Design, Characterization and Molecular Modeling of New Fluorinated Paramagnetic Contrast Agents for Dual 1H/19F MRI

Abstract

One major goal in medical imaging is the elaboration of more efficient contrast agents (CAs). Those agents need to be optimized for the detection of affected tissues such as cancers or tumors while decreasing the injected quantity of agents. The paramagnetic contrast agents containing fluorine atoms can be used for both proton and fluorine magnetic resonance imaging (MRI), and they open the possibility of simultaneously mapping the anatomy using 1H MRI and accurately locating the agents using 19F MRI. One of the challenges in this domain is to synthesize molecules containing several chemically equivalent fluorine atoms with relatively short relaxation times to allow the recording of 19F MR images in good conditions. With that aim, we propose to prepare a CA containing a paramagnetic center and nine chemically equivalent fluorine atoms using a cycloaddition reaction between two building blocks. These fluorinated contrast agents are characterized by 19F NMR, showing differences in the fluorine relaxation times T1 and T2 depending on the lanthanide ion. To complement the experimental results, molecular dynamics simulations are performed to shed light on the 3D-structure of the molecules in order to estimate the distance between the lanthanide ion and the fluorine atoms.

19F MRI Probes for Multimodal Imaging**

“…All reported 1 H/ 19 F dual contrasts featured very stable lanthanide complexes of cyclen‐based ligands containing 3–9 equivalent F atoms (Figure 28). Reported metal‐fluorine distances were in the range 4.5–10 Å [5,85] . Each probe allowed a short transverse relaxation time of the 19 F nuclei and demonstrated a low signal‐to‐noise ratio in 19 F NMR/MRI.…”

“…Reported metal-fluorine distances were in the range 4.5-10 Å. [5,85] Each probe allowed a short transverse relaxation time of the 19 F nuclei and demonstrated a low signal-to-noise ratio in 19 F NMR/MRI. Typically Gd(III) compounds were used but Dy(III), Tb(III) and Yb(III) also displayed favorable 19 F relaxation properties producing good contrast without special acquisition sequences.…”

“…Typically Gd(III) compounds were used but Dy(III), Tb(III) and Yb(III) also displayed favorable 19 F relaxation properties producing good contrast without special acquisition sequences. [85,86] On the other hand, only Gd(III) produced sufficient 1 H contrast. [85] The complexes could be observed at concentrations as low as 0.1 mM for either 1 H or 19 F images.…”

Recent Progress in Lipid Nanoparticles for Cancer Theranostics: Opportunity and Challenges

“…Furthermore, with 19 F in vivo tracing and imaging can be accomplished without any background signals created by endogenous fluorine. Nonetheless, there has been a limitation with fluorine as its large concentration (10-50 millimolar) is needed for adequate signal intensity in comparison to other contrast agents [27].…”

Fluorescent Submicron-Sized Poly(heptafluoro-n-butyl methacrylate) Particles with Long-Term Stability

“…Fluorinated composites with graphene have been used as possible insulators for flexible electronics [30]. Hybrid nanostructures based on fluorinated nanometer-sized silica particles have been proposed as a new material for self-cleaning, stain-resistant, nonfouling, abrasion-resistant coatings [31]. Molecules with 19F substituents are particularly attractive for use in drug tracking by 19F magnetic resonance imaging (MRI) because they produce no background signal in biological samples [32].…”