DOTASA revisited : 1H NMR and potentiometric studies of a highly asymmetrical ligand and its lanthanide(III) complexes

Abstract

DOTASA (1,4,7,10-tetraazacyclodo-decane-1-(R,S)-succinic acid-4,7,10-triacetic acid) is a DOTA-like macrocyclic ligand showing a carboxymethyl -CH2COOH substituent moiety at a C carbon of one of the four acetate pendant arms, present as a racemic mixture of R and S configurations.The protonation constants of the ligand were determined by potentiometry, giving values close to DOTA except for the extra pK3 value of 5.35 assigned to protonation of the extra carboxylate group in the succinyl arm. The 1H NMR spectra of DOTASA at different pH values are too complex to allow the determination of its microscopic protonation scheme, due to the presence of multiple isomeric structures in solution. The thermodynamic stability constant of its Gd3+ chelate was determined by a potentiometric method, and the value obtained, log KML = 27.2 (0.2), is higher than for the [Gd(DOTA)(H2O)]- complex. The solution structure of the asymmetrical Ln3+ chelates of DOTASA was studied by 1H NMR spectroscopy, indicating the presence of four isomers, corresponding to the combination of the antiprismatic (M) and twisted antiprismatic (m) helicities of the pendant arms and to the R and S configurations of the substituted pendant arm C atom. The m/M isomer ratio decreases along the lanthanide series, with the m isomer decreasing from 90% at La to about 50% from Eu-Lu. This shows that the expected m isomer population of the Gd3+ complex with DOTASA is higher than for the unsubstituted Gd3+-DOTA (~15%) but lower than for a Gd3+ chelate of a RRRR tetrasubstituted DOTA (~70%). Thus the stabilisation of the m isomer by C monosubstitution at the DOTA acetate pendant arms in [Gd(DOTASA)(H2O)]2- is responsible for its increased water exchange rate and higher relaxivity.