4-[18F]-Tetraphenylphosphonium as a PET Tracer for Myocardial Mitochondrial Membrane Potential

ObjectivesThis study tested the hypothesis that 4-[18F]fluorophenyltriphenylphosphonium (18F-TPP) is useful for in vivo positron emission tomography (PET) measurement of mitochondrial membrane potential (ΔΨm). Its utility as a blood flow tracer also was evaluated.BackgroundTetraphenylphosphonium is useful for in vitro measurement of ΔΨm. In vivo measurement of ΔΨm has potential value in the assessment of heart failure pathophysiology and therapy as well as assessment of myocardial viability and so may be a very useful clinical tool.MethodsAnesthetized swine (N = 6) with a balloon catheter in the left anterior descending coronary artery were studied. Microsphere measurements of myocardial blood flow (MBF) were made after balloon inflation (baseline) and ∼10 min after intravenous administration of adenosine and phenylephrine after which ∼10 mCi 18F-TPP was injected intravenously and dynamic PET data acquisition obtained for 30 min. After the swine were killed, the hearts were sectioned for microsphere measurement of MBF and 18F-TPP measured by well counter in these same samples. PET images provided whole blood and myocardial 18F-TPP concentration for determination of ΔΨm by the Nernst equation, corrected for nonspecific 18F-TPP binding. Microsphere MBF, absolute (ml/min/g) and relative, was compared with PET data (standard uptake value and K1).ResultsNonspecific binding of 18F-TPP overestimated ΔΨm measured by −37 ± 4 mV (mean ± SD). Normal zone ΔΨm of ex vivo samples (−91 ± 11 mV; N = 52; sample weight, 1.07 ± 0.18 g) correlated strongly (R2= 0.93) with normal zone by PET (−81 ± 13 mV). Both ex vivo and PET normal zone ΔΨm, although somewhat lower, compared well with that reported for tritium labeled triphenylphosphonium in normal working Langendorff rat heart (−100 mV). Although the relative MBF by 18F-TPP correlated strongly with relative microsphere MBF (R2= 0.83), there was no correlation between absolute MBF by 18F-TPP and microsphere MBF.Conclusions18F-TPP is a promising tracer for noninvasive PET measurement of ΔΨm in living subjects. It is useful as well for assessment of relative but not absolute MBF.