Rigid M^IIL₂Gd₂^III (M = Fe, Ru) Complexes of a Terpyridine-Based Heteroditopic Chelate:  A Class of Candidates for MRI Contrast Agents

Abstract

Rigid chelates of high-molecular weight, [M(tpy-DTTA)2]6- (M = Fe, Ru), are obtained upon self-assembly around one M(II) ion of two terpyridine-based molecules substituted in the 4'-position with the polyaminocarboxylate diethylenetriamine-N,N,N'',N''-tetraacetate, tpy-DTTA4-. The protonation constants of tpy-DTTA4- (log K1 = 8.65(4), log K2 = 7.63(4), log K3 = 5.25(6), log K4 = 3.30(7)) and [Fe(tpy-DTTA)2]6- (log K1 = 8.40(4), log K2 = 7.26(4)) have been determined by potentiometry, 1H NMR and UV-vis titrations. The thermodynamic stability constant log K(GdL) of [Fe(tpy-DTTA)2Gd2(H2O)4] measured at 25 degrees C by potentiometry is 10.87. This relatively low value is due to the direct linkage of the polyaminocarboxylate part to the electron-withdrawing terpyridine. UV-vis absorbance spectra of [M(tpy-DTTA)2Gd2(H2O)4] and 1H NMR spectra of [M(tpy-DTTA)2Eu2(H2O)4] revealed similar solution behavior of the Fe and Ru complexes. An I(d) water-exchange mechanism (DeltaV++ = +6.8 +/- 1 cm3 mol(-1)) with a rate constant of k(ex)298 = (5.1 +/- 0.3) x 10(6) s(-1) has been found for [Fe(tpy-DTTA)2Gd2(H2O)4] by 17O NMR. A slow rotational correlation time (tau(RO) = 410 +/- 10 ps) and the presence of two water molecules (q = 2) in the coordination inner-sphere of each Gd(III) ion have also been determined for this complex. A remarkably high relaxivity has been observed for both [M(tpy-DTTA)2Gd2(H2O)4] complexes (at 20 MHz and 37 degrees C, r(1) = 15.7 mM(-1) s(-1) for the Fe complex, and r(1) = 15.6 mM(-1) s(-1) for the Ru complex).

A Starburst‐Shaped Heterometallic Compound Incorporating Six Densely Packed Gd3+ Ions

“…[27] The stability constant of the Gd III complex of our ligand is remarkably higher than that with tpy-DTTA 4À , [19] which can be mainly ascribed to the different basicities of the central nitrogens. The log b value is comparable to that reported for…”

“…However, since there is a methylene linking group between the poly(amino carboxylate) and the bipyridine, the basicity decrease of this central nitrogen as compared to that in DTPA 5À is much more limited than in the case of the tpy-DTTA 4À ligand, in which the aromatic ring is directly attached to the amine nitrogen. [19] Consequently, one would expect a higher stability constant for the Gd…”

“…The ratio of the two rotational correlation times t lH /t lO was generally found to be~0.65 for monohydrated complexes, [37,38] while for bishydrated chelates, values close to 1 were obtained from the simultaneous fitting of longitudinal 17 O and 1 H relaxation rates. [19,39] Finally, a model-independent measure of the spatial restriction of the local motion is given by the generalized order parameter, S…”

“…Self-assembling systems previously studied in the context of MRI contrast agents. [17,19] Metallostars are by definition first-generation metallodendrimers. [21] Usually, only compounds having a core connectivity of three or greater are considered, which excludes topologically linear dinuclear and trinuclear systems.…”

High‐Relaxivity MRI Contrast Agents: Where Coordination Chemistry Meets Medical Imaging

“…Examples of dinuclear, q = 2 DTPA-based Gd III complexes proposed as improved high-relaxivity MRI contrast agents. [38,39] While the relaxometric properties of such q = 2 compounds are improved, the thermodynamic chelate stability suffers greatly in both cases. The increase in q ( Figure 5) from one to two is made possible by removing one carboxylate arm of the parent DTPA to open up a metal coordination site.…”