Hyperpolarized 13C magnetic resonance spectroscopy (MRS) is an emerging molecular imaging technique that allows for the rapid, noninvasive, and pathway-specific investigation of dynamic metabolic processes in vivo. This technology relies on the successful development and application of 13C-labeled molecular probes that interrogate biochemical pathways relevant to human diseases. Unfortunately, only a limited number of hyperpolarized 13C agents are currently available for assessment of the tricarboxylic acid (TCA) cycle, which is a major contributor to the distinctive metabolic alterations found in cancer cells known as the Warburg effect. In this area, probe development efforts have been stifled by the fact that di- and tri-carboxylic acids cannot be metabolized during the hyperpolarized MRS experiment time frame (1-3 min) because these TCA cycle intermediates do not readily cross cell membranes. To address these issues, this study examined TCA cycle alkyl-based probes that can more rapidly access the intracellular environment and then cleaved via an esterase-mediated mechanism to yield metabolites succinate and fumarate. A series of succinate and fumarate derivatives were successfully synthesized. Several physicochemical properties of the alkyl-based probes were then analyzed: (1) 13C relaxation times, (2) toxicity, (3) kinetics of cell uptake, and (4) rate of esterase-mediated cleavage. These studies provided a platform for assessment of the agents and then selection of a lead probe that can be translated to hyperpolarized 13C investigations. In turn, these novel TCA cycle probes have the potential for directly examining the Warburg effect and thereby providing a unique insight into the metabolic profiles of tumors.

Novel 13C hyperpolarized probes for assessing tricarboxylic acid cycle metabolism

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.