Structural Variations Across the Lanthanide Series of Macrocyclic DOTA Complexes:  Insights into the Design of Contrast Agents for Magnetic Resonance Imaging

Abstract

It was early shown that the macrocyclic Ln(DOTA) complexes (DOTA = 1,4,7,10-tetra-azacyclododecane-N,N',N' ',N' "-tetraacetic acid) exists in solution as a mixture of two enantiomeric pairs of diastereoisomers differing in the ligand conformation, namely, square antiprismatic (SA) and twisted square antiprismatic (TSA) geometries, respectively. Later, extensive (1)H NMR investigations suggested that a coordination change may be superimposed on this conformational equilibrium involving two additional structures in which the metal ion possesses a coordination number of eight (CN 8). It was predicted that these two species, lacking the apical coordinated water molecule, would maintain the SA and TSA coordination geometries, and therefore, they have been labeled as SA' and TSA', respectively. In this work we report the X-ray solid-state crystal structure determination of six Ln(DOTA) complexes representative of all four coordination geometry typologies deduced from NMR solution studies. A distinctive structural feature that discriminates SA (and SA') and TSA (and TSA') structures is represented by the twist angle between the two square planes of the antiprism, the basal four nitrogen, and the apical four oxygen planes. [Ce(DOTA)(H(2)O)](-) displays a TSA structural typology with a twist angle of 25 degrees and a Ce-O(water) distance of 2.59 A. The SA-type structure has been found in the case of complexes with Pr(III), Nd(III), and Dy(III), where the twist angle is 39, 39, and 38 degrees, respectively, and the metal-water oxygen distance varies significantly (Pr-O(w) 2.529 A; Nd-O(w) 2.508 A; and Dy-O(w) 2.474 A). [Tm(DOTA)](-) displays a TSA'-type structure with a twist angle of 24 degrees. As compared with the TSA structure of the corresponding Ce(III) complex, the Tm(III) complex shows an overall marked shrinkage of all metal-nitrogen and metal-oxygen distances (ca. 0.2 A), which reflects the contraction of the metal ionic radius across the series but also the effect associated with the decrease of the CN from 9 to 8. In [Sc(DOTA)](-), the even smaller ionic radius of Sc(III) shifts the geometry of the coordination cage to the more compact SA' typology with a twist angle of 41 degrees, a value very similar to that found in the SA structures of lanthanide(III) ions with CN 9. Finally, an investigation was made into the hydration spheres of the complexes with SA and TSA geometries to account for the experimental evidence of a markedly different rate of water exchange for the two isomeric structures. This is of fundamental importance to the understanding of the corresponding Gd(III) complexes as MRI contrast agents.

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

“…As the radius of the Ln III decreases, the central ions shift from the O 4 plane towards the N 4 base, as observed for Ln III complexes of H 4 dota or H 5 do3ap. [14,15,19,61] Despite a huge disorder of water solvate molecules found, the high number of water molecules and their localisation close to the O 4 plane point to a strong second-sphere hydration of the complexes, as suggested from the luminescence study on the Eu III -H 6 L complex. Analogous hydration has been observed in lanthanideA C H T U N G T R E N N U N G (III) complexes of H 5 do3ap [14,15] in the solid state and in europiumA C H T U N G T R E N N U N G (III) complexes of tetraphosphorus acid derivatives of cyclen in solution.…”

“…[14,15,61] In the second isostructural series, K 2 [Ln(HL)]·6.5 H 2 O, with smaller lanthanides (Ln = Sm, Eu, Tb, Dy, Er and Yb), the central ion is only octa-coordinated by the ligand donor atoms. There is not enough space for apical water coordination, as the values of the opening angle (f) (P)O-Ln-O(P) are much lower than the border value of approximately 1358 that is crucial for water binding (Table 8).…”

Static and Dynamic Stereochemistry of Chiral Ln DOTA Analogues

“…The most prominent structural difference between SA and TSA can be expressed by the angle f between the two squares, defining the bases of the coordination polyhedron as shown in Figure 4. [11,22] It is interesting to observe that the degree of van der Waals interactions in the two conformations is comparable, and it www.chemphyschem.org would be hard to predict which one is most stable, on simple stereochemical arguments based on the ligand alone.…”

A Bridge to Coordination Isomer Selection in Lanthanide(III) DOTA-tetraamide Complexes

“…The N 4 -O 4 twist angle (α) in Yb1 is −26.8, typical of the values observed for other complexes that adopt the TSAP isomer (Table 1). 25,26 The reason why Yb1 adopts a TSAP coordination geometry may be found by considering how the ligand system is viewed. As presented in Chart 1 it is easiest to consider the complex as a modified DOTA-type structure; however, this ligand system is in fact bicyclic, consisting of 12-and 21-membered ring systems.…”