Cerium(III), Europium(III), and Ytterbium(III) Complexes with Alcohol Donor Groups as Chemical Exchange Saturation Transfer Agents for MRI

Abstract

Lanthanide(III) complexes of macrocycles 1,4,7,10-tetrakis(2-hydroxyethyl)-1,4,7,10-tetraazacyclododecane (THED) and (1S,4S,7S,10S)-1,4,7,10-tetrakis(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane (S-THP) were studied as chemical exchange saturation transfer (CEST) agents for magnetic resonance imaging (MRI) applications. The four hyperfine-shifted alcohol protons of these Ln(III) complexes gave rise to a single 1H resonance in wet d3-acetonitrile that was separated from the bulk water resonance (Δω) by 8 ppm (Ce), 2 ppm (Nd), 7 ppm (Eu) or 17 ppm (Yb). A CEST peak corresponding to the alcohol protons was observed for all Ln(THED)3+ or Ln(S-THP)3+ complexes except Nd(III) at low water concentrations (< 1%). In 100% aqueous buffered solutions, the CEST hydroxyl peak is observed for the Eu(III), Ce(III) and Yb(III) complexes over a range of pH values. The optimal pH range for the CEST effect of each complex is related to the pKa of the hydroxyl/water ligands of the complex. Optimum pH values for the CEST effect from alcohol proton exchange are pH = 6.0 for Ce(S-THP)3+, pH = 4.5 for Eu(THED)3+, and pH= 3.0 for Yb(S-THP)3+.

Comparison of divalent transition metal ion paraCEST MRI contrast agents

“…The only other example with four of the same donor group is found in the [Ln(STHP)] 3+ complexes that have four alcohol pendent groups (Ln III = Ce III , Eu III and Yb III ) [31, 83–85]. Unfortunately, the CEST peaks of these agents are not highly shifted and the complex with the most highly shifted CEST peak, [Yb(STHP)] 3+ , produces CEST only at acidic pH values.…”

Static and Dynamic Stereochemistry of Chiral Ln DOTA Analogues

“…Naturally, this cannot be achieved on the sp 2 carboxylic carbon, but it becomes possible on a carbinolic derivative, THP (THP = 1,4,7,10-tetrakis(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane), depicted in Figure 7. [37][38][39][40][41] Following a procedure similar to what outlined for DOTMA in Figure 5, we can predict that the (SSSS)-configuration of the ligand will lead to D coordination, as shown in Figure 7.…”

“…[39,40] One can tentatively extend these findings to the whole Ln THP series, on account of the similar behaviour of the paramagnetic shifts recently reported for the Ce, Nd, Eu derivatives. [41] Chirality has been introduced at an even more remote position, outside the first coordination sphere, by derivatizing the carboxyl group with a chiral amine, as occurs for example with the amide DOTAMNp (Scheme 2). [42][43][44][45] It may appear surprising that in spite of the distance between the chiral centre and the DOTA scaffold, Yb DOTAMNp is completely rigid and does not show any dynamic process, in a wide range of solvents [methanol, dimethyl sulfoxide (DMSO), acetonitrile].…”

Dynamic cyclen–metal complexes for molecular sensing and chirality signaling

“…Since their sidearms had alcohol protons chemically exchangeable with bulk water, the Eu 3+ complex showed PARACEST signals at pH 6.5. 45 They further demonstrated that effective binding of 19-Eu 3+ with anions such as citrate and acetate shifted the PARACEST signals downfield, demonstrating its utility as an anion responsive probe. 46 The effect of pH on the water exchange process and relaxivity was investigated with lanthanide complexes with a series of DOTA-tetraamide ligands.…”