Exploring the potential of the novel imidazole‐4,5‐dicarboxyamide chemical exchange saturation transfer scaffold for pH and perfusion imaging

Abstract

Here, we describe and assess the potential of 14 newly synthesized imidazole‐4,5‐dicarboxyamides (I45DCs) for pH and perfusion imaging. A number of these aromatic compounds possess large labile proton chemical shifts (up to 7.7 ppm from water) because of their intramolecular hydrogen bonds and a second labile proton to allow for chemical exchange saturation transfer (CEST) signal ratio‐based pH measurements. We have found that the contrast produced is strong for a wide range of substitutions and that the inflection points in the CEST signal ratio versus pH plots used to generate concentration‐independent pH maps can be adjusted based on these subsitutions to tune the pH range that can be measured. These I45DC CEST agents have advantages over the triiodobenzenes currently employed for tumor and kidney pH mapping, both preclinically and in initial human studies. Finally, as CEST MRI combined with exogenous contrast has the potential to detect functional changes in the kidneys, we evaluated our highest performing anionic compound (I45DC‐diGlu) on a unilateral urinary obstruction mouse model and observed lower contrast uptake in the obstructed kidney compared with the unobstructed kidney and that the unobstructed kidney displayed a pH of ~ 6.5 while the obstructed kidney had elevated pH and an increased range in pH values. Based on this, we conclude that the I45DCs have excellent imaging properties and hold promise for a variety of medical imaging applications, particularly renal imaging.

Amide Proton Transfer-Weighted Magnetic Resonance Imaging for Application in Renal Fibrosis: A Radiological-Pathological-Based Analysis

“…The preclinical studies in animal studies [18] have revealed obstruction or decreased blood perfusion could cause damage to functioning nephrons and then result in impaired urinary acidification, thereby facilitating the exchange rate of amide protons with water protons. Previous studies [37,38] used CEST MRI technology to image renal pH changes and found that the renal pH of IRI or UUO rats was higher than for normal rats. Thus, a change in the microenvironment pH may also be involved in the increased APT value found for RF.…”

Special issue on chemical exchange saturation transfer MRI

“…Bo et al used a newly synthesized exogeneous CEST agent, namely imidazole-4,-5-dicarboxyamide (I45DC), for depicting perfusion and pH changes in kidney, and observed differences in contrast kinetics and pH between obstructed and unobstructed kidneys in a mouse model. 33 Also, to bridge the gap between solution phantoms and in vivo studies, Wu et al showed that 2D and 3D cell culture phantoms can play an important role in interpreting many CEST signals. 34 Here, they showed that CEST signals in cell culture phantoms were sensitive to incubation time over several days.…”