Low-molecular-weight paramagnetic 19F contrast agents for fluorine magnetic resonance imaging

Objective

¹⁹F MRI requires biocompatible and non-toxic soluble contrast agents with high fluorine content and with suitable ¹⁹F relaxation times. Probes based on a DOTP chelate with 12 magnetically equivalent fluorine atoms (DOTP-tfe) and a lanthanide(III) ion shortening the relaxation times were prepared and tested.

Methods

Complexes of DOTP-tfe with trivalent paramagnetic Ce, Dy, Ho, Tm, and Yb ions were synthetized and characterized. ¹⁹F relaxation times were determined and compared to those of the La complex and of the empty ligand. In vitro and in vivo ¹⁹F MRI was performed at 4.7 T.

Results

¹⁹F relaxation times strongly depended on the chelated lanthanide(III) ion. T₁ ranged from 6.5 to 287 ms, T₂ from 3.9 to 124.4 ms, and T₂* from 1.1 to 3.1 ms. All complexes in combination with optimized sequences provided sufficient signal in vitro under conditions mimicking experiments in vivo (concentrations 1.25 mM, 15-min scanning time). As a proof of concept, two contrast agents were injected into the rat muscle; ¹⁹F MRI in vivo confirmed the in vivo applicability of the probe.

Conclusion

DOTP-based ¹⁹F probes showed suitable properties for in vitro and in vivo visualization and biological applications. The lanthanide(III) ions enabled us to shorten the relaxation times and to trim the probes according to the actual needs. Similar to the clinically approved Gd³⁺ chelates, this customized probe design ensures consistent biochemical properties and similar safety profiles.