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The solution structure and dynamics of metal-bound water exchange have been investigated in a series of lanthanide complexes of primary, secondary, and tertiary tetraamide derivatives of 1,4,7,10-tetraazacyclododecane. In the gadolinium complexes at ambient pH, water exchange lifetimes (τm) determined by 17O NMR were sufficiently long (19 μs for [Gd·2]3+, 298 K, 17 μs for [Gd·3]3+, and 8 μs for [Gd·4]3+) to limit the measured relaxivity. Direct 1H NMR observation of the bound water resonance is possible for the corresponding Eu complexes at low temperature in CD3CN, and the rate of water proton exchange is about 50 times faster in the twisted square antiprismatic isomer (m) than in the isomeric square antiprismatic (M) complex. The ratio of these two isomers in solution is sensitive to the steric demand of the amide substituent, with m/M = 2 for [Eu·4]3+, but 0.25 for [Eu·2]3+. The slowness of coordinated water exchange has allowed the rate of prototropic exchange to be studied:  in basic media deprotonation of the bound water molecule or of proximate ligand amide NH protons leads to relaxivity enhancements, whereas in acidic media, hydration around the strongly ion-paired complexes is perturbed, facilitating water exchange. The X-ray crystal structure of ligand 3 reveals a hydrogen-bonded structure with two pairs of ring N-substituents related in a trans arrangement, contrasting with the structure of diprotonated DOTA in which the ligand is predisposed to bind metal ions. In the dysprosium complex [Dy·3·OH2](PF6)3, the metal ion adopts a regular monocapped square antiprismatic coordination geometry, with a water Dy−O bond length of 2.427(3) Å, and a PF6 counterion is strongly hydrogen-bonded to this bound water molecule.

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...

Magnetic resonance imaging (MRI) contrast agents have become an important tool in clinical medicine. The most common agents are Gd(3+)-based complexes that shorten bulk water T(1) by rapid exchange of a single inner-sphere water molecule with bulk solvent water. Current gadolinium agents lack tissue specificity and typically do not respond to their chemical environment. Recently, it has been demonstrated that MR contrast may be altered by an entirely different mechanism based on chemical exchange saturation transfer (CEST). CEST contrast can originate from exchange of endogenous amide or hydroxyl protons or from exchangeable sites on exogenous CEST agents. This has opened the door for the discovery of new classes of responsive agents ranging from MR gene reporter molecules to small molecules that sense their tissue environment and respond to biological events.