Rigid MIIL2Gd2III (M = Fe, Ru) complexes of a terpyridine-based heteroditopic chelate: a class of candidates for MRI contrast agents.

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).

Rotational dynamics account for pH-dependent relaxivities of PAMAM dendrimeric, Gd-based potential MRI contrast agents.

The EPTPA5) chelate, which ensures fast water exchange in GdIII complexes, has been coupled to three different generations (5, 7, and 9) of polyamidoamine (PAMAM) dendrimers through benzylthiourea linkages (H5EPTPA = ethylenepropylenetriamine-N,N,N',N'',N''-pentaacetic acid). The proton relaxivities measured at pH 7.4 for the dendrimer complexes G5-(GdEPTPA)111, G7-(GdEPTPA)253 and G9-(GdEPTPA)1157 decrease with increasing temperature, indicating that, for the first time for dendrimers, slow water exchange does not limit relaxivity. At a given field and temperature, the relaxivity increases from G5 to G7, and then slightly decreases for G9 (r1 = 20.5, 28.3 and 27.9 mM(-1) s(-1), respectively, at 37 degrees C, 30 MHz). The relaxivities show a strong and reversible pH dependency for all three dendrimer complexes. This originates from the pH-dependent rotational dynamics of the dendrimer skeleton, which was evidenced by a combined variable-temperature and multiple-field 17O NMR and 1H relaxivity study performed at pH 6.0 and 9.9 on G5-(GdEPTPA)111. The longitudinal 17O and 1H relaxation rates of the dendrimeric complex are strongly pH-dependent, whereas they are not for the [Gd(EPTPA)(H2O)]2- monomer chelate. The longitudinal 17O and 1H relaxation rates have been analysed by the Lipari-Szabo spectral density functions and correlation times have been calculated for the global motion of the entire macromolecule (tau(gO)) and the local motion of the GdIII chelates on the surface (tau(lO)), correlated by means of an order parameter S2. The dendrimer complex G5-(GdEPTPA)111 has a considerably higher tau(gO) under acidic than under basic conditions (tau(298)gO = 4040 ps and 2950 ps, respectively), while local motions are less influenced by pH (tau(298)lO = 150 and 125 ps). The order parameter, characterizing the rigidity of the macromolecule, is also higher at pH 6.0 than at pH 9.9 (S2 = 0.43 vs 0.36, respectively). The pH dependence of the global correlation time can be related to the protonation of the tertiary amine groups in the PAMAM skeleton, which leads to an expanded and more rigid dendrimeric structure at lower pH. The increase of tau(gO) with decreasing pH is responsible for the pH dependent proton relaxivities. The water exchange rate on G5-(GdEPTPA)111(k(298)ex = 150 x 10(6) s(-1)) shows no significant pH dependency and is similar to the one measured for the monomer [Gd(EPTPA)(H2O)]2-. The proton relaxivity of G5-(GdEPTPA)111 is mainly limited by the important flexibility of the dendrimer structure, and to a small extent, by a faster than optimal water exchange rate.

Kinetics of formation and dissociation of lanthanide(III) complexes with the 13-membered macrocyclic ligand TRITA4-.

The tetraazamacrocyclic ligand TRITA(4-) is intermediate in size between the widely studied and medically used 12-membered DOTA(4-) and the 14-membered TETA(4-). The kinetic inertness of GdTRITA(-) was characterized by the rates of exchange reactions with Zn(2+) and Eu(3+). In the Zn(2+) exchange, a second order [H(+)] dependence was found for the pseudo-first-order rate constant (k(0)=(4.2 +/- 0.5) x 10(-7) s(-1); k'=(3.5 +/- 0.3) x 10(-1) M(-1)s(-1), k" =(1.4 +/- 0.4) x 10(3) M(-2)s(-1)). In the Eu(3+) exchange, at pH <5 the rate decreases with increasing concentration of the exchanging ion, which can be accounted for by the transitional formation of dinuclear GdTRITAEu(2+) species. At physiological pH, the kinetic inertness of GdTRITA(-) is considerably lower than that of GdDOTA(-)(t(1/2)= 444 h (25 degrees C) vs. 3.8 x 10(5) h (37 degrees C), respectively). However, GdTRITA(-) is still kinetically more inert than GdDTPA(2-), the most commonly used MRI contrast agent (t(1/2)= 127 h). The formation reactions of LnTRITA(-) complexes (Ln = Ce, Gd and Yb) proceed via the rapid formation of a diprotonated intermediate and its subsequent deprotonation and rearrangement in a slow, OH(-) catalyzed process. The stability of the LnH(2)TRITA* intermediates (log K(LnH2L*)= 3.1-3.9) is lower than that of the DOTA-analogues. The rate constants of the OH(-) catalyzed step increase with decreasing lanthanide ion size, and are about twice as high as for DOTA-complexes.

Novel heteroditopic chelate for self-assembled gadolinium(III) complex with high relaxivity.

[Fe(tpy-DTTA)(2)Gd(2)] is a self-assembled trinuclear complex based on a novel ligand in which a terpyridine and a poly(amino carboxylate) moiety are connected; it has a well-defined topology with favourable features to attain high relaxivities, i.e. a rigid Fe(II)(tpy)(2) core, reduced flexibility at the periphery thanks to a short linker, and efficient separation of the two Gd(III) centres.

GdIII complexes with fast water exchange and high thermodynamic stability: potential building blocks for high-relaxivity MRI contrast agents.

On the basis of structural considerations in the inner sphere of nine-coordinate, monohydrated Gd(III) poly(aminocarboxylate) complexes, we succeeded in accelerating the water exchange by inducing steric compression around the water binding site. We modified the common DTPA(5-) ligand (DTPA=(diethylenetriamine-N,N,N',N",N"-pentaacetic acid) by replacing one (EPTPA(5-)) or two (DPTPA(5-)) ethylene bridges of the backbone by propylene bridges, or one coordinating acetate by a propionate arm (DTTA-prop(5-)). The ligand EPTPA(5-) was additionally functionalized with a nitrobenzyl linker group (EPTPA-bz-NO(2) (5-)) to allow for coupling of the chelate to macromolecules. The water exchange rate, determined from a combined variable-temperature (17)O NMR and EPR study, is two orders of magnitude higher on [Gd(eptpa-bz-NO(2))(H(2)O)](2-) and [Gd(eptpa)(H(2)O)](2-) than on [Gd(dtpa)(H(2)O)](2-) (k(ex)298=150x10(6), 330x10(6), and 3.3x10(6) s(-1), respectively). This is optimal for attaining maximum proton relaxivities for Gd(III)-based, macrocyclic MRI contrast agents. The activation volume of the water exchange, measured by variable-pressure (17)O NMR spectroscopy, evidences a dissociative interchange mechanism for [Gd(eptpa)(H(2)O)](2-) (DeltaV(not equal sign)=(+6.6+/-1.0) cm(3) mol(-1)). In contrast to [Gd(eptpa)(H(2)O)](2-), an interchange mechanism is proved for the macrocyclic [Gd(trita)(H(2)O)](-) (DeltaV (not equal sign)=(-1.5+/-1.0) cm(3) mol(-1)), which has one more CH(2) group in the macrocycle than the commercial MRI contrast agent [Gd(dota)(H(2)O)](-), and for which the elongation of the amine backbone also resulted in a remarkably fast water exchange. When one acetate of DTPA(5-) is substituted by a propionate, the water exchange rate on the Gd(III) complex increases by a factor of 10 (k(ex)298=31x10(6) s(-1)). The [Gd(dptpa)](2-) chelate has no inner-sphere water molecule. The protonation constants of the EPTPA-bz-NO(2) (5-) and DPTPA(5-) ligands and the stability constants of their complexes with Gd(III), Zn(II), Cu(II) and Ca(II) were determined by pH potentiometry. Although the thermodynamic stability of [Gd(eptpa-bz-NO(2))(H(2)O)](2-) is reduced to a slight extent in comparison with [Gd(dtpa)(H(2)O)](2-), it is stable enough to be used in medical diagnostics as an MRI contrast agent. Therefore both this chelate and [Gd(trita)(H(2)O)](-) are potential building blocks for the development of high-relaxivity macromolecular agents.

Accelerating water exchange for GdIII chelates by steric compression around the water binding site.

The water exchange process was accelerated for nine-coordinate, monohydrated macrocyclic GdIII complexes by inducing steric compression around the water binding site; the increased steric crowding was achieved by replacing an ethylene bridge of DOTA4- by a propylene bridge; in addition to the optimal water exchange rate, the stability of [Gd(TRITA)(H2O)]- is sufficiently high to ensure safe medical use which makes it a potential synthon for the development of high relaxivity, macromolecular MRI contrast agents.