Direct NMR Spectroscopic Observation of a Lanthanide-Coordinated Water Molecule whose Exchange Rate Is Dependent on the Conformation of the Complexes

Aime, Silvio; Botta, Mauro; Sousa, Alvaro S. de; Parker, David G.

doi:10.1002/(sici)1521-3773(19981016)37:19<2673::aid-anie2673>3.3.co;2-r

Cited by 71 publications

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“…One class of paramagnetic lanthanide complexes that had been ruled out as T 1 -shortening agents because water exchange was too slow were complexes formed with tetramide derivatives of DOTA. 6 Water exchange in some europium(III) DOTA tetraamide complexes has been observed to be so slow that a separate resonance for the Eu 3+ -coordinated water protons can be observed by high resolution NMR in dry acetonitrile 7 and even in water as solvent. 8 The importance of this for CEST was that the Eu 3+ -coordinated water molecule is shifted ~50 ppm away from the solvent water peak.…”

Section: Paracest: Its Origins and Advantagesmentioning

confidence: 99%

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Paramagnetic lanthanide complexes as PARACEST agents for medical imaging

2006

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This tutorial review examines the fundamental aspects of a new class of contrast media for MRI based upon the chemical shift saturation transfer (CEST) mechanism. Several paramagnetic versions called PARACEST agents have shown utility as responsive agents for reporting physiological or metabolic information by MRI. It is shown that basic NMR exchange theory can be used to predict how parameters such as chemical shift, bound water lifetimes, and relaxation rates can be optimized to maximize the sensitivity of PARACEST agents.Magnetic resonance imaging (MRI) is arguably the most important diagnostic imaging tool in clinical medicine today offering exquisite anatomical images of soft tissues based upon detection of protons largely in water and fat. Image contrast is readily manipulated by choosing from a standard set of pulse sequences that weight signal intensities based upon differences in proton densities and T 1 and T 2 relaxation rates. For many clinical applications, however, it now common practice to administer an exogenous contrast agent to highlight specific tissue regions based upon flow or agent biodistribution. MRI contrast agents so far have been largely confined to small paramagnetic metal complexes, typically gadolinium(III) complexes, that alter signal intensity by shortening the relaxation times of the water protons. 1 The mechanism of action of this class of agents is described in more detail in a separate review in this edition. Although such first generation agents are widely used in clinical medicine, the physical properties of such agents are limited when considering a new generation of MRI contrast agents that will provide functional as well as anatomical information. 2 New agents that operate by a CEST mechanism may ultimately be able to provide important metabolic information with exquisite anatomical resolution. What is CEST?CEST is an acronym for Chemical Exchange Saturation Transfer, the basics of which are well established in NMR spectroscopy. In early experiments, it was also referred to as Saturation Transfer or Magnetization Transfer (MT). As its name suggests CEST involves chemical exchange of a nucleus in the NMR experiment from one site to a chemically different site. Before introducing CEST, it is necessary to consider briefly the origin of an NMR signal, more © The Royal Society of Chemistry 2006Correspondence to: A. Dean Sherry. NIH Public Access Author ManuscriptChem Soc Rev. Author manuscript; available in PMC 2009 July 30. Published in final edited form as:Chem Soc Rev. 2006 June ; 35(6): 500-511. doi:10.1039/b509907m. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript detailed descriptions are available elsewhere. 3 When a nucleus having a net magnetic spin (the proton spin quantum number, I, equals ½) is placed in a magnetic field, the spins orient either in the same direction as the magnetic field (low energy-α) or against the field (high energy-β) (Fig. 1). The distribution of spins between these two energy states is determined by the Boltz...

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Section: Paracest: Its Origins and Advantagesmentioning

confidence: 99%

“…A numerical analysis that involves solution of the Bloch equations formulated to include exchange between two pools of protons shows that this optimal value is dependent upon the saturation power, ω 1 . 27 (6) This fundamental concept is graphically illustrated by Fig. 9.…”

Section: Using Exchange Theory To Optimize Paracest Agentsmentioning

confidence: 99%

Paramagnetic lanthanide complexes as PARACEST agents for medical imaging

2006

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“…Clearly, as the metal ion gets larger the distortion of the N-C-C-O torsion angle will increase until eventually it reaches 0° and there is no more give in the system. At this point the bridge is too short to reach across the complex if the 21-membered macrocycle adopts the [7,5,4,2,3] ring conformation shown in Figure 6 and observed in the crystal structure of Yb1. 35 The only way in which the bridge can span the complex is if the 21-membered macrocycle alters its confromation to make the bridging span longer.…”

Section: Ln8o 2 -Bridged-dotam Complexes In Solutionmentioning

confidence: 99%

“…[4][5][6] This, and the large lanthanide induced shifts (LIS) of the exchanging amide and coordinated water protons, make this type of complex attractive systems to study as CEST agents. 3 These paramagnetic CEST (PARACEST) agents offer some significant advantages over the diamagnetic molecules originally proposed as CEST agents; 3,7,8 most importantly, the large chemical shift difference between the exchanging protons on the agent and the bulk water reduces off-resonance direct saturation of the bulk water signal.…”

Section: Introductionmentioning

confidence: 99%

A Bridge to Coordination Isomer Selection in Lanthanide(III) DOTA-tetraamide Complexes

et al. 2007

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Interest in macrocyclic lanthanide complexes such as DOTA is driven largely through interest in their use as contrast agents for MRI. The lanthanide tetraamide derivatives of DOTA have shown considerable promise as PARACEST agents, taking advantage of the slow water exchange kinetics of this class of complex. We postulated that water exchange in these tetraamide complexes could be slowed even further by introducing a group to sterically encumber the space above the water coordination site, thereby hindering the departure and approach of water molecules to the complex. The ligand 8O 2 -bridged-DOTAM was synthesized in a 34% yield from cyclen. It was found that the lanthanide complexes of this ligand did not possess a water molecule in the inner coordination sphere of the bound lanthanide. The crystal structure of the ytterbium complex revealed that distortions to the coordination sphere were induced by the steric constraints imposed on the complex by the bridging unit. The extent of the distortion was found to increase with increasing ionic radius of the lanthanide ion, eventually resulting in a complete loss of symmetry in the complex. Because this ligand system is bicyclic, the conformation of each ring in the system is constrained by that of the other, in consequence inclusion of the bridging unit in the complexes means only a twisted square antiprismatic coordination geometry is observed for complexes of 8O 2 -bridged-DOTAM.

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“…[23] It has been shown for the complex [Eu(DOTAM)(H 2 O)] 3ϩ that the diastereoisomers have different exchange rates. [24] Recently, the study of interconversion mechanisms between the diastereoisomers proved that the global value of the residence time was mainly fixed by the minor stereoisomer. [25] The exchange rates measured for the bis(alkylamide) derivatives are therefore averages weighted by the molar fractions of the stereoisomers.…”

Section: Primary and Secondary Bis(amide) Dtpa Gd III -Chelatesmentioning

confidence: 99%