Issue 24, 2009
From the journal:

Dalton Transactions

Lanthanide chelates of (bis)-hydroxymethyl-substituted DTTA with potential application as contrast agents in magnetic resonance imaging†‡

Sara Silvério,a   Susana Torres,a   André F. Martins,b   José A. Martins,*a   João P. André,a   Lothar Helm,*c   M. Isabel M. Prata,d   Ana C. Santosd  and  Carlos F. G. C. Geraldes*b  

* Corresponding authors

a Centro de Química, Campus de Gualtar, Universidade do Minho, 4710-057 Braga, Portugal

b Departamento de Bioquímica, Faculdade de Ciências e Tecnologia, e Centro de Neurociências e Biologia Celular, Universidade de Coimbra, 3001–401 Coimbra, Portugal
E-mail: geraldes@bioq.uc.pt
Fax: +35 1239853607
Tel: +35 1239853608

c Laboratoire de Chimie Inorganique et Bioinorganique, Ecole Polytechnique Fédérale de Lausanne, EPFL-BCH, CH-1015 Lausanne, Switzerland

d Instituto de Biofísica e Biomatemática, Faculdade de Medicina, Universidade de Coimbra, Portugal

Abstract

A novel bis-hydroxymethyl-substituted DTTA chelatorN′-Bz-C4,4′-(CH2OH)2-DTTA (1) and its DTPA analogue C4,4′-(CH2OH)2-DTPA (2) were synthesized and characterized. A variable-temperature 1H NMR spectroscopy study of the solution dynamics of their diamagnetic (La) and paramagnetic (Sm, Eu) Ln3+ complexes showed them to be rigid when compared with analogous Ln3+-DTTA and Ln3+-DTPA complexes, as a result of their C4,4′-(CH2OH)2 ligand backbone substitution. The parameters that govern the water1H relaxivity of the [Gd(1)(H2O)2]− and [Gd(2)(H2O)]2− complexes were obtained by 17O and 1H NMR relaxometry. While the relaxometric behaviour of the [Gd(2)(H2O)]2− complex is very similar to the parent [Gd(DTPA)(H2O)]2− system, the [Gd(1)(H2O)2]− complex displays higher relaxivity, due to the presence of two inner sphere water molecules and an accelerated, near optimal water exchange rate. The [Gd(1)(H2O)2]− complex interacts weakly with human serum albumin (HSA), and its fully bound relaxivity is limited by slow water exchange, as monitored by 1H NMR relaxometry. This complex interacts weakly with phosphate, but does not form ternary complexes with bidentate bicarbonate and L-lactate anions, indicating that the two inner-sphere water molecules of the [Gd(1)(H2O)2]− complex are not located in adjacent positions in the coordination sphere of the Gd3+ ion. The transmetallation reaction rate of [Gd(1)(H2O)2]− with Zn2+ in phosphate buffer solution (pH 7.0) was measured to be similar to that of the backbone unsubstituted [Gd(DTTA-Me)(H2O)2]−, but twice faster than for [Gd(DTPA-BMA)(H2O)]. The in vivo biodistribution studies of the 153Sm3+-labelled ligand (1) in Wistar rats reveal slow blood elimination and short term fixation in various organs, indicating some dissociation. The bis-hydroxymethyl-substituted DTTA skeleton can be seen as a new lead for the synthesis of high relaxivity contrast agents, although its low thermodynamic and kinetic stability will limit its use to in vitro and animal studies.

Graphical abstract: Lanthanide chelates of (bis)-hydroxymethyl-substituted DTTA with potential application as contrast agents in magnetic resonance imaging

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Article information

DOI
https://doi.org/10.1039/B823402G
Article type
Paper
Submitted
05 Jan 2009
Accepted
11 Mar 2009
First published
22 Apr 2009

Dalton Trans., 2009, 4656-4670

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Lanthanide chelates of (bis)-hydroxymethyl-substituted DTTA with potential application as contrast agents in magnetic resonance imaging

S. Silvério, S. Torres, A. F. Martins, J. A. Martins, J. P. André, L. Helm, M. I. M. Prata, A. C. Santos and C. F. G. C. Geraldes, Dalton Trans., 2009, 4656 DOI: 10.1039/B823402G

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