Triethylenetetramine penta- and hexa-acetamide ligands and their ytterbium complexes as paraCEST contrast agents for MRI

Dirk Burdinski, Johan Lub, Jeroen A. Pikkemaat, Diana Moreno Jalón, Sophie Martial, Carolina Del Pozo Ochoa

Onderzoeksoutput: Bijdrage aan tijdschriftTijdschriftartikelAcademicpeer review

14 Citaten (Scopus)


The ligand triethylenetetramine-N,N,N′,N″,N′″, N′″-hexaacetamide (ttham) was synthesized with the aim of forming lanthanide complexes suitable as contrast agents for magnetic resonance imaging applications utilizing the chemical exchange-dependent saturation transfer (CEST) effect. It was designed to exclude water molecules from the first coordination sphere and provide a high number of CEST active amide protons per lanthanide ion. The ligand was characterized by its protonation behavior and its complexation properties with ytterbium ions in aqueous solution. The basicity of the ttham backbone amine protons decreases in the order N central(1) > Nterminal(1) > Nterminal(2) > Ncentral(2), as deduced from NMR titration experiments and from a comparison of its protonation constants with those of two ttham derivatives, in which either a terminal (N-benzyl-triethylenetetramine-N,N′,N″, N′″,N′″-pentaacetamide, 1bttpam) or a central acetamide group (N′-benzyl-triethylenetetramine-N,N,N″,N′″, N′″-pentaacetamide, 4bttpam) is substituted with a benzyl group. This protonation sequence results from the combined influence of inductive effects, the intramolecular hydrogen bonding network, and the Coulomb repulsion between protonated ammonium groups. The ytterbium complex of ttham, [Yb(ttham)]Cl3, is coordinatively frustrated. Due to steric constraints, in addition to the four backbone nitrogen atoms, only three of the four symmetry-equivalent terminal acetamide donors can coordinate simultaneously to the ytterbium ion, and the dangling fourth one exchanges quickly with the other three. The ytterbium complexes of a total of five ligands (ttham, 1bttpam, 4bttpam, 2,2′,2″-triaminotriethylaminehexaacetamide (ttaham), and diethylenetriamine-N,N,N′,N″,N″-pentaacetamide (dtpam)) were studied with respect to their CEST properties. In solution, all of these complexes have a low symmetry. The presence of multiple magnetically different amide groups in each complex prevents the realization of very high CEST effects. These results nevertheless form an excellent basis for a further optimization of this class of ligands.

Originele taal-2Engels
Pagina's (van-tot)4138-4151
Aantal pagina's14
TijdschriftDalton Transactions
Nummer van het tijdschrift31
StatusGepubliceerd - 18 aug 2008
Extern gepubliceerdJa

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