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

Kriti Srivastava, Evan A. Weitz, Katie L. Peterson, Małgorzata Marjańska, Valérie C. Pierre

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


A series of fluorinated macrocyclic complexes, M-DOTAm-F12, where M is LaIII, EuIII, GdIII, TbIII, DyIII, HoIII, ErIII, TmIII, YbIII, and FeII, 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 HoIII and FeII, and to a lesser extent TmIII and YbIII. 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, HoIII-DOTAm-F12, could not be detected in blood. TmIII yielded the most sensitive lanthanide fluorine probe in blood. Notably, the relaxation times of the fluorine nuclei of FeII-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.

Original languageEnglish (US)
Pages (from-to)1546-1557
Number of pages12
JournalInorganic chemistry
Issue number3
StatePublished - Feb 6 2017

Bibliographical note

Funding Information:
This work was supported by the National Science Foundation Grant No. CAREER 1151665 and by the NIH Clinical and Translational Science Award at the Univ. of Minnesota (8UL1TR000114), the NIBIB (P41 EB015894 and P30 NS076408) of the National Institutes of Health, and the W. M. Keck Foundation. Support to E.A.W. through a Wayland E. Noland Fellowship from the Dept. of Chemistry of the Univ. of Minnesota and to K.L.P. from the NIH?CBITG (GM 08700) and through a Dosdall fellowship are gratefully acknowledged. We thank L. J. Clouston and V. G. Young Jr. for X-ray crystallography, including data collection and structure solution and refinement.

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