Hydrazo‐CEST: Hydrazone‐Dependent Chemical Exchange Saturation Transfer Magnetic Resonance Imaging Contrast Agents

• Published in: Chemistry : a European journal Vol. 24; no. 36; pp. 9148 - 9156
• Main Authors: Dang, Trina, Suchy, Mojmír, Truong, Yen J., Oakden, Wendy, Lam, Wilfred W., Lazurko, Caitlin, Facey, Glenn, Stanisz, Greg J., Shuhendler, Adam J.
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 26-06-2018
• Subjects: Aldehydes; Anthranilic acid; Aromatic compounds; Carboxylic acids; chemical exchange saturation transfer; Chemistry; Contrast agents; Diamagnetism; Hydrazine; Hydrazines; Hydrazones; Magnetic resonance imaging; Medical imaging; Nitrogen; NMR; Nuclear magnetic resonance; Organic chemistry; Physiology; Resonance; Saturation; magnetic resonance imaging, chemical exchange saturation transfer, contrast agents, hydrazones, aldehydes
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201801671

The rapid formation of hydrazones under physiological conditions was exploited for the detection of aldehydes through chemical exchange saturation transfer magnetic resonance imaging (CEST‐MRI). A metal‐free, diamagnetic contrast agent derived from N‐amino anthranilic acid was introduced, which selectively “turned‐on” upon hydrazone formation through an effect termed Hydrazo‐CEST. While the hydrazine form of the probe produced no CEST‐MRI signal enhancement, the formation of the aryl hydrazone resulted in >20 % intensity decrease in the bulk water signal through the CEST effect, as measured by 300 MHz 1H NMR, 3 T and 7 T MRI. Both the electronic contributions of the N‐amino anthranilate and the aldehyde binding partner were shown to directly impact the exchange rate of the proton on the ring‐proximal nitrogen, and thus the imaging signal. Additionally, the presence of the carboxylic acid moiety ortho to the hydrazine was necessary not only for contrast production, but also for rapid hydrazone formation and prolonged hydrazone product stability under physiological conditions. This work provided the first example of an MRI‐based contrast agent capable of a “turn on” response upon reaction with bioactive aldehydes, and outlined both the structural and electronic requirements to expand on Hydrazo‐CEST, a novel, hydrazone‐dependent subtype of diamagnetic CEST‐MRI.
Aldehyde and seek! A novel class of contrast agents that conditionally provide chemical exchange saturation transfer magnetic resonance imaging (CEST‐MRI) signal upon in situ reaction with aldehydes is introduced.