In-vivo Imaging of Mitochondrial Depolarization of Myocardium With Positron Emission Tomography and a Proton Gradient Uncoupler • Center for Molecular Imaging Technology and Translation

Alpert NM, Pelletier-Galarneau M, Kim SJW, Petibon Y, Sun T, Ramos-Torres KM, Normandin MD, El Fakhri G.

Front Physiol. 2020 May 15;11:491.

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 ¹⁸F-TPP⁺ and mitochondrial membrane potential (ΔΨ_m).

**Figure 3.** Effect of BAM15 on ¹⁸F-TPP⁺ volume of distribution (V_T; top) and tissue membrane potential (ΔΨ_T; bottom). Shown aIntracoronary infusion of BAM15 in the left anterior descending artery reduces the V_T of the tracer in apical and apical septal segments (white arrows) of the myocardium.

We tested these hypotheses by measuring decreases of ¹⁸F-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.

Experiments were conducted in pigs, first to determine the concentration of BAM15 infusate necessary to perturb the ¹⁸F-TPP⁺ concentration, then to administer an intravenous bolus plus infusion of ¹⁸F-TPP⁺ to reach secular equilibrium followed by an intracoronary infusion of BAM15.

Intracoronary BAM15 infusion led to a clear decrease in ¹⁸F-TPP⁺ concentration, falling to a lower level, and then recovering. A second BAM15 infusion reduced the ¹⁸F-TPP⁺ level in a similar fashion. We observed a maximum depolarization of 10 mV as a result of the BAM15 infusion.

This work provides evidence that the total membrane potential measured with ¹⁸F-TPP⁺ PET is sensitive to temporal changes in mitochondrial membrane potential.