PET imaging of Mitochondrial Membrane Potential

 

MMP

Mitochondrial membrane potential is upregulated in cancer. Mitochondrial membrane potential (MMP) plays a key role in cardiac failure and cancer. The electron transport chain contained within the impermeable inner mitochondrial membrane gives rise to a negative membrane potential (ca. 150 mV to 170 mV) in healthy cells. In cancerous and ischaemic heart cells, mitochondrial dysfunction can substantially disrupt the MMP resulting in up to a tenfold increase in accumulation of MMP-dependent compounds. During apoptotic or necrotic cell death, complete membrane depolarisation occurs and no uptake is observed. Lipophilic cations carrying a positive charge can pass through lipid bilayers in the mitochondria and accumulate proportionally to the change in membrane potential gradient.

Optical agents have been developed for MMP-dependent imaging,
with many derivatives based on rhodamine and tetramethyl-rosamine structures, with the highly effective Mitotrackers series now in common use. Boron-dipyrromethene (BODIPY) type structures are regularly used in optical biomedical imaging due to their tunable wavelength emission, photostability, remarkable brightness and biological media compatibility. Recently, the use of BODIPYs has been further extended by the incorporation of the positron emitting radioisotope, 18F, resulting in multimodal positron emission tomography (PET)/optical imaging agents. Formation of BODIPY based PET/optical multimodal imaging can be achieved via B–F bond formation or modification of the structural backbone to incorporate the radiolabel.

To date, there have been no reports of BODIPY-based agents capable of imaging both cancer and heart cells in a MMP-dependent
manner. Phosphonium-based lipophilic cations have been receiving interest, most notably in the development of PET imaging agents. Recently, Yuan et al. described a BODIPY triphenyl-phosphonium-based lipophilic cation designed for multimodal imaging which did not show MMP-dependent mitochondrial uptake. The Archibald and Cawthorne groups at the University of Hull, in collaboration with the Higham group at the University of Newcastle,  have developed MMP-dependent BODIPY-based tracers would offer the capability for detection of mitochondrial dysfunction in cardiac disease and cancer together with the potential for monitoring of therapeutic responses.

MMP

Above: struture of fluorinated BODIPY dye and FACS data showing MMP-dependent uptake in breast cancer cells and rat cardiomyocytes.

School of Biological, Biomedical and Environmental Sciences