Membrane potential-dependent uptake of 18F-triphenylphosphonium-a new voltage sensor as an imaging agent for detecting burn-induced apoptosis

Background: Mitochondrial dysfunction has been closely related to many pathologic processes, such as cellular apoptosis. Alterations in organelle membrane potential are associated with mitochondrial dysfunction. A fluorine-18 labeled phosphonium compound: F-18-triphenylphosphonium (F-18-TPP) was prepared to determine its potential use as a mitochondria-targeting radiopharmaceutical to evaluate cellular apoptosis. Methods: Studies were conducted in both ex vivo cell lines and in vivo using a burned animal model. Uptake of F-18-TPP was assessed in PC-3 cells by gamma counting under the following conditions: graded levels of extracellular potassium concentrations, incubation with carbonyl cyanide m-chlorophenylhydrazone and staurosporine. Apoptosis was studied in a burn animal model using terminal deoxynucleotidyl transferase dUTP nick end labeling staining and simultaneous assessment of F-18-TPP uptake by biodistribution. Results: We found that stepwise membrane depolarization by potassium (K) resulted in a linear decrease in F-18-TPP uptake, with a slope of 0.62 +/- 0.08 and a correlation coefficient of 0.936 +/- 0.11. Gradually increased concentrations of m-chlorophenylhydrazone lead to decreased uptake of F-18-TPP. Staurosporine significantly decreased the uptake of F-18-TPP in PC-3 cells from 14.2 +/- 3.8% to 5.6 +/- 1.3% (P < 0.001). Burn-induced significant apoptosis (sham: 4.4 +/- 1.8% versus burn: 24.6 +/- 6.7 %; P < 0.005) and a reduced uptake of tracer in the spleens of burn-injured animals as compared with sham burn controls (burn: 1.13 +/- 0.24% versus sham: 3.28 +/- 0.67%; P < 0.005). Biodistribution studies demonstrated that burn-induced significant reduction in F-18-TPP uptake in spleen, heart, lung, and liver, which were associated with significantly increased apoptosis. Conclusions: F-18-TPP is a promising new voltage sensor for detecting mitochondrial dysfunction and apoptosis in various tissues. (C) 2014 Elsevier Inc. All rights reserved.