In-vivo Imaging of Mitochondrial Depolarization of Myocardium With Positron Emission Tomography and a Proton Gradient Uncoupler

BACKGROUND: We recently reported a method using positron emission tomography (PET) and the tracer (18)F-labeled tetraphenylphosphonium ((18)F-TPP(+)) for mapping the tissue (i.e., cellular plus mitochondrial) membrane potential (ΔΨ(T)) in the myocardium. The purpose of this work is to provide additional experimental evidence that our methods can be used to observe transient changes in the volume of distribution for (18)F-TPP(+) and mitochondrial membrane potential (ΔΨ(m)). METHODS: We tested these hypotheses by measuring decreases of (18)F-TPP(+) concentration elicited when a proton gradient uncoupler, BAM15, is administered by intracoronary infusion during PET scanning. BAM15 is the first proton gradient uncoupler shown to affect the mitochondrial membrane without affecting the cellular membrane potential. Preliminary dose response experiments were conducted in two pigs to determine the concentration of BAM15 infusate necessary to perturb the (18)F-TPP(+) concentration. More definitive experiments were performed in two additional pigs, in which we administered an intravenous bolus plus infusion of (18)F-TPP(+) to reach secular equilibrium followed by an intracoronary infusion of BAM15. RESULTS: Intracoronary BAM15 infusion led to a clear decrease in (18)F-TPP(+) concentration, falling to a lower level, and then recovering. A second BAM15 infusion reduced the (18)F-TPP(+) level in a similar fashion. We observed a maximum depolarization of 10 mV as a result of the BAM15 infusion. SUMMARY: This work provides evidence that the total membrane potential measured with (18)F-TPP(+) PET is sensitive to temporal changes in mitochondrial membrane potential.