Lanthanide(III) Complexes of a Mono(methylphosphonate) Analogue of H₄dota: The Influence of Protonation of the Phosphonate Moiety on the TSAP/SAP Isomer Ratio and the Water Exchange Rate

Abstract

A monophosphonate analogue of H4dota, 1,4,7,10-tetraazacyclododecane-4,7,10-tris(carboxymethyl)-1-methylphosphonic acid (H5do3aP), and its complexes with lanthanides were synthesized. Multinuclear NMR studies reveal that, in aqueous solution, lanthanide(III) complexes of the ligand exhibit structures analogous to those of H4dota complexes. Thus, the central ion is nine-coordinate, surrounded by four nitrogen atoms, three acetate and one phosphonate oxygen atoms, and one water molecule in an apical position. For complexes of H5do3aP with Ln(III) ions in the middle of the series, the abundance of the desired twisted square-antiprismatic (TSAP) isomer is higher than for the corresponding H4dota complexes. The TSAP/square-antiprismatic (SAP) isomer ratio is highly sensitive to protonation of the phosphonate group: a higher abundance of the TSAP isomer was found in acidic solutions. The microscopic protonation constants of the TSAP isomers are higher than those of the SAP isomers. The presence of one water molecule in the first coordination sphere of the complexes in the pH region studied (pH 2.5-7.0) is confirmed by 17O NMR spectroscopy. The results of a simultaneous fit of variable-temperature 17O NMR relaxation data and 1H NMRD profiles show that the residence time of water (tauM) in the Gd(III) complex is much smaller than for [Gd(dota)(H2O)]-. The exchange rate appears to be dependent on the pH of the solution. The values of tauM are 37, 40, and 14 ns at pH 2.5, 4.7, and 7.0, respectively. These observations can be explained by an extensive second-sphere hydrogen-bonding network that varies with the state of protonation of the phosphonate moiety. Upon protonation of the complex, the second-sphere hydration probably becomes more ordered, which may result in a decrease in penetrability and an increase in tauM. The relaxivity of the Gd(III) complex is almost independent of the pH and is equal to 4.7 s(-1) mM(-1) (20 MHz, pH 7 and 37 degrees C). The solid-state structure was determined for the Nd(III) complex. It crystallizes as the TSAP isomer and the unit cell contains two independent molecules of the complex with different Nd-O(water) bond lengths of 2.499 and 2.591 A.

Lanthanide(III) Complexes of 4,10‐Bis(phosphonomethyl)‐1,4,7,10‐tetraazacyclododecane‐1,7‐diacetic acid (trans‐H6do2a2p) in Solution and in the Solid State: Structural Studies Along the Series

“…[2,3,6,9] However, solid-state structures of complexes with derivatives that have phosphorus-containing pendant arms have not been studied in so much detail, most probably due to the difficulties in getting single crystals suitable for X-ray diffraction analysis. [13][14][15][16][17][18][19] Generally, the structures of dota and dotp complexes are similar in a way that all ligand donor atoms are bound to the central lanthanideA C H T U N G T R E N N U N G (III) ion in an octadentate fashion, thereby forming parallel N 4 and O 4 planes that sandwich the central ion. However, the structures of lanthanideA C H T U N G T R E N N U N G (III) dota and dotp complexes differ in some other aspects.…”

“…The complexes of monophosphorus acid dota derivatives again show biodistributions similar to those of dota complexes. [32,33] Following our previous work on tetraazamacrocycles that bear phosphonate and/or acetate pendant arms, [13][14][15]25,29,[30][31][32][33][34] we have recently reported on the synthesis and characterisation of 1,4,7,10-tetraazacyclododecane-1,7-bis(acetic acid)-4,10-bis(methylenephosphonic acid) (trans-H 6 do2a2p, H 6 L; Scheme 1), on its interaction with 153 …”

“…[18,22] Properties of complexes of the ligands that have one phosphorus acid and three acetic arms are similar to those of dota. [3,14,15,19,23] However, only limited data are available for Ln III complexes of the dota-like ligands with other numbers (two or three) of phosphorus-containing pendant arms. [24][25][26][27][28] The biological behaviour of lanthanideA C H T U N G T R E N N U N G (III) dota and dotp complexes is also different.…”

Study of Thermodynamic and Kinetic Stability of Transition Metal and Lanthanide Complexes of DTPA Analogues with a Phosphorus Acid Pendant Arm

“…H 5 do3ap or H 4 do3ap ABn , Scheme 1) comparing to H 4 dota. [17,18] Furthermore, the relatively easy substitution on the phosphorus atom offers the possibility to attach the complex to a macromolecular carrier, [19][20][21] or to bind it non-covalently to plasma proteins (e.g. by hydrophobic interactions).…”

Vibrational dynamics of zero-field-splitting hamiltonian in gadolinium-based MRI contrast agents from ab initio molecular dynamics

“…We now compare the previous results with analogous calculations for the [Gd(DO3AP)(H 2 O)] 2− complex synthesized by Rudovsky et al 35 The chelate is not neutral anymore but bears a negative charge. In addition, the presence of a bulky phosphonate pendant arm increases the asymmetry of the coordination cage.…”