Chemical exchange saturation transfer imaging and spectroscopy

Research output: Contribution to journalReview article

Abstract

The study of chemical exchange processes is one of the oldest and still most vigorously investigated topics in NMR spectroscopy. The effects of chemical exchange on the NMR spectrum were reported as early as 1951 [1,2] and investigated intensively during the early days of NMR [3-10]. In a landmark paper published in 1963, Forsen and Hoffman [8] studied moderately rapid chemical reactions by means of nuclear magnetic double resonance. Especially since the advent of two-dimensional (2D) NMR [11,12], numerous important advancements have occurred [13-16]. In addition to protons (1H), exchange spectroscopy has been applied to other NMR nuclei such as phosphorus (31P), fluorine (19F), and carbon (13C). Over the past half century, much valuable information on chemical reactions and exchange processes has been obtained by NMR spectroscopy studies. In the last six years, there has been a surge in NMR exchange applications because of the realization that saturation transfer experiments can be designed that allow a large sensitivity enhancement. The first to demonstrate that exchange between labile protons of low-concentration solutes and water protons provides a sensitivity enhancement scheme were Balaban et al. [17-19], who dubbed this new MRI contrast mechanism chemical exchange dependent saturation transfer (CEST) [19]. After this initial work on small solutes, van Zijl and colleagues [20,21] showed that enormous increases in sensitivity could be obtained for macromolecules with a large number of exchanging sites of similar chemical shift. Enhancements as large as 500,000 were demonstrated for amide protons on cationic polymers [20], such as poly-l-lysine (PLL) and dendrimers, while a record enhancement of 107 or more was reported for the imino protons of polyuridilic acid (poly(rU)) [21]. At the same time, Zhang et al. [22,23] and Aime et al. [24] reported several paramagnetic CEST (PARACEST) agents that made the approach more flexible by significantly enlarging the frequency range for the exchanging sites. By analogy to this nomenclature, we will call the other compounds diamagnetic CEST (DIACEST) agents. In 2003, Zhou et al. [25,26] showed that endogenous mobile proteins and peptides at very low concentration in biological tissue could also be detected via the water signal. In this so-called amide proton transfer (APT) imaging approach, the endogenous composite amide resonance around 8.3 ppm is saturated and detected indirectly by MRI, allowing the investigator to image tissue pH [25] and tissue protein and peptide content [26]. The large number of important achievements in NMR exchange spectroscopy since 1951 have been summarized in numerous excellent review articles [27-34] and textbooks [14,35-38] and are not covered in the current review. We also do not review exchange studies using heteronuclei such as 31P [15,16,39-47], 19F [48,49], 13C [50,51], and others. Instead, the goal of the current review is to present a systematic summary of proton saturation transfer studies in MRI and MRS with the purpose of imaging. Specifically, this review covers the first paper in this field suggesting the exchange enhancement in 1990 [17] and a number of important findings published between 1998 and November 2005. Because MRI is mostly a water-based approach in the clinic, we focus on water-related chemical exchange processes such as between low-concentration solute protons and water protons, which theoretically correspond to the case of exchange between a small pool being irradiated and a large pool being detected. The main reason that this approach is becoming important is that it presents a sensitivity enhancement scheme in which continuous saturation of the small pool causes cumulative saturation of the big pool, as will be explained below. Application of off-resonance irradiation saturation transfer is not the only way to image effects due to chemical exchange. Many alternative, non-saturation-transfer techniques have been proposed, including inversion transfer [52-55], T1 in the rotating frame [56-60], T2 in the rotating frame [61,62], and recently on-resonance exchange-sensitive low-power pulse trains [63], but these are not reviewed here. Finally, for more background reading, the early PARACEST findings including basic chemistry have been summarized in an excellent review article [64], and APT imaging has been reviewed in a recent conference proceeding [65]. An overview of exchange between small and large proton pools in principle would need to include both conventional magnetization transfer (MT) contrast [66-69] based on magnetization exchange between cellular solid and semisolid phases and the water protons, as well as the recent approach of CEST imaging, based on chemical exchange between protons of solutes and water. Conventional MT in biological tissues [66-69] has become a commonly employed MRI contrast parameter. Even though the exact mechanism is still under dispute, it is very likely that chemical exchange is a significant contributor [70-75] in addition to dipolar through-space magnetization exchange [66-69]. Many excellent reviews have appeared on classical MT imaging [67-69], and we here focus on the more novel approach of CEST imaging. CEST effects depend on several parameters, such as agent concentration, exchange rates, temperature, etc. In the brief period since 1998, researchers have suggested many different applications, including the design of new families of diamagnetic [20,21,76] and paramagnetic [22-24] MRI contrast agents, detection of metabolites [18,77-79], imaging of mobile proteins and peptides [26], and monitoring of pH effects [19,24,25,80-83]. Even an MR reporter gene [84] based on the CEST principle has been designed. In view of the favorable property of CEST imaging contrast that it can be switched on-and-off at will, many more applications are expected in the future. The present review consists of eight sections. Section 2 presents the theoretical background for CEST imaging and discusses its relationship to conventional MT contrast in vivo. Section 3 gives an overview of different types of exchangeable protons and their properties. Applications of CEST imaging and spectroscopy are summarized in Sections 4-6, respectively, corresponding to the three main members of the CEST family, namely, DIACEST, PARACEST, and APT. Section 7 deals with some technical issues that have to be kept in mind when using CEST technology.

Original languageEnglish (US)
Pages (from-to)109-136
Number of pages28
JournalProgress in Nuclear Magnetic Resonance Spectroscopy
Volume48
Issue number2-3
DOIs
StatePublished - May 30 2006

Keywords

  • APT (amide proton transfer)
  • Amide proton
  • CEST (chemical exchange dependent saturation transfer)
  • Chemical exchange
  • Contrast agent
  • Contrast mechanism
  • DIACEST (diamagnetic chemical exchange dependent saturation transfer)
  • Exchange rate
  • Hydrogen exchange
  • Lanthanide complex
  • MRI
  • Magnetization transfer
  • Metabolite
  • Molecular imaging
  • PARACEST (paramagnetic chemical exchange dependent saturation transfer)
  • Peptide
  • Protein
  • Proton exchange
  • Saturation transfer
  • pH imaging

ASJC Scopus subject areas

  • Analytical Chemistry
  • Biochemistry
  • Nuclear and High Energy Physics
  • Spectroscopy

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