Solution Structures, Stabilities, Kinetics, and Dynamics of DO3A and DO3A–Sulphonamide Complexes

The Gd3+-DO3A–arylsulphonamide
(DO3A–SA)
complex is a promising pH-sensitive MRI agent. The stability constants
of the DO3A–SA and DO3A complexes formed with Mg2+, Ca2+, Mn2+, Zn2+, and Cu2+ ions are similar, whereas the logKLnL values of Ln­(DO3A–SA) complexes are 2 orders of magnitude
higher than those of the Ln­(DO3A) complexes. The protonation constant
(log KMHL) of the sulphonamide nitrogen
in the Mg2+, Ca2+, Mn2+, Zn2+, and Cu2+ complexes is very similar to that of the free
ligand, whereas the logKLnHL values of
the Ln­(DO3A–SA) complexes are lower by about 4 logK units, indicating a strong interaction between the Ln3+ ions and the sulphonamide N atom. The Ln­(HDO3A–SA) complexes
are formed via triprotonated *Ln­(H3DO3A–SA) intermediates
which rearrange to the final complex in an OH–-assisted
deprotonation process. The transmetalation reaction of Gd­(HDO3A–SA)
with Cu2+ is very slow (t1/2 = 5.6 × 103 h at pH = 7.4), and it mainly occurs
through proton-assisted dissociation of the complex. The 1H and 13C NMR spectra of the La-, Eu-, Y-, and Lu­(DO3A–SA)
complexes have been assigned using 2D correlation spectroscopy (COSY,
EXSY, HSQC). Two sets of signals are observed for Eu-, Y-, and Lu­(DO3A–SA),
showing two coordination isomers in solution, that is, square antiprismatic
(SAP) and twisted square antiprismatic (TSAP) geometries with ratios
of 86–14, 93– 7, and 94–6%, respectively. Line
shape analysis of the 13C NMR spectra of La-, Y- , and
Lu­(DO3A–SA) gives higher rates and lower activation entropy
values compared to Ln­(DOTA) for the arm rotation, which indicates
that the Ln­(DO3A–SA) complexes are less rigid due to the larger
flexibility of the ethylene group in the sulphonamide pendant arm.
The fast isomerization and the lower activation parameters of Ln­(DO3A–SA)
have been confirmed by theoretical calculations in vacuo and by using
the polarizable continuum model. The solid state X-ray structure of
Cu­(H2DO3A–SA) shows distorted octahedral coordination.
The coordination sites of Cu2+ are occupied by two ring
N- and two carboxylate O-atoms in equatorial position. The other two
ring N-atoms complete the coordination sphere in axial positions.
The solid state structure also indicates that a carboxylate O atom
and the sulphonamide nitrogen are protonated and noncoordinated.