Solution Structures, Stabilities, Kinetics, and Dynamics of DO3A and DO3A−Sulphonamide Complexes Anett Taka ́ cs, † Roberta Napolitano, ⊥ Miha ́ ly Purgel, ‡ Attila Csaba Be ́ nyei, § La ́ szló Ze ́ ka ́ ny, † Ernő Brü cher, † Imre Tó th, † Zsolt Baranyai,* ,† and Silvio Aime* ,∥ † Department of Inorganic and Analytical Chemistry, ‡ MTA-DE Homogeneous Catalysis and Reaction Mechanisms Research Group, § Department of Physical Chemistry, University of Debrecen, H-4032 Debrecen, Egyetem te ́ r 1, Hungary ⊥ Centro Ricerche Bracco, Bracco Imaging Spa, Via Ribes 5, I-10010 Colleretto Giacosa, Italy ∥ Department of Molecular Biotechnology and Health Sciences, Molecular Imaging Center, University of Torino, Via Nizza 52, 10126 Torino, Italy * S Supporting Information ABSTRACT: The Gd 3+ -DO3A−arylsulphonamide (DO3A−SA) complex is a promising pH-sensitive MRI agent. The stability constants of the DO3A−SA and DO3A complexes formed with Mg 2+ , Ca 2+ , Mn 2+ , Zn 2+ , and Cu 2+ ions are similar, whereas the logK LnL values of Ln(DO3A−SA) complexes are 2 orders of magnitude higher than those of the Ln(DO3A) complexes. The protonation constant (log K MHL ) of the sulphonamide nitrogen in the Mg 2+ , Ca 2+ , Mn 2+ , Zn 2+ , and Cu 2+ complexes is very similar to that of the free ligand, whereas the logK LnHL values of the Ln(DO3A−SA) complexes are lower by about 4 logK units, indicating a strong interaction between the Ln 3+ ions and the sulphonamide N atom. The Ln(HDO3A−SA) complexes are formed via triprotonated *Ln(H 3 DO3A−SA) intermediates which rearrange to the final complex in an OH − -assisted deprotonation process. The transmetalation reaction of Gd(HDO3A−SA) with Cu 2+ is very slow (t 1/2 = 5.6 × 10 3 h at pH = 7.4), and it mainly occurs through proton-assisted dissociation of the complex. The 1 H and 13 C 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 13 C 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(H 2 DO3A−SA) shows distorted octahedral coordination. The coordination sites of Cu 2+ 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. ■ INTRODUCTION Since the introduction of the open-chain Gd(DTPA) and macrocyclic Gd(DOTA) complexes as nonspecific, extracellular contrast agents (CAs) in MRI examinations in 1988, several similar, as well as tissue specific (liver imaging and blood pool) agents were developed and approved for clinical use. 1,2 In recent years, considerable efforts are made to develop contrast agents for the detection of changes in pH, pO 2 , metal ions, small molecules, and enzyme concentrations in tissues by “responsive” or “smart” contrast agents. 3−5 The detection of pH changes in principle can localize tumor tissues, sites of inflammation, and infection where the pH is lower (5.5−7.0) than the physiological pH. 3,4,6−10 The contrast-enhancing effect of Gd 3+ complexes is based on the increase of proton relaxation rates (R 1 = 1/T 1 , where T 1 is the longitudinal relaxation time) in tissues in the vicinity of contrast agents. The relaxation effect of contrast agents is expressed by the relaxivity, that is, the increase in the water proton relaxation rates per unit concentration of contrast agent (r 1 , mM −1 s −1 ). In all the commercial contrast agents, Gd 3+ is coordinated by an octadentate aminopolycarboxylate ligand, and the ninth coordination site of Gd 3+ is occupied by a water molecule. This water exchanges rapidly with the surrounding water molecules and transfers the paramagnetic effect of Gd 3+ Received: October 14, 2013 Published: February 24, 2014 Article pubs.acs.org/IC © 2014 American Chemical Society 2858 dx.doi.org/10.1021/ic4025958 | Inorg. Chem. 2014, 53, 2858−2872