Tuning Phenols with Intra‐Molecular Bond Shifted HYdrogens (IM‐SHY) as diaCEST MRI Contrast Agents

Abstract

We characterize what the optimal exchange properties are for CEST contrast agents on 3T clinical scanners using CW saturation transfer, and demonstrate that the exchangeable protons in phenols can be tuned to reach these criteria through proper ring substitution. Systematic modification allows the chemical shift of the exchangeable protons to be positioned between 4.8 ppm to 12 ppm from water and enables adjustment of the proton exchange rate to maximize CEST contrast at these shifts. In particular, 44 hydrogen-bonded phenols are investigated for their potential as CEST MRI contrast agents and the stereoelectronic effects on their CEST properties summarized. Furthermore, we identify a pair of compounds, 2,5-dihydroxyterephthalic acid (42) and 4,6-dihydroxyisophthalic acid (43), which produce the highest sensitivity through incorporating two exchangeable protons per ring.

Screening CEST contrast agents using ultrafast CEST imaging

“…Even though the exchange rates from UFZ (except for sample 5 and 6 ) were comparable with those previously reported in the literature using the individually acquired QUEST Z-spectra [13], they were slightly faster than the conventional QUEST. Inherently, there is a signal loss during each image readout period, which is a tradeoff of the ultrafast method compared to the conventional QUEST approach.…”

“…The chemical shift of the exchangeable protons in each compound appears at the same frequency as reported previously by Yang et al using the conventional frequency sweeping method. [13] One can appreciate the uniform baseline of the water signal in these Z-spectra. Since the saturation pulse has only been applied once, magnetic field drift caused by gradient heating can be effectively avoided.…”

“…Each tube contained one of the following compounds: Salicylic acid ( 1 ), 3,5-Dibromosalicylic acid ( 2 ), 3-Nitrosalicylic acid ( 3 ), 2-Cyclohexylamino-benzoic acid ( 4 ), 5-amino-2-(methanesulfonamido)-benzoic acid ( 5 ), 2-(methylsulfonyl)amino-benzoic acid ( 6 ), 4,6-Dihydroxyisophthalic acid ( 7 ) and 2,5-Dihydroxyterephthalic acid ( 8 ). These compounds were randomly selected from the library of compounds reported in the literature [13, 15]. A 10 mM solution of each compound was prepared in a phosphate buffered saline solution with a pH of 7.3, titrated by highly concentrated HCl/NaOH solutions…”

“…For example, strong and relatively short saturation helps to achieve more weighting towards the fast-exchanging amine protons over slow-exchanging amide protons [12]. Similarly for exogenous CEST agents, knowledge regarding the exchange rate is essential in designing the ideal contrast agent [13-15]. Exchange rates can be quantified by acquiring a series of full Z-spectra with different saturation times or saturation powers (QUEST and QUESP methods) [16-18].…”

Cardiac Chemical Exchange Saturation Transfer MR Imaging Tracking of Cell Survival or Rejection in Mouse Models of Cell Therapy

“…Further study is warranted as to whether labeling of cells with paramagnetic CEST agents induces changes in gene expression similar to those observed with iron oxide-based agents. However, emerging CEST MR imaging labels, including CEST-active reporter genes (16,18,32) and engineered nonmetallic CEST macromolecules (33,34), could be used in place of lanthanide metal-based labels. A secondary limitation to our study is the use of high radiofrequency saturation power to generate CEST contrast that would not be possible in clinical settings.…”