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))(H(2)O)] and [Ln(do3ap(OEt))(H(2)O)](-) were studied using (31)P and (1)H 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 H(4)do3ap(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 Gd(3+)-complex. The calculated fraction of the TSAP isomer in the gadolinium(III) complexes increases in the order [Gd(DOTA)(H(2)O)](-) < [Gd(do3ap(OEt2))(H(2)O)] < [Gd(do3ap(OEt))(H(2)O)](-) < [Gd(do3ap)(H(2)O)](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))(H(2)O)] and [Gd(do3ap(OEt))(H(2)O)](-) complexes were studied by variable-temperature (17)O NMR and (1)H 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))(H(2)O)](-) complex with TSAP molar fraction equal to 0.36 has the water exchange rate of 20 x 10(6) s(-1) (tau(M) = 50 ns) while neutral [Gd(do3ap(OEt2))(H(2)O)] complex with TSAP molar fraction 0.28 has an exchange rate equal to 4.4 x 10(6) s(-1) (tau(M) = 227 ns).

Lanthanide(III) Complexes of Phosphorus Acid Analogues of H4DOTA as Model Compounds for the Evaluation of the Second‐Sphere Hydration

“…[46] The observed relaxivities of all [Gd(DOTP R )] -complexes fall into the narrow region 2.1-2.8 s -1 m -1 (20 MHz, 37°C). The relaxivity of Gd III complexes with DOTA-like ligands having one inner-sphere water molecule is higher (≈ 4), [22,54] although in these cases the inner-sphere contributions are about 50 % of the final value, whereas the second-sphere water molecules of the presently studied complexes have a contribution of only 10-15 % to the total relaxivity. The ligands studied differ in the size and hydrophilic/hydrophobic character of the substituents on the phosphorus atoms and in the isomeric distributions of their complexes in solution.…”

“…[25] It has been shown recently that the second-sphere contribution to the overall relaxivity is significant even in complexes of H 5 DTPA (H 5 DTPA = 1,4,7-triazaheptane-1,1,4,7,7-pentaacetic acid, Scheme 1) [26] or H 4 DOTA derivatives containing only one phosphonic/phosphinic acid group. [20][21][22] This contribution was found to be more pronounced when complexes of these monophosphorus acid ligands were bound to macromolecules. [27,28] Theoretical approaches to treat the second-sphere hydration have confirmed that phosphonic acid groups enhance the hydration of complexes of DOTAlike ligands [29] as well as of open-chain ligands.…”

Synthesis and Characterisation of First Generation Luminescent Lanthanide Complexes Suitable for Being Adapted for Uptake via the Mannose Receptor

“…The yields for 3 and 4, 18% and 35%, respectively, were lower than those generated for 1 and 2, which may be attributable to interaction of the carboxylic acid pendant arms with the copper catalyst. [19,20]. In the spectra of complexes 3 and 4, there is a small broad resonance at 10.4 ppm.…”

Hydroxy double salts intercalated with Mn(II) complexes as potential contrast agents

“…However, the contribution of water molecules present for long lifetimes in the second-sphere of complexes can also be significant [22,23]. This is particularly true for polyaminophosphonate complexes, due to hydrogen bonding of water molecules with the phosphonate oxygens [24]. This effect is even more noticeable in phosphonate complexes with no inner-sphere water, such as Gd(DOTMP) [26].…”