Gadolinium(iii) complexes of mono- and diethyl esters of monophosphonic acid analogue of DOTA as potential MRI contrast agents: solution structures and relaxometric studies

Abstract

Two new macrocyclic DOTA-like chelates containing one phosphonate pendant arm were synthesised as potential contrast agents for MRI (magnetic resonance imaging). The chelates bind to the lanthanide(III) in an octadentate manner, via four nitrogen atoms, three carboxylate and one phosphonate oxygen atoms. Solution structures of [Ln(do3ap^OEt2)(H₂O)] and [Ln(do3ap^OEt)(H₂O)]⁻ were studied using ³¹P and ¹H NMR spectroscopy and SAP (square-antiprismatic)/TSAP (twisted square-antiprismatic) isomerism was observed. Depending on the nature of the lanthanide(III) ion, the lanthanide(III) complexes of H₄do3ap^OEt are present in solution as up to four different diastereoisomers observable with NMR. The TSAP isomer is the most abundant at the beginning of the lanthanide series and, with a decrease of the ionic radius of lanthanide(III) ions, both TSAP and SAP forms were observed. A second interconversion (SAP↔TSAP′) becomes important at the end of the series (TSAP′ means the TSAP species without a coordinated water molecule). The remaining axial coordination site is occupied by one water molecule for the Gd³⁺-complex. The calculated fraction of the TSAP isomer in the gadolinium(III) complexes increases in the order [Gd(DOTA)(H₂O)]⁻ < [Gd(do3ap^OEt2)(H₂O)] < [Gd(do3ap^OEt)(H₂O)]⁻ < [Gd(do3ap)(H₂O)]²⁻. Gadolinium(III) complexes of phosphorus-containing chelates, generally, have the advantage of a relatively fast water exchange rate due to a greater sterical demand of the phosphorus acid moiety and of the presence of the second-sphere water shell, which also contributes to the overall relaxivity. The [Gd(do3ap^OEt2)(H₂O)] and [Gd(do3ap^OEt)(H₂O)]⁻ complexes were studied by variable-temperature ¹⁷O NMR and ¹H NMRD. The experimental data were evaluated simultaneously with commonly used equations based on Solomon–Bloembergen–Morgan approximation, extended by a contribution of the second coordination sphere. The water exchange rates were found to be strongly dependent on the TSAP/SAP isomeric ratio and the overall charge of the complex: the monoanionic [Gd(do3ap^OEt)(H₂O)]⁻ complex with TSAP molar fraction equal to 0.36 has the water exchange rate of 20 × 10⁶ s⁻¹ (τ_M = 50 ns) while neutral [Gd(do3ap^OEt2)(H₂O)] complex with TSAP molar fraction 0.28 has an exchange rate equal to 4.4 × 10⁶ s⁻¹ (τ_M = 227 ns).