Maximizing the relaxivity of HSA-bound gadolinium complexes by simultaneous optimization of rotation and water exchange (original) (raw)
Related papers
Magnetic Resonance in Chemistry, 2004
The Gd(III) complexes of the two dimeric ligands [en(DO3A)2] {N,N′-bis[1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-10-yl-methylcarbonyl]-N,N′-ethylenediamine} and [pi(DTTA)2]8− [bisdiethylenetriaminepentaacetic acid (trans-1,2-cyclohexanediamine)] were synthesized and characterized. The 17O NMR chemical shift of H2O induced by [en{Dy(DO3A)}2] and [pi{Dy(DTTA)}2]2− at pH 6.80 proved the presence of 2.1 and 2.2 inner-sphere water molecules, respectively. Water proton spin–lattice relaxation rates for [en{Gd(DO3A)(H2O)}2] and [pi{Gd(DTTA)(H2O)}2]2− at 37.0 ± 0.1° C and 20 MHz are 3.60 ± 0.05 and 5.25 ± 0.05 mM−1 s−1 per Gd, respectively. The EPR transverse electronic relaxation rate and 17O NMR transverse relaxation time for the exchange lifetime of the coordinated H2O molecule and the 2H NMR longitudinal relaxation rate of the deuterated diamagnetic lanthanum complex for the rotational correlation time were thoroughly investigated, and the results were compared with those reported previously for other lanthanide(III) complexes. The exchange lifetimes for [en{Gd(DO3A)(H2O)}2] (769 ± 10 ns) and [pi{Gd(DTTA)(H2O)}2]2− (910 ± 10 ns) are significantly higher than those of [Gd(DOTA)(H2O)]− (243 ns) and [Gd(DTPA)(H2O)]2− (303 ns) complexes. The rotational correlation times for [en{Gd(DO3A)(H2O)}2] (150 ± 11 ps) and [pi{Gd(DTTA)(H2O)}2]2− (130 ± 12 ps) are slightly greater than those of [Gd(DOTA)(H2O)]− (77 ps) and [Gd(DTPA)(H2O)]2− (58 ps) complexes. The marked increase in relaxivity (r1) of [en{Gd(DO3A)(H2O)}2] and [pi{Gd(DTTA)(H2O)}2]2− result mainly from their longer rotational correlation time and higher molecular weight. Copyright © 2004 John Wiley & Sons, Ltd.
NMR relaxometric studies of Gd(III) complexes with heptadentate macrocyclic ligands
Magnetic Resonance in Chemistry, 1998
The water 1H and 17O NMR relaxation properties of solutions containing Gd(III) chelates of the heptadentate DO3A, PCTA[12] and PCTP[12] ligands were thoroughly investigated and the results obtained are compared with those previously reported for other Gd(III) complexes with octadentate ligands MH 3 DO3A \ 1,4,7-triacetic acid ; 1,4,7,10-tetraazacyclododecane H 3 PCTA[12] \ 3,6,9,15-tetraazabicyclo[9.3.1]pentadecaacid ; 1(15),11,13-triene-3,6,9-triacetic H 6 PCTP[12] \ 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1 ,11,13-triene-acidN. The observed behaviour is consistent with a hydration number q \ 2 in the 3,6,9-tris(methanephosphonic) case of GdDO3A and GdPCTA[12] and q \ 1 in the case of PCTP . The high relaxivity of the latter complex is accounted for in terms of the occurrence of an additional contribution arising from water molecules tightly bound to the phosphonate moieties on the surface of the paramagnetic chelate. Furthermore, it was found that the decreased relaxation rates observed at basic pH in the case of GdDO3A and GdPCTA can probably be ascribed to a partial decrease in their hydration. The measurement of 17O NMR transverse relaxation rates, in the temperature range 273È342 K, allowed the assessment of the water exchange rate between the coordination site and the bulk solvent. A particularly short exchange lifetime was measured for the octacoordinate GdPCTP , which suggests the occurrence of an associative exchange mechanism. Further insights into the understanding of the structural properties of the three complexes were gained by measuring the magnetic Ðeld dependence (NMRD proÐles) of the proton relaxivity on a KoenigÈBrown Ðeld cycling relaxometer.
Relaxivity and Water Exchange Studies of a Cationic Macrocyclic Gadolinium(III) Complex
Chemistry, 2001
We conducted relaxometric and water exchange studies of the cationic [Gd((S,S,S,S)-THP)(H 2 O)] 3 complex (THP 1,4,7,10-tetrakis(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane). While the NMRD profiles obtained are typical for DOTA-like complexes (DOTA 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate), variable-temperature 17 O NMR investigations revealed a relatively high water exchange rate (k 298 ex 1.89 Â 10 7 s À1 ). These results dif-fer from those reported for other cationic tetraamide macrocyclic Gd III complexes, which exhibit characteristically low exchange rates. Since the low exchange rates are attributed partially to the geometry of the M isomer (square antiprismatic) in the tetraamide derivatives, the atypical water exchange rate observed in [Gd((S,S,S,S)-THP-(H 2 O)] 3 may result from a twisted square antiprismatic structure in this complex and from the relatively high steric strain at the water coordination site as a result of the presence of methyl groups at the a-position with respect to the Gd III -bound O atoms of THP.
High-resolution NMR and relaxometric studies of Ln(III) complexes of relevance to MRI
Journal of Alloys and Compounds, 1995
The solution structure and dynamics and the relaxation properties of the lanthanide(III) complexes with ethylenebis(oxyethylenenitrilo)tetraacetic acid (EGTA) are studied by NMR techniques. The longitudinal water proton relaxation rates as a function of the magnetic field in a solution of Gd(EGTA)-are investigated and analysed. The experimental results are compared with existing data for other linear and macrocyclic complexes and interpreted as indicative of the presence of a single coordinated water molecule and of an unusual symmetry and stereochemical rigidity of the coordination cage. Variable temperature high resolution 1H and 13C NMR spectra for the Eu(III), Ho(III) and Yb(III) complexes confirm the above hypothesis and suggest a dodecahedral geometry for the complexes as well as a marked increase of rigidity along the lanthanide series.
Helvetica Chimica Acta, 2007
To confirm the obsewation that lcd(ttda) I derivatives have a significantly shorter residence time zy of the coordinated H2O molecule than [Gd(dtpa)], four new C-functionalized [Gd(ttda)] complexes, [Gd(4-Mertda)] (1), [Gd(4-Ph-ttda)] (2), [Gd(e-Me-ttda)] (3), and [Gd(e-Ph-fida)] (4), were prepared and characterized (Hrttda:3,6,1O-tris(carboxymethyl)-3,6,1O-triazadodecanedioic acid; Hrdtpa:3,6,9-tris(carboxymethyl)-3,6,9-tiazaundecanedioic acid). The temperature dependence of the proton relaxivity for these complexes at 0.47 T and of the 17O transverse relaxation rate of Hr17O at 7.05 T confirm that the proton relaxivity is not limited by the H2O-exchange rate. The residence time of the H2O molecules in the first coordination sphere of the gadolinium complexes at 310 K, as calculated from l7O-NMR data, is 13, 43,2.9, and 56 ns for 1,2,3, and 4, respectively. At 310 K, the longitudinal relaxivity of 2 is higher than for the parent compound [Gd(ttda)] and the other complexes of the series. The stability of the new compounds was studied by transmetallation with Znz+ ions. All the new complexes are more stable than the parent compound [Gd(ttda)].
The Journal of Chemical Physics
Longitudinal and transverse 1 H NMR nuclear relaxivities of Ln(III)-DOTA complexes (with Ln = Gd, Dy, Tb, Er; DOTA = 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid) and Mn(II) aqueous solutions were measured in a wide range of frequencies, 10 kHz-700 MHz. The experimental data were interpreted by means of models derived from the Solomon-Bloembergen-Morgan theory. The data analysis was performed assuming the orbital angular momentum L = 0 for Gd-DOTA and the aqua ion [Mn(H2O)6] 2+ and L ≠ 0 for Dy-, Tb-, Er-DOTA. A refined estimation of the Zero-Field-Splitting barrier Δ and of the modulation correlation time τv was obtained for [Mn(H2O)6] 2+ by extending the fitting of NMRD profiles to the low-field regime. The Gd-DOTA fitting parameters resulted in good agreement with the literature, and the fit of transverse relaxivity data confirmed the negligibility of the scalar interaction in the nuclear relaxation mechanism. Larger transverse relaxivities of Dy-DOTA and Tb-DOTA (10 mM-1 s-1) with respect to Er-DOTA (1 mM-1 s-1) were observed at 16 Tesla. Such higher values are suggested to be due to a shorter residence time τm, that is possibly linked to the fluctuations of the hyperfine interaction and the different shape of the magnetic anisotropy. The possible employment of Dy-DOTA, Tb-DOTA, and Er-DOTA as negative MRI contrast agents for high-field applications was envisaged by collecting spin-echo images at 7 Tesla. Particularly in Dy-and Tb-derivatives the transverse relaxivity at 16 Tesla is of the order of the Gd-one at 1.5 Tesla.