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

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(β-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 (T1) 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 T1 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 β-diketonate or its iron complex in formed PFC nanoemulsion
did not induce cytotoxicity in intracellularly labeled macrophages.
Overall, ferric tris­(β-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.