ABSTRACT
Since the early days of chemical exchange saturation transfer (CEST)
contrast agents, it was clear that sensitivity would be the Achilles’
heel of these probes. The first series of compounds tested as
CEST agents, by Balaban et al., were small diamagnetic molecules
whose detection threshold was in the mM range. Obviously, the
low sensitivity in generating contrast reduced the clinical potential
of this novel class of diamagnetic agents. This is particularly true
in the era of molecular imaging whose applications require the
development of imaging reporters able to visualize very diluted
targets (in the nano/picomolar range). Therefore, in the last 15
years, much work in CEST area has addressed strategies to enhance
the detection sensitivity of these agents. The saturation transfer
efficiency depends on many parameters. Among them, the most
important and easiest to control are the number of equivalent
mobile protons to be irradiated and their exchange rate with
bulk water (kex). Thus, the sensitivity issue has been primarily faced with two approaches: (1) increasing kex, and (2) increasing the number of mobile protons per single molecule. As, for any
CEST agent, the condicio sine qua non is that the chemical shift separation between the exchanging protons has to be larger than
their exchange rate (ω > kex), it is evident that the task of increasing kex endlessly is not desirable. A strategy that has been pursued to improve the sensitivity via kex, by using paramagnetic molecules (paraCEST see Chapter 11) in virtue of their ability
to induce large ω values, has led to important achievements,
although the sensitivity enhancements of these molecules are still
far below the detection threshold imposed by molecular imaging
applications. Increasing the number of mobile protons per single
molecule has been pursued following different approaches: (1) use
of polyaminoacids or RNA-like polymers [1, 2]; (2) formation of
supramolecular adducts between paramagnetic shift reagents (SRs)
and diamagnetic substrates rich in mobile protons [3]; (3) design of
macromolecular/nanoparticulate scaffolds (polymers, dendrimers,
micelles, perfluorocarbon nanoemulsions, silica particles, virus
capsides) covalently conjugated with a large number of paraCEST
agents [4-9]; and (4) design of systems containing water protons
compartmentalized in phospholipid-based vesicles (lipoCEST and
cellCEST) [10, 11]. The latter approach allowed to reach the highest
sensitivity reported so far for CEST agents and will be the topic of
this chapter.
