Cell-Permeable Esterase-Activated Ca(II)-Sensitive MRI Contrast Agent

Calcium [Ca­(II)] is a fundamental transducer of electrical activity in the central nervous system (CNS). Influx of Ca­(II) into the cytosol is responsible for action potential initiation and propagation, and initiates interneuronal communication via release of neurotransmitters and activation of gene expression. Despite the importance of Ca­(II) in physiology, it remains a challenge to visualize Ca­(II) flux in the central nervous system (CNS) in vivo. To address these challenges, we have developed a new generation, Ca­(II)-activated MRI contrast agent that utilizes ethyl esters to increase cell labeling and prevent extracellular divalent Ca­(II) binding. Following labeling, the ethyl esters can be cleaved, thus allowing the agent to bind Ca­(II), increasing relaxivity and resulting in enhanced positive MR image contrast. The ability of this probe to discriminate between extra- and intracellular Ca­(II) may allow for spatiotemporal in vivo imaging of Ca­(II) flux during seizures or ischemia where large Ca­(II) fluxes (1–10 μM) can result in cell death.