Polymethylated DOTA Ligands. 1. Synthesis of Rigidified Ligands and Studies on the Effects of Alkyl Substitution on Acid−Base Properties and Conformational Mobility

Abstract

This work describes the synthesis and the conformational properties of new polymethylated macrocyclic ligands of potential interest for magnetic resonance imaging. M4cyclen, (2S,5S,8S,11S)-2,5,8,11-tetramethyl-1,4,7,10-tetraazacyclododecane, was obtained by cyclotetramerization of (2S)-1-benzyl-2-methylaziridine followed by catalytic hydrogenation. The ligands M4DOTA, [(2S,5S,8S,11S)-4,7,10-tris-carboxymethyl-2,5,8,11-tetramethyl- 1,4,7,10-tetraazacyclododecan-1-yl]acetic acid, and M4DOTMA, (R)-2-[(2S,5S,8S,11S)-4,7,10-tris-((R)-1-carboxyethyl)-2,5,8,11-tetramethyl-1,4,7,10-tetraazacyclododecan-1-yl]propionic acid, were prepared by carboxyalkylation of M4cyclen in the presence of Na(2)CO(3). The triacetic ligand M4DO3A, [(2S,5S,8S,11S)-4,7-bis-carboxymethyl-2,5,8,11-tetramethyl-1,4,7,10-tetraazacyclododecan-1-yl]acetic acid, was obtained in good yields without traces of M4DOTA if NaHCO(3) was the acid scavenger when adding the carboxylic arms. In the same conditions, cyclen yielded M4DOTA in 82% yield. The difference between the reactivity of cyclen and M4cyclen is assigned to the high basicity of the substituted tetraamine as estimated by NMR titration. The one- and two-dimensional (1)H and (13)C NMR spectra of M4DOTA and M4DOTMA in the H(4)L or H(6)L(2+) forms are interpreted as arising from a slow exchange between two elongated geometries in which the methyl substituents are in one of the two possible equatorial-like positions, either close to or away from the carboxylic arms. The axial-like positions are sterically too crowded and cannot be occupied by the methyl groups. An elongated conformation is also adopted by DOTMA, (R)-2-[4,7,10-tris-((R)-carboxyethyl)-1,4,7,10-tetraazacyclododecan-1-yl]propionic acid, in the H(6)L(2+) form. The rigidification of the polymethylated ligands allows a detailed NMR analysis that cannot be carried out on the parent unsubstituted ligand DOTA.

Towards the Rational Design of Magnetic Resonance Imaging Contrast Agents: Isolation of the Two Coordination Isomers of Lanthanide DOTA‐Type Complexes

“…[22] The most important comparison, with respect to the design of high-relaxivity contrast agents, is that of the rate at which these water molecules exchange with the bulk solvent. The rate of water exchange is reflected in the transverse relaxation rate of 17 O nuclei in the bulk solvent. Thus, water exchange rates may be obtained by line-width analysis of the 17 O NMR spectrum of the solvent recorded as a function of temperature.…”

“…The rate of water exchange is reflected in the transverse relaxation rate of 17 O nuclei in the bulk solvent. Thus, water exchange rates may be obtained by line-width analysis of the 17 O NMR spectrum of the solvent recorded as a function of temperature. [10] The two complexes [Gd(S-RRRR-1)] À and [Gd(S-SSSS-1)] À are characterized by extremely different transverse relaxation rate temperature profiles (Figure 2).…”

“…We have shown that the conformation of the macrocycle may also be locked by substitution on the ring. [16] Although four methyl groups are necessary to "sterically lock" the macrocycle, [17,18] we found that the same effect can be achieved by using one nitrobenzyl substituent. [16] These observations suggest that a DOTA complex may be "locked" into one or other coordination geometry by suitably substituting both the macrocyclic ring and the pendant arms of the complex.…”

Static and Dynamic Stereochemistry of Chiral Ln DOTA Analogues

“…[31,32] Consequently, the cyclen backbone incorporates four chiral centres, which combine with the labile elements depicted in the previous section. There is a marked preference for one stereoisomer, which accounts for about 90 % of Yb M4DOTA.…”

Synthesis of 1,4,7,10‐Tetra‐azacyclododecan‐1,4,7,10‐tetra‐azidoethylacetic Acid (DOTAZA) and Related “Clickable” DOTA Derivatives

“…This phenomenon is known to be influenced by the degree of protonation and sharp NMR signals are often observed at low pH values. [31] However, DOTA 30 did not Crystallization of NaÀDOTA ester 31 from a mixture of toluene and EtOAc gave single crystals suitable for X-ray analysis (Figure 2 a). The structure revealed a twisted square-pyramidal octahedral coordination mode of sodium, with all four ester carbonyl groups participating in sodium complexation.…”