Characterization of membrane potential-dependent uptake of the novel PET tracer ¹⁸F-fluorobenzyl triphenylphosphonium cation

Purpose: Mitochondrial dysfunction has been attributed a critical role in the etiology and pathogenesis of numerous diseases, and is manifested by alterations of the organelle's membrane potential (Δψ_m). This suggests that Δψ_m measurement can be highly useful for diagnostic purposes. In the current study, we characterized the capability of the novel PET agent ¹⁸F-fluorobenzyl triphenylphosphonium ( ¹⁸F-FBnTP) to assess Δψ_m, compared with the well-established voltage sensor ³H-tetraphenylphosphonium ( ³H-TPP). Methods: ¹⁸F-FBnTP and ³H-TPP uptake under conditions known to alter Δψ_m and plasma membrane potential (Δψ_p) was assayed in the H345 lung carcinoma cell line. ¹⁸F-FBnTP biodistribution was assessed in CD1 mice using dynamic PET and ex vivo gamma well counting. Results: ¹⁸F-FBnTP and ³H-TPP demonstrated similar uptake kinetics and plateau concentrations in H345 cells. Stepwise membrane depolarization resulted in a linear decrease in ¹⁸F-FBnTP cellular uptake, with a slope (-0.58±0.06) and correlation coefficient (0.94±0.07) similar (p>0.17) to those measured for ³H-TPP (-0.63±0.06 and 0.96±0.05, respectively). Selective collapse of Δψ_m caused a substantial decrease in cellular uptake for ¹⁸F-FBnTP (81.6±8.1%) and ³H-TPP (85.4±6.7%), compared with control. Exposure to the proapoptotic staurosporine, known to collapse Δψ_m, resulted in a decrease of 68.7±10.1% and 71.5±8.4% in ¹⁸F-FBnTP and ³H-TPP cellular uptake, respectively. ¹⁸F-FBnTP accumulated mainly in kidney, heart and liver. Conclusion: ¹⁸F-FBnTP is a mitochondria-targeting PET radiopharmaceutical responsive to alterations in membrane potential with voltage-dependent performance similar to that of ³H-TPP. ¹⁸F-FBnTP is a promising new voltage sensor for detection of physiological and pathological processes associated with mitochondrial dysfunction, such as apoptosis, using PET.