Fluorous-Soluble Metal Chelate for Sensitive Fluorine-19 Magnetic Resonance Imaging Nanoemulsion Probes

Fluorine-19 MRI is
an emerging cellular imaging approach, enabling
lucid, quantitative “hot-spot” imaging with no background
signal. The utility of 19F-MRI to detect inflammation and
cell therapy products in vivo could be expanded by
improving the intrinsic sensitivity of the probe by molecular design.
We describe a metal chelate based on a salicylidene-tris­(aminomethyl)­ethane
core, with solubility in perfluorocarbon (PFC) oils, and a potent
accelerator of the 19F longitudinal relaxation time (T1). Shortening T1 can increase the 19F image sensitivity per time and decrease
the minimum number of detectable cells. We used the condensation between
the tripodal ligand tris-1,1,1-(aminomethyl)­ethane and salicylaldehyde
to form the salicylidene-tris­(aminomethyl)ethane chelating agent (SALTAME). We purified four isomers
of SALTAME, elucidated structures using X-ray scattering and NMR,
and identified a single isomer with high PFC solubility. Mn4+, Fe3+, Co3+, and Ga3+ cations formed
stable and separable chelates with SALTAME, but only Fe3+ yielded superior T1 shortening with
modest line broadening at 3 and 9.4 T. We mixed Fe3+ chelate
with perfluorooctyl bromide (PFOB) to formulate a stable paramagnetic
nanoemulsion imaging probe and assessed its biocompatibility in macrophages in vitro using proliferation, cytotoxicity, and phenotypic
cell assays. Signal-to-noise modeling of paramagnetic PFOB shows that
sensitivity enhancement of nearly 4-fold is feasible at clinical magnetic
field strengths using a 19F spin-density-weighted gradient-echo
pulse sequence. We demonstrate the utility of this paramagnetic nanoemulsion
as an in vivo MRI probe for detecting inflammation
macrophages in mice. Overall, these paramagnetic PFC compounds represent
a platform for the development of sensitive 19F probes.