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

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

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 (Δψm). This suggests that Δψm 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 Δψm, compared with the well-established voltage sensor 3H-tetraphenylphosphonium (3H-TPP).

Methods

18F-FBnTP and 3H-TPP uptake under conditions known to alter Δψm and plasma membrane potential (Δψp) 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 Δψm 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 Δψm, 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.

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Acknowledgements

We thank Dr. Hagai Rottenberg for fruitful discussions and James Fox for the acquisition of the PET scans. This work was supported in part by R24 CA92871.

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Authors and Affiliations

  1. Division of Nuclear Medicine, The Russell H. Morgan Department of Radiology, The Johns Hopkins Medical Institutions, JHOC 4230, 601 N. Caroline St., Baltimore, MD, 21287, USA

    Igal Madar, Hayden Ravert, Masroor Abro, Martin Pomper, Robert Dannals & James J. Frost

  2. Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Medical Institutions, Baltimore, MD, USA

    Barry Nelkin

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  1. Igal Madar
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Correspondence to Igal Madar.

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Madar, I., Ravert, H., Nelkin, B. et al. Characterization of membrane potential-dependent uptake of the novel PET tracer 18F-fluorobenzyl triphenylphosphonium cation. Eur J Nucl Med Mol Imaging 34, 2057–2065 (2007). https://doi.org/10.1007/s00259-007-0500-8

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  • DOI: https://doi.org/10.1007/s00259-007-0500-8

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