Water Exchange and Rotational Dynamics of the Dimeric Gadolinium(III) Complex [BO{Gd(DO3A)(H₂O)}₂]:  A Variable-Temperature and -Pressure ¹⁷O NMR Study¹

Abstract

Rapid water exchange and slow rotation are essential for high relaxivity MRI contrast agents. A variable-temperature and -pressure (17)O NMR study at 14.1, 9.4, and 1.4 T has been performed on the dimeric BO(DO3A)(2), 2,11-dihydroxy-4,9-dioxa-1,12-bis[1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)cyclododecyl]dodecane, complex of Gd(III). This complex is of relevance to MRI as an attempt to gain higher (1)H relaxivity by slowing down the rotation of the molecule compared to monomeric Gd(III) complexes used as contrast agents. From the (17)O NMR longitudinal and transverse relaxation rates and chemical shifts we determined the parameters characterizing water exchange kinetics and the rotational motion of the complex, both of which influence (1)H relaxivity. The rate constant and the activation enthalpy for the water exchange, k(ex) and DeltaH(), are (1.0 +/- 0.1) x 10(6) s(-)(1)and (30.0 +/- 0.2) kJ mol(-)(1), respectively, and the activation volume, DeltaV(), of the process is (+0.5 +/- 0.2) cm(3) mol(-)(1), indicating an interchange mechanism. The rotational correlation time becomes about three times longer compared to monomeric Gd(III) polyamino-polyacetate complexes studied so far: tau(R) = (250 +/- 5) ps, which results in an enhanced proton relaxivity by raising the correlation time for the paramagnetic interaction.

Unexpected Aggregation of Neutral, Xylene‐Cored Dinuclear GdIII Chelates in Aqueous Solution

“…The t g values obtained for our aggregates (Table 1) are~10 times larger than those of similarsize complexes, [5,6] we thus estimate an average aggregation number of ten.…”

“…[4] Dinuclear Gd III chelates, both macrocyclic and acyclic, have been investigated in the context of contrast agent development. [5][6][7][8] The increased molecular size of a dimer with regard to a monomer gives rise to slower rotational motion, which is favourable for contrast agent efficacy, although this improvement is often negligible in comparison to the macromolecular systems that have been proposed for MRI contrast agent purposes. Some of the formerly reported dinuclear chelates were derived from the triacetate macrocyclic DO3A 3À ligand in which the hydrogen atom on the fourth nitrogen has been replaced by a linker that bridges the two chelating subunits.…”

Physicochemical characterization of the dimeric lanthanide complexes [en{Ln(DO3A)(H2O)}2] and [pi{Ln(DTTA)(H2O)}2]2−: a variable‐temperature 17O NMR study

“…The dimeric MRI contrast agents possess two gadolinium(III) ions and will increase relaxivity. This has been confirmed for H 6 BO DO3A 2 , 3 in which the Gd(III) complex incorporates several desirable features. As the ligand is a DOTA [DOTA D 1,4,7,10-tetraaza-1,4,7,10-tetrakis(carboxymethyl)cyclododecane] derivative, we can expect high kinetic inertness and thermodynamic stability, and as a neutral complex it is preferable from the point of view of application (a less painful injection because of lower osmolality).…”

Improving the relaxivity by dimerizing Gd-AAZTA: Insights for enhancing the sensitivity of MRI contrast agents

“…The relaxivity found for (Gd-AAZTA) 2 is doubled with respect to that of the parent monomeric Gd-AAZTA, sensibly higher than that of other reported mono-aquo dimers [7][8][9][10][11] and almost comparable to that of related di-acquo dimers [12]. A detailed relaxometric characterization of the Gd-complex has been obtained by the measurement of the 1 H-relaxivity field dependence (NMRDNuclear Magnetic Resonance Dispersion profiles) at two different temperatures and from the 17 O transverse relaxation rate profile as a function of temperature (Fig.…”