Abstract
In the search for improvement in the properties of gadolinium-based contrast agents, cyclodextrins (CDs) are interesting hydrophilic scaffolds with high molecular weight. The impact of the hydrophilicity of these systems on the MRI efficacy has been studied using five β-CDs substituted with DOTA or TTHA ligands which, respectively, allow for one (q = 1) or no water molecule (q = 0) in the inner coordination sphere of the Gd3+ ion. Original synthetic pathways were developed to immobilize the ligands at C-6 position of various hydroxylated and permethylated β-CDs via an amide bond. To describe the influence of alcohol and ether oxide functions of the CD macrocycle on the relaxation properties of the Gd3+ complexes, 1H Nuclear Magnetic Relaxation Dispersion (NMRD) profiles, and 17O transverse relaxation rates have been measured at various temperatures. The differences observed between the hydroxylated and permethylated β-CDs bearing non-hydrated GdTTHA complexes can be rationalized by a second sphere contribution to the relaxivity in the case of the hydroxylated derivatives, induced by hydrogen-bound water molecules around the hydroxyl groups. In contrast, for the DOTA analogs the exchange rate of the water molecule directly coordinated to the Gd3+ is clearly influenced by the number of hydroxyl groups present on the CD, which in turn influences the relaxivity and gives rise to a very complex behavior of these hydrophilic systems.
Highlights
Magnetic resonance imaging (MRI) is currently used to diagnose diseases and to monitor treatment progress in deep tissues
We have focused our study on cyclodextrins (CDs) as interesting and versatile scaffolds to design potential MRI contrast agents
Synthesis of CDs Functionalized with DOTA Ligand
Summary
Magnetic resonance imaging (MRI) is currently used to diagnose diseases and to monitor treatment progress in deep tissues. A second sphere (2S) mechanism might be operating for systems containing water molecules strongly hydrogen-bonded to the functional groups of the complex. A 40% relaxivity enhancement was observed with perhydroxylated β-CDs (4.6 mM−1 s−1 and 6.5 mM−1 s−1 , respectively) As these complexes had similar structure and identical hydration number (q = 2), the relaxivity difference was attributed to the presence of hydrogen-bound water molecules around the hydroxyl groups inducing an important second-sphere (2S) contribution to relaxivity. TTHA is a commercially available linear ligand with six carboxylic acid and four amine functions which can chelate the Gd3+ ion This full coordination by the ligand prevents inner sphere (IS) binding of any water molecule.
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