TY - JOUR
T1 - Enantiomeric Recognition of d - And l -Lactate by CEST with the Aid of a Paramagnetic Shift Reagent
AU - Zhang, Lei
AU - Martins, André F.
AU - Zhao, Piyu
AU - Tieu, Michael
AU - Esteban-Gómez, David
AU - McCandless, Gregory T.
AU - Platas-Iglesias, Carlos
AU - Sherry, A. Dean
N1 - Funding Information:
The authors acknowledge partial financial support for this work from the National Institutes of Health (CA-115531, EB-01598, EB-00482), Harold C. Simmons Cancer Center through an NCI Cancer Center Support Grant, 1P30 CA142543, and the Robert A. Welch Foundation (AT-584). The authors C. P.-I. and D. E.-G. thank Ministerio de Economía y Competitivad (CTQ2016-76756-P) and Centro de Supercomputación de Galicia (CESGA) for providing the computer facilities.
Funding Information:
In this study, we investigated whether the substitution of a δ chiral carbon in the pendant arms of YbDO3A-amide type complexes can limit the number of stereoisomers present in solution and thereby enhance detection of lactate by CEST NMR. Our results show that with different substitutions at the δ-position on the pendant arms, a single energetically favorable isomer is formed. This was supported by both high resolution 1H NMR and CEST data. In the presence of (D or L)-lactate, the achiral Yb0 complex forms two equally populated Λ(δδδδ) and Δ(λλλλ) isomers with lactate whereas the Ybx complexes having δ chiral centers yield a single isomer (shown to be the S-Λ(δδδδ) isomer for the Yb3 complexes by analysis of the pseudocontact shifts). The second finding of this study was the observation of enantiomeric discrimination of D-and L-lactate by the chiral DO3A-derived Ybx complexes. In summary, our study shows that heptadentate macrocyclic Yb-complexes with δ chiral centers serve as key predictors of the conformational orientation of lanthanide complexes with macrocyclic ligands and powerful discriminators of enantiomeric substrates such as D-and L-lactate. Ternary complexes are formed with the lactate OH group bound to the Yb3+ ion in an apical position as reported previously for lactate·EuDO3A.7 The lactate OH proton is highly shifted downfield in the presence of the Yb-complexes as seen by CEST NMR. The approach used magnifies the chemical shift of lactate OH CEST which may ultimately prove useful in the design of metabolite-specific shift reagents for functional MRI. L-lactate is considered the only form produced by cancer cells while D-lactate, although rarely produced by human cells, is a metabolic product of some essential bacteria that exist in the human microbiota. Consequently, D-lactate acidosis has been associated with several diseases including bowel syndrome and D-lactate encephalopathy.36,37 Given that the development of enantio-pure agents is of interest in molecular imaging, this work is a positive step forward toward optimizing inorganic responsive agents (shift reagents) for selective identification of important biomarkers and metabolic profiles.
Publisher Copyright:
© 2017 American Chemical Society.
PY - 2017/12/6
Y1 - 2017/12/6
N2 - A previous report demonstrated that EuDO3A could be used as an NMR shift reagent for imaging extracellular lactate produced by cancer cells using CEST imaging. In this work, a series of heptadentate macrocyclic YbDO3A-trisamide complexes with δ-chiral carbons in the three pendant side-arms were examined as shift reagents for lactate detection. High resolution 1H NMR spectra and DFT calculations provided evidence for the formation of stereoselective lactate·YbDO3A-trisamide complexes each with a different CEST signature. This stereoselectivity allowed discrimination of d- versus l-lactate by both high-resolution NMR and CEST. This work demonstrates that lanthanide-based paramagnetic shift reagents can be designed to detect important metabolites by CEST MRI selectively.
AB - A previous report demonstrated that EuDO3A could be used as an NMR shift reagent for imaging extracellular lactate produced by cancer cells using CEST imaging. In this work, a series of heptadentate macrocyclic YbDO3A-trisamide complexes with δ-chiral carbons in the three pendant side-arms were examined as shift reagents for lactate detection. High resolution 1H NMR spectra and DFT calculations provided evidence for the formation of stereoselective lactate·YbDO3A-trisamide complexes each with a different CEST signature. This stereoselectivity allowed discrimination of d- versus l-lactate by both high-resolution NMR and CEST. This work demonstrates that lanthanide-based paramagnetic shift reagents can be designed to detect important metabolites by CEST MRI selectively.
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U2 - 10.1021/jacs.7b08292
DO - 10.1021/jacs.7b08292
M3 - Article
C2 - 29083166
AN - SCOPUS:85037529268
SN - 0002-7863
VL - 139
SP - 17431
EP - 17437
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 48
ER -