Cyclen-Based Phenylboronate Ligands and Their Eu³⁺ Complexes for Sensing Glucose by MRI

Abstract

Novel cyclen-based phenylboronate ligands and their corresponding Eu(3+) complexes have been examined as glucose sensors using chemical exchange saturation transfer (CEST) MR imaging for detection. Two isomeric bis-phenylboronate complexes, Eu(4) and Eu(10), and a mono-phenylboronate complex, Eu(12), had been prepared and characterized by UV and circular dichroism spectroscopy, mass spectrometry, and CEST imaging. Both the free ligands and their Eu(3+) complexes bind to simple sugars, but their selectivity and binding affinities vary with sugar structure. Interestingly, the free ligands, 4 and 10, are selective for fructose over glucose, but this selectivity order switches in the respective Eu(3+) complexes. Of the complexes examined, Eu(4) shows the highest selectivity and binding affinity for glucose (2275 +/- 266 M(-)(1) at pH 10.2 and 339 +/- 29 M(-)(1) at pH 7). Glucose acts as a "capping"moiety in the Eu(4).glucose binary complex and modulates water exchange between a single Eu(3+)-bound water molecule and bulk water, an effect that can be detected by CEST imaging. Thus, Eu(4) represents a new class of metabolite-specific imaging agents that may allow mapping of metabolites by MRI of the bulk water signal.

Paramagnetic lanthanide complexes as PARACEST agents for medical imaging

“…This single pool ratiometric approach has shown that it is possible to determine glucose concentration in the physiologically relevant range (~5 mM) for imaging systems. 24 Of course glucose is not the only sugar that contains a cis-diol; however, experiments with other sugars, such as fructose and galactose, showed that EuDTMA-2PB 3+ has a strong preference for glucose over these other sugars, and since the physiological concentrations of these other sugars are normally much lower than that of glucose, they are not anticipated to prevent the use of this complex in vivo.Although the experiment has not yet been performed, it is easy to see from the spectra shown ( Fig. 7) how this single-pool ratiometric approach could also be applied to the measurement of temperature and, in principle, any of the other responsive PARACEST agents discussed here, such as a recently reported sensor for the biologically important Zn 2+ ion.…”

Glycoconjugate Probes and Targets for Molecular Imaging Using Magnetic Resonance

“…The distance between the pendant boronate arms appears to be an important factor in determining the affinities for the various saccharides. The 1,7-disubstituted derivative 38 (Eu-DOTAM-2M-2PB; FiguRe 19) had a high and selective binding affinity for glucose (apparent stability constant of the resulting boronate ester: 339 ± 29 M -1 at pH 7) [64,65]. The glucose is bound to the complex in a 1:1 fashion by forming a bridge above the Eu(III)-bound water molecule (FiguRe 19).…”

“…Since the plasma concentration of this material is normally relatively low, this should not interfere with the use of the complex as a glucose sensor. On the other hand, the good affinity for glycated HSA allows the in vitro determination of the degree of glycation in serum, using MRI and high-throughput methods [65].…”

Development of Responsive Lanthanide-Based Magnetic Resonance Imaging and Luminescent Probes for Biological Applications

“…For example, some bioactivated MRI contrast agents, whose ability to relax water protons is greatly enhanced by recognition of a biomolecule, have been reported for monitoring of enzyme activity, Ca 2ϩ , pH, p(O 2 ), etc. [11][12][13][14][15] These MRI contrast agents induce a change in the water proton relaxation time (T 1 or T 2 ) in response to the presence of the target biomolecule.…”