Triazoles as T2 -Exchange Magnetic Resonance Imaging Contrast Agents for the Detection of Nitrilase Activity.

Abstract

We characterized the T2 -exchange (T2ex ) magnetic resonance imaging (MRI) contrast of azole protons that have large chemical shifts from the water proton resonance as a function of pH, temperature, and chemical modification. Our results showed that 1,2,4-triazoles could be tuned into excellent diamagnetic T2ex contrast agents, with an optimal exchange-based relaxivity r2ex of 0.10 s-1 mm-1 at physiological pH and B0 =9.4 T. A fit of r2ex data to the Swift-Connick equation indicated that imino proton exchange of triazoles is dominated by a base-catalyzed process at higher pH values and an acid-catalyzed process at lower pH. The magnitude of r2ex was also found to be heavily dependent on chemical modifications, that is, enhanced by electron-donating groups, such as amines and methyls, or by intramolecular hydrogen bonding between the imino proton and the carboxyl, and weakened by electron-withdrawing groups like bromo, cyano, and nitro. In light of these findings, we applied T2ex MRI to assess the activity of nitrilase, an enzyme catalyzing the hydrolysis of 1,2,4-triazole-3-carbonitrile to 1,2,4-triazole-3-carboxylic acid, resulting in the enhancement of R2ex . Our findings suggest that 1,2,4-triazoles have potential to provide sensitive and tunable diagnostic probes for MRI.