Office of Technology Development (OTD)

Balaraman Kalyanaraman, PhD

Many magnetic resonance imaging (MRI) contrast agents are used to target specific cells and organelles within cells to better understand issues such as cellular necrosis and molecular function. Cells are targeted for example with gadolinium or manganese reagents to more clearly see damage due to infarction or grafted tissue rejection. Some organelle studies are delineating the function of cells at the molecular level. The mitochondria play a key role in cellular function and consequently disease when they malfunction. It is crucial to better see mitochondria function with non-invasive methods such as MRI.

Nitroxide radicals, due to a single unpaired electron, exhibit T1 contrast enhancement. Nitroxides have also been shown to exhibit T1  contrast enhancement in vivo. In vivo studies demonstrate that Mito-Carboxy Proxyl (Mito-CP), as featured in this invention, preferentially targets mitochondria. It is thought that the Mito-CP is taken up by the mitochondria for two reasons. First, a lipophilic cation portion of the Mito-CP, distributes its charge over a large surface area allowing it to easily penetrate the lipid bilayers. Second, uptake of lipophilic ions through the lipid bilayers is increased 10-fold for every 61.5 mV difference in the membrane potential. This would explain the uptake of Mito-CP across the plasma membrane (30-60 mV) and across the mitochondria membrane (150-180 mV). MRI contrast studies using Mito-CP demonstrate that this novel MRI contrast agent does specifically target mitochondria in vivo. An MRI contrast agent specific to mitochondria would provide a marker of metabolic and/or mitotic activity. Pathologies, such as tumors, where metabolic activity is significantly increased would benefit from spatial identification in vivo.

• Mito-CP nitroxide radical easily seen with MRI in vivo
• Marker for mitochondrial metabolic activity
• Mitotic activity observed via mitochondria
• Spatial identification of tumors in vivo

Mitochondria in vivo readily incorporate Mito-CP