Synthesis and Characterization of DOTA‐(amide)₄ Derivatives: Equilibrium and Kinetic Behavior of Their Lanthanide(III) Complexes

Abstract

Lanthanide complexes of tetraamide derivatives of DOTA are of interest today because of their application as chemical exchange saturation transfer (CEST) agents for magnetic resonance imaging (MRI). The protonation constants of some simple tetraamide derivatives of DOTA and the stability constants of the complexes formed with some endogenous metal ions, namely Mg 2+ , Ca 2+ , Cu 2+ , Zn 2+ , and lanthanide(III) ions, have been studied. These complexes were found to be considerably less stable than the corresponding [M(DOTA)] 2− complexes, largely due to the lower basicity of the tetraamide ligands. The Mg 2+ and Ca 2+ complexes are well described by formation of only ML species at equilibrium while the Zn 2+ and Cu 2+ complexes exhibit one and two additional deprotonation steps above a pH of around 6, respectively. The extra deprotonation that occurs at high pH for the [Zn{DOTA-(amide) 4 }] 2+ complexes has been assigned to an amide deprotonation by 1 H NMR spectroscopy. The first deprotonation step for the Cu 2+ complexes was traced to formation of the ternary hydroxo complexes ML(OH) (by UV/Vis spectrophotometry) while the second step corresponds to deprotonation of an amide group to form ML(OH)H −1 -type complexes. The trends in the stability constants of the [Ln{DOTA-(amide) 4 }] 3+ complexes follow similar trends with respect to ion size as those reported previously for the corresponding [Ln(DOTA)] − complexes, but again, the stability constants are about 10-11 orders of magnitude lower. A kinetic analysis of complex formation has shown that complexes are directly formed between a Ln 3+ cation and fully deprotonated L without formation of a protonated intermediate. [Ln{DOTA-(MeAm) 4 }] 3+ complex formation occurs at a rate that is two to three orders of magnitude slower than those of the corresponding [Ln(DOTA)] − complexes, while the variation in complex formation rates with Ln 3+ ion size is opposite to that observed for the corresponding [Ln(DOTA)] − complexes. The Ce 3+ and Correspondence to: Gyula Tircsó; A. Dean Sherry. Supporting information for this article is available on the WWW under http://www.eurjic.org or from the author. Eu 3+ complexes of DOTA-(MeAm) 4 are kinetically inert with respect to acid-catalyzed dissociation, which suggests that these complexes may potentially be safe for use in vivo.

New Insights into the Complexation of Lead(II) by 1,4,7,10‐Tetrakis(carbamoylmethyl)‐1,4,7,10‐tetraazacyclododecane (DOTAM): Structural, Thermodynamic, and Kinetic Studies

“…The new data agree well with those reported by Brücher and co-workers in potassium-salt-containing solutions. [70,71] As previously shown, the tetraamines bearing acetamide groups behave like weak diprotic bases between p[H] 2 and 11.…”

Structure, Dynamics, and Computational Studies of Lanthanide‐Based Contrast Agents

“…These include unsubstituted aliphatic (5, 7-14) [417][418][419][420][421], aromatic (4, 15-20) [421][422][423][424] and heterocyclic (6, 21-23) [420,[424][425][426] hydrocarbon chains, as well as carboxylate and ester groups (24)(25)(26)(27)(28)(29)(30)(31) [417,418,420,421,426,427], ketone (32) [428], phosphonate (33) and phosphinate (34) [417,421,424] groups, as well as dipeptides (35 and 36) [429], and methylated β-cyclodextrin (37) [422] complexes have nine-coordinate TSA geometries. The solution TSA/SA composition of several tetraamide complexes was studied by 1 H NMR, where the signature of these two isomers is easily seen since the macrocyclic H 4 proton has very different PCS values in the two isomers.…”

A Bisamide Derivative of [Mn(1,4‐DO2A)] – Solution Thermodynamic, Kinetic, and NMR Relaxometric Studies

“…The replacement of acetate for amide donor groups slows down the rate of the dissociation reactions of Ln-DOTA-like complexes. [7,8] This property has been attributed to both the decreased negative charge of the complex, which hinders the protonation and then the acid-catalysed dissociation, and to the low basicity of the amide oxygen atom, which makes proton transfer to the ring nitrogen atom very unlikely. [8] Moreover, the presence of neutral amide coordinating groups and the formation of a cationic Mn II complex should impact its relaxometric properties.…”

“…[7,8] This property has been attributed to both the decreased negative charge of the complex, which hinders the protonation and then the acid-catalysed dissociation, and to the low basicity of the amide oxygen atom, which makes proton transfer to the ring nitrogen atom very unlikely. [8] Moreover, the presence of neutral amide coordinating groups and the formation of a cationic Mn II complex should impact its relaxometric properties. [9] We are particularly interested in the evaluation of the water exchange rate (k ex = 1/τ M ) of Mn(1,4-DO2AM) by 17 O NMR spectroscopy techniques to ascertain the influence of the chemical nature of the donor group on this key parameter.…”