The heterotritopic ligand [bpy(DTTA)2]8- has two diethylenediamine-tetraacetate units for selective lanthanide(III) coordination and one bipyridine function for selective Fe(II) 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]22- 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 K(GdL) = 18.2; log K(ZnL) = 18.0; log K(ZnHL) = 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 (k(ex)298 = 8.1 +/- 0.3 x 10(6) and 7.4 +/- 0.2 x 10(6) s(-1), respectively), and are comparable to k(ex)298 for similar Gd(III) 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, tau(lO)298 = 190 +/- 15 ps and tau(gO)298 = 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 degrees C). It packs six efficiently relaxing Gd(III) 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 Gd(III) complex. The [bpy(DTTA)2]8- ligand is also a prime candidate as a terminal ligand for constructing larger sized, Fe(II) (or Ru(II))-based metallostars or metallodendrimers loaded with Gd(III) on the surface.

CommunicationsSelf-assembly of a poly(aminocarboxylate)-bipyridine ligand L with Fe II and Gd III ions gives rise to a stable metallostar structure [Fe{GdL(H 2 O) 2 } 3 ] 4À that displays a remarkable relaxivity. In their Communication on the following pages, E. Tóth and co-workers discuss the properties of this complex with regards to its application as an MRI contrast agent.

A novel ligand, H(12)L, based on a trimethylbenzene core bearing three methylenediethylenetriamine-N,N,N'',N''-tetraacetate moieties (-CH(2)DTTA(4-)) for Gd(3+) chelation has been synthesized, and its trinuclear Gd(3+) complex [Gd(3)L(H(2)O)(6)](3-) investigated with respect to MRI contrast agent applications. A multiple-field, variable-temperature (17)O NMR and proton relaxivity study on [Gd(3)L(H(2)O)(6)](3-) yielded the parameters characterizing water exchange and rotational dynamics. On the basis of the (17)O chemical shifts, bishydration of Gd(3+) could be evidenced. The water exchange rate, k(ex)(298)=9.0+/-3.0 s(-1) is around twice as high as k(ex)(298) of the commercial [Gd(DTPA)(H(2)O)](2-) and comparable to those on analogous Gd(3+)-DTTA chelates. Despite the relatively small size of the complex, the rotational dynamics had to be described with the Lipari-Szabo approach, by separating global and local motions. The difference between the local and global rotational correlation times, tau(lO)(298)=170+/-10 ps and tau(gO)(298)=540+/-100 ps respectively, shows that [Gd(3)L(H(2)O)(6)](3-) is not fully rigid; its flexibility originates from the CH(2) linker between the benzene core and the poly(amino carboxylate) moiety. As a consequence of the two inner-sphere water molecules per Gd(3+), their close to optimal exchange rate and the appropriate size and limited flexibility of the molecule, [Gd(3)L(H(2)O)(6)](3-) has remarkable proton relaxivities when compared with commercial contrast agents, particularly at high magnetic fields (r(1)=21.6, 17.0 and 10.7 mM(-1)s(-1) at 60, 200 and 400 MHz respectively, at 25 degrees C; r(1) is the paramagnetic enhancement of the longitudinal water proton relaxation rate, referred to 1 mM concentration of Gd(3+)).

À ¼ GdDOTA). The metallostar was well tolerated by the animals at the concentrations of 0.0500 (high dose) and 0.0125 (low dose) mmol Gd kg À1 body weight; (BW). The signal enhancement in the inversion recovery fast low angle shot (IR FLASH) images after the high-dose metallostar injection was considerably higher than after GdDOTA injection (0.1 mmol Gd kg À1 BW), despite the higher dose of the latter. The high-dose metallostar injection resulted in a greater drop in the spin-lattice relaxation time (T 1 ), as calculated from the inversion recovery true fast imaging with steady-state precession (IR TrueFISP) data for various tissues, than the GdDOTA or the low dose metallostar injection. In summary, these studies have confirmed that the approximately four times higher relaxivity measured in vitro for the metallostar is retained under in vivo conditions. The pharmacokinetics of the metallostar was found to be similar to that of GdDOTA, involving fast renal clearance, a leakage to the extracellular space in the muscle tissue and no leakage to the brain. As expected on the basis of its moderate molecular weight, the metallostar does not function as a blood pool agent. The dynamic g scintigraphic studies performed in Wistar rats with the metallostar compound having 153 Sm enrichment also proved the renal elimination pathway. The biodistribution experiments are in full accordance with the MR and scintigraphic imaging. At 15 min post-injection the activity is primarily localized in the urine, while at 24 h post-injection almost all radioactivity is cleared from tissues and organs.

Klein, aber oho: Der Metallosternkomplex [Fe{Gd2L(H2O)4}3]4− (siehe Bild; L ist ein Bipyridin‐Poly(aminocarboxylat)‐Ligand) weist eine für seine recht geringe Molekülmasse außergewöhnlich hohe Protonenrelaxivität auf. Erklärt wird dies mit einer starren supramolekularen Struktur, zwei Wassermolekülen in der inneren Sphäre mit nahezu optimaler Austauschgeschwindigkeit und sechs effizient relaxierenden, räumlich eng benachbarten GdIII‐Zentren.

Gd(3)L is a trinuclear Gd(3+) complex of intermediate size, designed for contrast agent applications in high field magnetic resonance imaging (H(12)L is based on a trimethylbenzene core bearing three methylene-diethylenetriamine- N,N,N'',N''-tetraacetate moieties). Thanks to its appropriate size, the presence of two inner sphere water molecules and a fast water exchange, Gd(3)L has remarkable proton relaxivities at high magnetic field (r(1) = 10.2 vs 3.0 mM(-1) s(-1) for GdDOTA at 9.4 T, 37 degrees C, in H(2)O). Here we report an in vivo MRI feasibility study, complemented with dynamic gamma scintigraphic imaging and biodistribution experiments using the (153)Sm-enriched analog. MRI experiments were performed at 9.4 T in mice with Gd(3)L and the commercial contrast agent gadolinium(III)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate (GdDOTA). Gd(3)L was well tolerated by the animals at the dose of 8 micromol Gd kg(-1) body weight. Dynamic contrast enhanced (DCE) images showed considerably higher signal enhancement in the kidney medulla and cortex after Gd(3)L injection than after GdDOTA injection at an identical dose. The relaxation rates, DeltaR(1), were calculated from the IR TrueFISP data. During the excretory phase, the DeltaR(1) for various tissues was similar for Gd(3)L and GdDOTA, when the latter was injected at a three-fold higher dose (24 vs 8 micromol Gd kg(-1) body weight). These results point to an approximately three times higher in vivo relaxivity (per Gd) for Gd(3)L relative to GdDOTA, thus the ratio of the relaxivities of the two compounds determined in vitro is retained under in vivo conditions. They also indicate that the two inner sphere water molecules per Gd in Gd(3)L are not substantially replaced by endogenous anions or other donor groups under physiological conditions. Gd(3)L has a pharmacokinetics typical of small, hydrophilic complexes, involving fast renal clearance and no retention in the blood pool. The dynamic gamma scintigraphic studies and the biodistribution experiments performed in Wistar rats with (153)Sm-enriched (*)Sm(3)L are also indicative of a fast elimination via the kidneys.

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