In vivo MRI assessment of a novel GdIII-based contrast agent designed for high magnetic field applications

Authors

  • Paulo Loureiro de Sousa,

    1. Centre de Biophysique Moléculaire, CNRS, rue Charles Sadron, 45071 Orléans, France
    Current affiliation:
    1. NMR Laboratory, AIM and CEA, Institut de Myologie, La Pitié-Salpêtrière University Hospital, Paris, France.
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  • João Bruno Livramento,

    1. Laboratoire de Chimie Inorganique et Bioinorganique, Ecole Polytechnique Fédérale de Lausanne, EPFL-BCH; CH-1015 Lausanne, Switzerland
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  • Lothar Helm,

    1. Laboratoire de Chimie Inorganique et Bioinorganique, Ecole Polytechnique Fédérale de Lausanne, EPFL-BCH; CH-1015 Lausanne, Switzerland
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  • André E. Merbach,

    1. Laboratoire de Chimie Inorganique et Bioinorganique, Ecole Polytechnique Fédérale de Lausanne, EPFL-BCH; CH-1015 Lausanne, Switzerland
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  • William Même,

    1. UPRES EA 2633, Laboratoire de Neurobiologie, Université d'Orléans, Orléans, France
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  • Bich-Thuy Doan,

    1. Centre de Biophysique Moléculaire, CNRS, rue Charles Sadron, 45071 Orléans, France
    2. ICSN, CNRS, avenue de la Terrasse, 91198 Gif sur Yvette, cedex, France
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  • Jean-Claude Beloeil,

    1. Centre de Biophysique Moléculaire, CNRS, rue Charles Sadron, 45071 Orléans, France
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  • Maria I. M. Prata,

    1. Instituto de Biofísica e Biomatemática, Faculdade de Medicina, Universidade de Coimbra, Portugal
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  • Ana C. Santos,

    1. Instituto de Biofísica e Biomatemática, Faculdade de Medicina, Universidade de Coimbra, Portugal
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  • Carlos F. G. C. Geraldes,

    1. Departamento de Bioquímica, Centro de RMN e Centro de Neurociências e Biologia Celular, Faculdade de Ciências e Tecnologia, Universidade de Coimbra, Coimbra, Portugal
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  • Éva Tóth

    Corresponding author
    1. Centre de Biophysique Moléculaire, CNRS, rue Charles Sadron, 45071 Orléans, France
    2. Laboratoire de Chimie Inorganique et Bioinorganique, Ecole Polytechnique Fédérale de Lausanne, EPFL-BCH; CH-1015 Lausanne, Switzerland
    • Centre de Biophysique Moléculaire, CNRS, Rue Charles-Sadron - 45071 Orléans cedex 2, France.
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Abstract

Gd3L is a trinuclear Gd3+ complex of intermediate size, designed for contrast agent applications in high field magnetic resonance imaging (H12L is based on a trimethylbenzene core bearing three methylene-diethylenetriamine- N,N,N″,N″-tetraacetate moieties). Thanks to its appropriate size, the presence of two inner sphere water molecules and a fast water exchange, Gd3L has remarkable proton relaxivities at high magnetic field (r1 = 10.2 vs 3.0 mM−1 s−1 for GdDOTA at 9.4 T, 37°C, in H2O). Here we report an in vivo MRI feasibility study, complemented with dynamic γ scintigraphic imaging and biodistribution experiments using the 153Sm-enriched analog. MRI experiments were performed at 9.4 T in mice with Gd3L and the commercial contrast agent gadolinium(III)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate (GdDOTA). Gd3L was well tolerated by the animals at the dose of 8 µmol Gd kg−1 body weight. Dynamic contrast enhanced (DCE) images showed considerably higher signal enhancement in the kidney medulla and cortex after Gd3L injection than after GdDOTA injection at an identical dose. The relaxation rates, ΔR1, were calculated from the IR TrueFISP data. During the excretory phase, the ΔR1 for various tissues was similar for Gd3L and GdDOTA, when the latter was injected at a three-fold higher dose (24 vs 8 µmol Gd kg−1 body weight). These results point to an approximately three times higher in vivo relaxivity (per Gd) for Gd3L relative to GdDOTA, thus the ratio of the relaxivities of the two compounds determined in vitro is retained under in vivo conditions. They also indicate that the two inner sphere water molecules per Gd in Gd3L are not substantially replaced by endogenous anions or other donor groups under physiological conditions. Gd3L has a pharmacokinetics typical of small, hydrophilic complexes, involving fast renal clearance and no retention in the blood pool. The dynamic γ scintigraphic studies and the biodistribution experiments performed in Wistar rats with 153Sm-enriched *Sm3L are also indicative of a fast elimination via the kidneys. Copyright © 2008 John Wiley & Sons, Ltd.

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