Dimer formation of GdDO3A-arylsulfonamide complexes causes loss of pH-dependency of relaxivity

Abstract

Gadolinium(iii) complexes with pH-dependent relaxivities have been proposed as responsive magnetic resonance imaging (MRI) contrast agents (CA) for mapping of pH value in living subjects. The latter is clinically relevant because hypoxia-induced reduction of interstitial pH (acidosis) is a hallmark of tumor progression and resistance against chemotherapy. In order to obtain versatile building blocks for integration of a pH-responsive MRI-CA functionality into larger molecular assemblies, such as bioconjugates, micelles or nanoparticles, we equipped the structural motif GdDO3A-ethylene(arylsulfonic acid) with additional carboxylic acid moieties in the aromatic para-position. Two novel compounds were characterized concerning their pH-dependent relaxivity as well as by O NMR andH NMRD, augmented by determination of luminescence lifetimes of the respective Eu(iii) complexes and structural modelling by density functional theory (TPSSh/LCRECP/6-31G(d)). Unexpected involvement of the peripheral carboxylates into metal ion complexation effected self-assembly of the lanthanide(iii) complexes, resulting in dimeric species comprising two lanthanide ions, two symmetrically bridging ligands, and one coordinated water molecule per Gd(iii) (q = 1). These structures are stable even at low concentrations and in presence of competing anions like phosphate. The pH-sensitive sulfonamide moieties are not involved into Gd(iii) coordination, resulting in virtually constant relaxivities of r = 6.7 mM s (298 K, 20 MHz) over the biologically relevant pH range (4 to 9). Since further functionalisation on the peripheral carboxylates would effectively inhibit dimer formation, the compounds are nonetheless suited for the initially envisaged field of application.

Macrocyclic Pyclen-Based Gd3+ Complex with High Relaxivity and pH Response

“…Coordination of the negatively charged iminodiacetate unit is also consistent with the spectral changes observed in the emission spectra of the Eu 3+ complex upon increasing pH. A few examples of Ln 3+ complexes that form stable aggregates in solution assembled through bridging carboxylate units have been reported in the literature. − The formation of these aggregates does not cause loss of the pH dependency of relaxivity, as reported recently for GdDO3A–arylsulfonamide complexes …”

“…99−101 The formation these aggregates does not cause loss of the pH dependency of relaxivity, as reported recently for GdDO3A−arylsulfonamide complexes. 102 ■ CONCLUSIONS…”

Lanthanide Complexes with 1H paraCEST and 19F Response for Magnetic Resonance Imaging Applications

“…The D 298 value determined for [EuL 2 ] + is somewhat lower, which is explained by the larger hydrodynamic radius associated with its higher molecular weight and positive charge. Nevertheless, the diffusion coefficients measured for these complexes are similar to those reported for lanthanide complexes with similar size and higher than the D 298 value reported for lanthanide DO3A derivatives that form stable dimeric species in solution (for comparative purposes, the D 298 values measured in D 2 O must be scaled by a factor of 1.24 to account for the different viscosities of H 2 O and D 2 O). Thus, we conclude that the complexes investigated here adopt discrete mononuclear structures in a H 2 O solution.…”

Synthesis and Photophysical Properties of Lanthanide Pyridinylphosphonic Tacn and Pyclen Derivatives: From Mononuclear Complexes to Supramolecular Heteronuclear Assemblies

“…The diffusion coefficient measured in D 2 O is somewhat lower than those reported for small mononuclear Ln 3+ complexes (3.9–5.4 × 10 –10 m 2 ·s –1 ). − DFT calculations were also used to estimate the molecular volume of [Lu L2 ], which turned out to be 678 Å 3 , as defined by a contour of electron density of 0.001 e·Bohr –3 (Table S3). This molecular volume corresponds to that of a sphere with a radius of 5.5 Å.…”