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(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 19 F longitudinal relaxation time (T 1 ) to <100 ms with modest line broadening and displays superior properties for 19 F MRI applications. The sensitivity enhancement by Fe(III) laden PFC nanoemulsion was confirmed in MRI phantom studies, where reduced T 1 speeds data acquisition thereby increasing the 19 F image sensitivity per time via signal averaging. Additionally, 19 F relaxivity of nanoemulsions incorporating other metal ions, including Gd, Er, Ho, Dy, Mn, Cr, and Ni, were evaluated. Highmoment 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 19 F in nanoemulsion, which makes them potentially useful for multichromatic 19 F 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 19 F MRI probes. More generally, it can functionalize PFC oil, whose chemical modification remains challenging.

19F MRI Nanotheranostics for Cancer Management: Progress and Prospects

“…Notably, paramagnetic metals can shorten the relaxation times of adjacent 19 F nuclei by the paramagnetic relaxation enhancement (PRE) effect [38] . Moreover, paramagnetic metal complexes with anisotropic unpaired electrons can change the chemical shift of fluorine nuclei through the pseudocontact shift effect [39] . Therefore, it is an ideal strategy to achieve high‐performance 19 F MRI by reasonably modulating T 1 and T 2 , designing application‐oriented exogenous fluorine‐containing contrast agents, introducing paramagnetic metals to regulate their chemical shifts, and assisting with specific fluorine detection channels.…”

Emergent Fluorous Molecules and Their Uses in Molecular Imaging

“…Increasing R 1 allows more signal averages, thereby increasing SNR per time and decreases the minimum number of detectable cells per voxel. We synthesized multiple fluorous chelates that differ in metal binding affinity and solubilities and demonstrated their use in ultrasensitive 19 F MRI for both ex vivo and in vivo cell labeling. ,, …”

“…Moreover, we explored the use of commercially available (perfluoroheptanoyl)­acetone (PFHA) chelator . X-ray crystallography shows that Fe-PFHA possesses an octahedral structure with an averaged Fe–O bond length of 1.993 Å and O–Fe–O angle of 174.7° (Figure b).…”

Enhanced detection of paramagnetic fluorine‐19 magnetic resonance imaging agents using zero echo time sequence and compressed sensing

“…More recently, functionalized PFC nanoemulsions containing iron‐binding, fluorous chelates display a paramagnetic relaxation enhancement (PRE) effect that reduces the 19 F T 1 relaxation time by more than 10‐fold 21 . These metallo‐PFC (MPFC) nanoemulsions can significantly boost 19 F MRI SNR with repetitive signal averaging at constant total scan time 22,23 . However, T 2 linewidth broadening can limit the amount of metal additive in MPFC, potentially constraining the achievable SNR performance.…”

“…21 These metallo-PFC (MPFC) nanoemulsions can significantly boost 19 F MRI SNR with repetitive signal averaging at constant total scan time. 22,23 However, T 2 linewidth broadening can limit the amount of metal additive in MPFC, potentially constraining the achievable SNR performance.…”