Fe- and Ln-DOTAm-F12 Are Effective Paramagnetic Fluorine Contrast Agents for MRI in Water and Blood

A series of fluorinated macrocyclic complexes, M-DOTAm-F12, where M is La-III, Eu-III, Tb-III, Dy-III, Ho-III, Er-III, Tm-III, and Fe-III, was synthesized, and their potential as fluorine magnetic resonance imaging (MRI) contrast agents was evaluated. The high water solubility of these complexes and the presence of a single fluorine NMR signal, two necessary parameters for in vivo MRI, are substantial advantages over currently used organic polyfluorocarbons and other reported paramagnetic F-19 probes. Importantly, the sensitivity of the paramagnetic probes on a per fluorine basis is at least 1 order of magnitude higher than that of diamagnetic organic probes. This increased sensitivity is due to a substantial up to 100-fold- decrease in the longitudinal relaxation time (T-1) of the fluorine nuclei. The shorter T-1 allows for a greater number of scans to be obtained in an equivalent time frame. The sensitivity of the fluorine probes is proportional to the T-2/T-1 ratio. In water, the optimal metal complexes for imaging applications are those containing Ho-III and Fe-III, and to a lesser extent Tm-III and Yb-III. -Whereas T-1 of the lanthanide complexes are little affected by blood, the T-2 are notably shorter in blood than in water. The sensitivity of Ln-DOTAm-F12 complexes is lower in blood than in water, such that the most sensitive complex in water, Ho-III-DOTAm-F12, could not be detected in blood. Tm-III yielded the most sensitive lanthanide fluorine probe in blood. Notably, the relaxation times of the fluorine nuclei of Fe-II-DOTAm-F12 are similar in water and in blood. That complex has the highest T-2/T-1 ratio (0.57) and the lowest limit of detection (300 mu M) in blood. The combination of high water solubility, single fluorine signal, and high T-2/T-1 of M-DOTAm-F12 facilitates the acquisition of three-dimensional magnetic resonance images.