MRI ParaCEST agents that improve amide based pH measurements by limiting inner sphere water T2 exchange

Abstract

A series of Dy³⁺ and Tm³⁺ tetra-substituted DOTAM paraCEST agents incorporating para-substituted anilines has been synthesized and their paraCEST and relaxation properties evaluated. The response of selected agents (aniline and p-methoxyaniline) to changes in pH near the physiological range has also been studied. A crystal structure of Tm³⁺-p-OMe agent indicates a TSAP geometry with the absence of an inner sphere water molecule (denoted as TSAP'), which is thought to be due to the bulky nature of the amide nitrogen substituent. Two distinct amide signals are observed in the CEST spectrum for this compound, one for each of the isomers that exist in solution: SAP and TSAP with the larger chemical shift centred at −83 ppm compared to bulk water. Due to the non-optimal inner sphere water exchange, these agents produce minimal shortening of T₁ and T₂ relaxation time constants and therefore decrease relaxation induced signal losses during imaging.