Abstract

The heterotritopic ligand [bpy(DTTA)2]8- has two diethylenediamine-tetraacetate units for selective lanthanide(III) coordination and one bipyridine function for selective FeII coordination. In aqueous solution and in the presence of these metals, the ligand is capable of self-assembly to form a rigid supramolecular metallostar structure, {Fe[Gd2bpy(DTTA)2(H2O)4]3}4-. We report here the physicochemical characterization of the dinuclear complex [Gd2bpy(DTTA)2(H2O)4]2- and the metallostar {Fe[Gd2bpy(DTTA)2(H2O)4]3}4- with regard to potential MRI contrast agent applications. A combination of pH potentiometry and 1H NMR spectroscopy has been used to determine protonation constants for the ligand [bpy(DTTA)2]8- and for the complexes [Fe{bpy(DTTA)2}3]2- and [Y2bpy(DTTA)2]2-. In addition, stability constants have been measured for the dinuclear chelates [M2bpy(DTTA)2]n- formed with M = Gd3+ and Zn2+ (log KGdL = 18.2; log KZnL = 18.0; log KZnHL = 3.4). A multiple field, variable-temperature 17O NMR and proton relaxivity study on [Gd2bpy(DTTA)2(H2O)4]2- and {Fe[Gd2bpy(DTTA)2(H2O)4]3}4- yielded the parameters for water exchange and the rotational dynamics. The 17O chemical shifts are indicative of bishydration of the lanthanide ion. The exchange rates of the two inner-sphere water molecules are very similar in the dinuclear [Gd2bpy(DTTA)2(H2O)4]2- and in the metallostar (kex298 = 8.1+/-0.3 x 10^6 and 7.4+/-0.2 x 10^6 s-1, respectively), and are comparable to kex298 for similar GdIII poly(amino carboxylates). The rotational dynamics of the metallostar has been described by means of the Lipari-Szabo approach, which involves separating global and local motions. The difference between the local and global rotational correlation times, lO298 = 190�15 ps and gO298 = 930+/-50 ps, respectively, shows that the metallostar is not completely rigid. However, the relatively high value of S2 = 0.60+/-0.04, describing the restriction of the local motions with regard to the global one, points to a limited flexibility compared with previously reported macromolecules such as dendrimers. As a result of the two inner-sphere water molecules, with their near-optimal exchange rate, and the limited flexibility, the metallostar has a remarkable molar proton relaxivity, particularly at high magnetic fields (r1 = 33.2 and 16.4 mM-1 s-1 at 60 and 200 MHz, respectively, at 25 �C). It packs six efficiently relaxing GdIII ions into a small molecular space, which leads, to the best of our knowledge, to the highest relaxivity per molecular mass ever reported for a GdIII complex. The [bpy(DTTA)2]8- ligand is also a prime candidate as a terminal ligand for constructing larger sized, FeII (or RuII)-based metallostars or metallodendrimers loaded with GdIII on the surface.

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