gd(III), display severe line broadening, but other ions [e.g., Ho(III)] induce pseudocontact chemical shifts (up to 0.5 ppm) of ¹⁹F in nanoemulsion, which makes them potentially useful for multichromatic ¹⁹F imaging. Formulated nanoemulsions have a shelf life >200 days. Free <i>β</i>-diketonate or its iron complex in formed PFC nanoemulsion did not induce cytotoxicity in intracellularly labeled macrophages. Overall, ferric tris(<i>β</i>-diketonate) chelate provides a scalable approach for boosting sensitivity of PFC-based ¹⁹F MRI probes. More generally, it can functionalize PFC oil, whose chemical modification remains challenging.