title: 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 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 paramagnetic19F 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 T1allows 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/T1ratio. In water, the optimal metal complexes for imaging applications are those containing HoIIIand FeII, and to a lesser extent TmIIIand YbIII. Whereas T1of the lanthanide complexes are little affected by blood, the T2are 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. TmIIIyielded 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/T1ratio (0.57) and the lowest limit of detection (300 μM) in blood. The combination of high water solubility, single fluorine signal, and high T2/T1of M-DOTAm-F12 facilitates the acquisition of three-dimensional magnetic resonance images.
authors.affiliation: Department of Chemistry and ‡Center for Magnetic Resonance Research and Department of Radiology, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Kriti
authors.initials: K
authors.lastname: Srivastava
authors.affiliation: Department of Chemistry and ‡Center for Magnetic Resonance Research and Department of Radiology, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Evan A
authors.initials: EA
authors.lastname: Weitz
authors.affiliation: Department of Chemistry and ‡Center for Magnetic Resonance Research and Department of Radiology, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Katie L
authors.initials: KL
authors.lastname: Peterson
authors.affiliation: Department of Chemistry and ‡Center for Magnetic Resonance Research and Department of Radiology, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Marjańska
authors.affiliation: Department of Chemistry and ‡Center for Magnetic Resonance Research and Department of Radiology, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Valérie C
authors.identifier: http://orcid.org/0000-0002-0907-8395
authors.initials: VC
authors.lastname: Pierre
mesh_terms: D003287:Contrast Media / Q000138:chemical synthesis / Q000737:chemistry*; D056831:Coordination Complexes / Q000097:blood* / Q000138:chemical synthesis / Q000737:chemistry*; D005461:Fluorine / Q000097:blood / Q000737:chemistry; D006801:Humans; D007501:Iron / Q000097:blood / Q000737:chemistry; D028581:Lanthanoid Series Elements / Q000097:blood / Q000737:chemistry; D008279:Magnetic Resonance Imaging; D015394:Molecular Structure; D012995:Solubility; D014867:Water / Q000737:chemistry
chemical_list: D003287:Contrast Media; D056831:Coordination Complexes; D028581:Lanthanoid Series Elements; D014867:Water; D005461:Fluorine; D007501:Iron