Fe(III)-Templated Gd(III) Self-AssembliesA New Route toward Macromolecular MRI Contrast Agents

Abstract

The Solomon-Bloembergen-Morgan theory predicts that the longitudinal relaxivity of a small Gd(III) complex, r 1p , increases upon slowing down its rotational correlation time. This is usually achieved by grafting the complex onto a macromolecule. Previous efforts in designing such macromolecules have concentrated on the synthesis of dendrimeric analogues and covalent or reversible protein conjugates. 2 These studies demonstrated the necessity not only of attaining fast water exchange but also of creating rigid systems in attaining high relaxivity agents. 3 Surprisingly there has been little study of supramolecular self-assemblies. These complexes, however, present several advantages as their synthesis require fewer steps and they can be highly rigid. Although several mixed f block/d block self-assemblies have already been described, 4 the macromolecular MRI contrast agents studied have been only Gd(III) chelates grafted onto tris-bidentate Fe(III) complexes. 5 However, these do not constitute true supramolecular self-assemblies 6 in that in each case the Gd(III) complexes were already completely synthesized prior to building the macromolecule.Herein we describe our approach to Gd(III)-containing supramolecular self-assemblies using Fe(III) as a template. Bis-bidentate ligands were designed comprising two different binding sites, one more selective for Gd(III) and the other for Fe(III). It has previously been shown (Figure 1) that Gd(III) is selective for 1-methyl-2,3-dihydroxypyridinone (HOPO) over 2,3-dihydroxyterephthalamide (TAM) (pGd TREN-trisHOPO = 19.2, pGd TREN-trisTAM < 13) 7 whereas Fe(III) is selective for TAM over HOPO (pFe TREN-trisHOPO = 26.8, pFe TREN-trisTAM = 34.2). 8,9 It was therefore predicted that three bis-bidentate ligands each comprising both one HOPO and one TAM moiety would coordinate both one Gd(III) and one Fe(III).In the complexes studied (Figure 2), each ligand contains one TAM moiety (for Fe(III) coordination) linked to either one or two HOPO moieties (for Gd(III) coordination) through a three-carbon linker. This linker has been shown to favor the formation of triple-stranded helicates. 10 In Fe,Gd-L1, the three strands are joined by a TREN backbone, while in the other two complexes Fe,Gd-3L2 and Fe,2Gd-3L3, they are left free to self-assemble (or raymond@socrates.berkeley.edu. Supporting Information Available: Detailed experimental procedures and characterization data for the synthesis of the complexes Fe,Gd-L A , Fe,Gd-3L B and Fe,2Gd-3L C ; pH-dependence of the selectivity of Fe(III) for TAM over HOPO ligands; inner-and outersphere contributions to the NMRD profiles of the assemblies; MM3 energy minimization of the assemblies. This information is available free of charge via the internet at http://pubs.acs.org. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript not). All complexes are −3 charged. In Fe,Gd-3L2, a small PEG chain was grafted for increased water solubility.The mixed complexes were synthesized in six, four, and three steps, r...

Structure, Dynamics, and Computational Studies of Lanthanide‐Based Contrast Agents

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Graphene oxide-Fe3O4 nanoparticle composite with high transverse proton relaxivity value for magnetic resonance imaging

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1,2-Hydroxypyridonates as Contrast Agents for Magnetic Resonance Imaging: TREN-1,2-HOPO

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