FULL PAPER DOI: 10.1002/ejic.200601170 Bis(phenylethylamide) Derivatives of Gd-DTPA as Potential Receptor-Specific MRI Contrast Agents Sophie Laurent, [a] Tatjana N. Parac-Vogt,* [b] Kristof Kimpe, [b] Coralie Thirifays, [a] Koen Binnemans, [b] Robert N. Muller, [a] and Luce Vander Elst* [a] Keywords: Lanthanides / MRI contrast agents / N,O ligands / NMRD / 17 O NMR spectroscopy DTPA-bis(amide) derivatives bearing phenyl, phenol or cate- chol groups that mimic side chains of naturally occurring amino acids, such as phenylalanine, tyrosine or dopamine, were synthesized and characterized by elemental analysis, electrospray mass spectrometry, NMR spectroscopy and IR spectroscopy. The gadolinium(III) complexes of the ligands DTPA-bis(tyramide) [DTPA-(TA) 2 ], DTPA-bis(3-hydroxy- tyramide) [DTPA-(HTA) 2 ] and DTPA-bis(phenylalanine ethyl ester) [DTPA-(PAE) 2 ], were prepared and then studied in vi- tro by 17 O NMR spectroscopy and by nuclear magnetic relax- ation dispersion (NMRD) measurements. The residence time Introduction Magnetic resonance imaging (MRI) is a powerful diag- nostic technique which is used for obtaining images of in- ternal organs and tissues. [1] Nowadays, an increasing number of MRI scans are performed employing contrast agents, which are able to greatly increase the contrast be- tween tissues in magnetic resonance images. [2] The efficiency of contrast agents is related to their ability to enhance the proton relaxation of water tissues. This property, called re- laxivity , depends on different factors such as the molecular mobility of the contrast agent, the water dynamics and the noncovalent binding of the contrast agent to endogenous proteins. [3,4] In recent years, new developments in molecular imaging applications have prompted the development of a novel class of contrast agents characterized by a higher con- trasting ability and improved targeting capabilities. Several strategies have been explored in order to slow down the rotational motion of the gadolinium(III)-based contrast agents and thus to increase their relaxation effi- ciency. These approaches include (i) the synthesis of coval- ently or noncovalently bound macromolecular gadolini- [a] Department of General, Organic and Biomedical Chemistry, NMR and Molecular Imaging Laboratory, University of Mons- Hainaut, 7000 Mons, Belgium Fax: +32-65-373520 E-mail: Luce.VanderElst@umh.ac.be [b] Department of Chemistry, Katholieke Universiteit Leuven, Celestijnenlaan 200F, 3001 Leuven, Belgium Fax: +32-16-327992 E-mail: Tatjana.Vogt@chem.kuleuven.be Eur. J. Inorg. Chem. 2007, 2061–2067 © 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 2061 of the coordinated water in gadolinium(III) complexes was obtained from 17 O NMR relaxometric T 2 measurements. At 310 K, the following τ M values were obtained: Gd-DTPA- (TA) 2 582 ns, Gd-DTPA-(HTA) 2 372 ns and Gd-DTPA-(PAE) 2 809 ns. As shown by the analysis of the proton NMRD pro- files, the larger proton relaxivities of the gadolinium(III) com- plexes at 310 K relative to that of the parent Gd-DTPA com- plex are mainly because of the increase in the rotational correlation time. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007) um(III) chelates such as dendrimers, linear polymers or pro- teins; [5–7] (ii) the synthesis of amphiphilic gadolinium(III) complexes which can self-assemble to micelles; [8,9] (iii) lipo- philic gadolinium(III) complexes incorporated in supramo- lecular systems with a better control of the size such as mixed micelles; [10–12] and (iv) incorporation of amphipathic gadolinium(III) complexes into the membranes of lipo- somes. [13–17] The properties of the contrast agents that are important for the tissue specificity include molecular size, charge and lipophilicity. Since most of the specific cell-cell interactions or recognitions are regulated by special proteins, receptor targeting can be attained by mimicking signal peptides. For example, adhesive proteins present in extracellular matrices and in blood, such as fibrinogen and collagens, contain the tripeptide arginine–glycine–aspartic acid as the cell recogni- tion site. [18] Using this binding domain or similar sequences, small peptides can be designed to target receptors. [19] Ad- ditionally, some receptors have an affinity for certain classes of substrates such as amino acids or catechol amines. [20] These receptors may also bind molecules that resemble the substrate, for example, a derivative of an amino acid that is present in a peptide substrate or an amide derivative of a naturally occurring catechol amine such as dopamine. The coupling of these potential recognition groups to high re- laxivity moieties such as [Gd(DTPA)(H 2 O)] 2– could thus lead to tissue specificity of the contrast agent. In this paper we report on ligands based on bis(amide) derivatives of DTPA bearing phenyl, phenol or catechol groups that mimic the side chains of naturally occurring