Abstract
The ligand H~5~dotasa (=(αRS)‐α‐(carboxymethyl)‐1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid) is a H~4~dota‐like macrocyclic ligand with a carboxymethyl CH~2~COOH substituent at the C(α) atom of one of the four acetate pendant arms of H~4~dota (=1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid), present as a racemic mixture of (αR) and (αS) enantiomers. The protonation constants of the ligand were determined by potentiometry, giving values close to those of H~4~dota except for the extra p__K__~3~ value of 5.35 assigned to protonation of the extra carboxylate group in the α‐substituted (=succinic acid) pendant arm. The ^1^H‐NMR spectra of H~5~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 Gd^3+^ chelate was determined by a potentiometric method, and the value obtained, log K~ML~=27.2 (0.2), is higher than for the [Gd(dota)(OH~2~)]^−^ complex. The solution structure of the asymmetric Ln^3+^ chelates of dotasa was studied by ^1^H‐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 (αR) and (αS) configurations at the substituted pendant arm. The m/M isomer ratio decreases along the lanthanide series, with the m isomer decreasing from 90% at La to ca. 50% from Eu–Lu. This shows that the expected m isomer population of the [Gd(dotasa)(OH~2~)]^2−^ complex is higher than for the unsubstituted [Gd(dota)(OH~2~)]^−^ (ca. 15%) but lower than for a Gd^3+^ chelate of an α,α′,α″,α′′′‐tetrasubstituted (RRRR)‐configurated dota (ca. 70%). Thus the stabilization of the m isomer by C~'~ monosubstitution at the dota acetate pendant arm in [Gd(dotasa)(OH~2~)]^2−^ is responsible for its increased H~2~O‐exchange rate and higher relaxivity.