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) due to their intramolecular hydrogen bonds and a second labile proton to allow for 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 ratios vs 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 being employed for tumor and kidney pH mapping both preclinically and in intial 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 to the unobstructed kidney and that the unobstructed kidney displayed a pH ~ 6.5 while the obstructed kidney had elevated pH and 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.