Synthesis, Characterization, and Pharmacokinetic Evaluation of a Potential MRI Contrast Agent Containing Two Paramagnetic Centers with Albumin Binding Affinity Tatjana N. Parac-Vogt, [a] Kristof Kimpe, [a] Sophie Laurent, [b] Luce Vander Elst, [b] Carmen Burtea, [b] Feng Chen, [c] Robert N. Muller, [b] Yicheng Ni, [c] Alfons Verbruggen, [d] and Koen Binnemans* [a] Introduction Magnetic resonance imaging (MRI) is routinely used in vari- ous diagnostic imaging procedures. Although excellent soft- tissue images can be obtained by this method, early experi- ments showed that contrast agents might greatly increase its diagnostic value. Consequently, the development of MRI techniques has been accompanied by an increased interest in developing contrast agents. [1–3] The first MRI contrast agent approved for use in humans, the gadolinium(iii ) com- Abstract: A dinuclear gadolinium(iii ) complex of an amphiphilic chelating ligand, containing two diethylenetri- amine-N,N,N’,N’’,N’’-pentaacetate (DTPA) moieties bridged by a bisin- dole derivative with three methoxy groups, has been synthesized and eval- uated as a potential magnetic reso- nance imaging (MRI) contrast agent. Nuclear magnetic relaxation dispersion (NMRD) measurements indicate that at 20 MHz and 37 8C the dinuclear gadolinium(iii ) complex has a much higher relaxivity than [Gd(DTPA)] (6.8 vs 3.9 s 1 mmol 1 ). The higher relaxivity of the dinuclear gadolinium(iii ) com- plex can be related to its reduced motion and larger rotational correla- tion time relative to [Gd(DTPA)]. In the presence of human serum albumin (HSA) the relaxivity value of the non- covalently bound dinuclear complex in- creases to 15.2 s 1 per mmol of Gd 3 + , due to its relatively strong interaction with this protein. The fitted value of the binding constant to HSA (K a ) was found to be 10 4 m 1 . Because of its in- teraction with HSA, the dinuclear com- plex exhibits a longer elimination half- life from the plasma, and a better con- finement to the vascular space com- pared to the commercially available [Gd(DTPA)] contrast agent. Transme- talation of the dinuclear gadolinium(iii ) complex by zinc(ii ) has been investigat- ed. Biodistribution studies suggest that the complex is excreted by the renal pathway, and possibly by the hepato- biliary route. In vivo studies indicated that half of the normal dose of the gadolinium(iii ) complex enhanced the contrast in hepatic tissues around 40 % more effectively than [Gd(DTPA)]. The dinuclear gadolinium(iii ) complex was tested as a potential necrosis avid contrast agent (NACA), but despite the binding to HSA, it did not exhibit necrosis avidity, implying that binding to albumin is not a key parameter for necrosis-targeting properties. Keywords: gadolinium · imaging agents · lanthanides · NMR spectroscopy · rare earths [a] Dr. T. N. Parac-Vogt, Dr. K. Kimpe, Prof. Dr. K. Binnemans Department of Chemistry, Katholieke Universiteit Leuven Celestijnenlaan 200F, 3001 Leuven (Belgium) Fax: (+ 32) 16-327-992 E-mail : koen.binnemans@chem.kuleuven.ac.be [b] Dr. S. Laurent, Prof. Dr. L. Vander Elst, Dr. C. Burtea, Prof. Dr. R. N. Muller NMR and Molecular Imaging Laboratory Department of Organic and Biomedical Chemistry University of Mons-Hainaut, 7000 Mons (Belgium) [c] Dr. F. Chen, Prof.Dr. Y. Ni Biomedical Imaging Interventional Therapy and Contrast Media Research Department of Radiology, University Hospitals, K.U. Leuven Herestraat 49, 3000 Leuven (Belgium) [d] Prof. Dr. A. Verbruggen Laboratory of Radiopharmaceutical Chemistry Department of Pharmaceutical Sciences Van Evenstraat 4, 3000 Leuven (Belgium) Supporting information for this article is available on the WWW under http://www.chemeurj.org/ or from the author. Chem. Eur. J. 2005, 11, 3077 – 3086 DOI: 10.1002/chem.200401207  2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 3077 FULL PAPER