Paramagnetic, fluorinated and water-soluble metal complexes for 19F MRI

19F MRI relies mainly on the use of fluorine-dense perfluorocarbon nanoemulsions. However, poor water solubility, limited stability, droplet heterogeneity, rigorous liver accumulation of the particles, as well as the relatively long fluorine relaxation times often limit their applicability. Fe(III) and Mn(II) have the most advantageous paramagnetic properties to shorten T1 relaxation time of 19F without strong line-broadening T2 effect, deleterious for 19F MRI detection. The combination of these paramagnetic metal ions with small molecular weight ligands containing maximized number of magnetically equivalent fluorine atoms is proposed here to circumvent the problems associated with perfluorocarbon nanoemulsions. We will create complexes that provide high thermodynamic stability and kinetic inertness important for safe biological application, good water solubility, as well as short 19F T1 relaxation time, allowing for fast MRI scans and high signal to noise ratio. A series of open-chain and macrocyclic ligands will be synthetized and their Mn(II) and Fe(III) complexes characterized with respect to their application as 19F MRI agents (water solubility, thermodynamic and kinetic stability, 19F relaxation properties). Structural variations of the ligands will allow for optimizing the 19F-metal distance for optimized relaxation effect. For a proof of concept cell labelling study, we will choose dendritic cells (DC) and T lymphocytes (TL), two cell types frequently used for adoptive cell transfer strategies in oncology. Cytotoxicity and cell labelling capacity of the probes will be assessed and in vitro MRI phantom images will be acquired on cells labelled with the paramagnetic complexes.