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

Abstract

A series of fluorinated macrocyclic complexes, M-DOTAm-F12, where M is La^III, Eu^III, Gd^III, Tb^III, Dy^III, Ho^III, Er^III, Tm^III, Yb^III, and Fe^II, 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 ¹⁹F 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 (T₁) of the fluorine nuclei. The shorter T₁ 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 T₂/T₁ ratio. In water, the optimal metal complexes for imaging applications are those containing Ho^III and Fe^II, and to a lesser extent Tm^III and Yb^III. Whereas T₁ of the lanthanide complexes are little affected by blood, the T₂ 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 T₂/T₁ ratio (0.57) and the lowest limit of detection (300 μM) in blood. The combination of high water solubility, single fluorine signal, and high T₂/T₁ of M-DOTAm-F12 facilitates the acquisition of three-dimensional magnetic resonance images.