Paramagnetic lanthanide complexes as PARACEST agents for medical imaging

Abstract

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...

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

“…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.…”

“…The results of this analysis show that as the presaturation power is reduced the exchange rate required to produce the largest CEST effect becomes slower and slower. 7,9 In consequence, the design of more efficient CEST agents for use at lower pre-saturation powers requires the design of lanthanide complexes with extremely slow water exchange rates, τ M > 1 ms (τ M = 1/k ex ). 7,9 In order to achieve this goal it is necessary to have a good understanding of the factors that affect water exchange in DOTA-tetraamide complexes.…”

Understanding quantitative pulsed CEST in the presence of MT

“…As the chemical exchange is sensitive to hydrogen ion concentration, CEST experiments may allow quantification of pH as well. Quantitative measurements of the exchange rate constant and concentration for different lanthanide-based CEST contrast agents have been obtained from phantom experiments (10,11), but in vivo CEST quantification has been less successful. One of the main challenges for producing quantitative CEST measurements in vivo is the added interference of proton exchange with the semi-solid macromolecular protons, the magnetization transfer (MT) effect, that may reduce the asymmetry in the CEST spectra (12).…”

Optimized MRI contrast for on‐resonance proton exchange processes of PARACEST agents in biological systems

“…Diamagnetic and paramagnetic chemical exchange saturation transfer (PARACEST) (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) agents have many possible medical and biologic applications, including the measurement of tissue pH based on the pH dependence of the exchange rate of amide protons with bulk water protons (13)(14)(15), the measurement of tissue temperature using the linear dependence of the bound water chemical shift on temperature (16,17), enzymatic activity (18), and metabolite levels (19)(20)(21). The CEST detection sensitivity (or CEST effect) is defined as the change in the bulk water signal intensity of the agent solution following irradiation of the exchangeable protons.…”