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

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.

Renal pH Mapping Using Chemical Exchange Saturation Transfer (CEST) MRI: Experimental Protocol.

Chemical exchange saturation transfer (CEST) is recognized as one of the premier methods for measuring pH with this environmental variable expected to be an excellent biomarker for kidney diseases. Here we describe step-by-step CEST MRI experimental protocols for producing pH and perfusion maps for monitoring kidney pH homeostasis in rodents after administering iopamidol as contrast agent. Several CEST techniques, acquisition protocols and ratiometric approaches are described. The impact of length of acquisition time on the quality of the maps is detailed. These methods may be useful for investigating progression in kidney disease in vivo for rodent models.This chapter is based upon work from the COST Action PARENCHIMA, a community-driven network funded by the European Cooperation in Science and Technology (COST) program of the European Union, which aims to improve the reproducibility and standardization of renal MRI biomarkers. This experimental protocol is complemented by two separate chapters describing the basic concepts and data analysis.