title: Characterization of membrane potential-dependent uptake of the novel PET tracer 18F-fluorobenzyl triphenylphosphonium cation.
abstract: OBJECTIVE
  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 (Deltapsi(m)). This suggests that Deltapsi(m) measurement can be highly useful for diagnostic purposes. In the current study, we characterized the capability of the novel PET agent (18)F-fluorobenzyl triphenylphosphonium ((18)F-FBnTP) to assess Deltapsi(m), compared with the well-established voltage sensor (3)H-tetraphenylphosphonium ((3)H-TPP).
  
  
  METHODS
  (18)F-FBnTP and (3)H-TPP uptake under conditions known to alter Deltapsi(m) and plasma membrane potential (Deltapsi(p)) was assayed in the H345 lung carcinoma cell line. (18)F-FBnTP biodistribution was assessed in CD1 mice using dynamic PET and ex vivo gamma well counting.
  
  
  RESULTS
  (18)F-FBnTP and (3)H-TPP demonstrated similar uptake kinetics and plateau concentrations in H345 cells. Stepwise membrane depolarization resulted in a linear decrease in (18)F-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 (3)H-TPP (-0.63+/-0.06 and 0.96+/-0.05, respectively). Selective collapse of Deltapsi(m) caused a substantial decrease in cellular uptake for (18)F-FBnTP (81.6+/-8.1%) and (3)H-TPP (85.4+/-6.7%), compared with control. Exposure to the proapoptotic staurosporine, known to collapse Deltapsi(m), resulted in a decrease of 68.7+/-10.1% and 71.5+/-8.4% in (18)F-FBnTP and (3)H-TPP cellular uptake, respectively. (18)F-FBnTP accumulated mainly in kidney, heart and liver.
  
  
  CONCLUSIONS
  (18)F-FBnTP is a mitochondria-targeting PET radiopharmaceutical responsive to alterations in membrane potential with voltage-dependent performance similar to that of (3)H-TPP. (18)F-FBnTP is a promising new voltage sensor for detection of physiological and pathological processes associated with mitochondrial dysfunction, such as apoptosis, using PET.
authors.affiliation: Division of Nuclear Medicine, The Russell H. Morgan Department of Radiology, The Johns Hopkins Medical Institutions, 601 N. Caroline Street, Baltimore, MD 21287, USA. imadar@jhmi.edu
authors.forename: Igal
authors.initials: I
authors.lastname: Madar
authors.forename: Hayden
authors.initials: H
authors.lastname: Ravert
authors.forename: Barry
authors.initials: B
authors.lastname: Nelkin
authors.forename: Masroor
authors.initials: M
authors.lastname: Abro
authors.forename: Martin
authors.initials: M
authors.lastname: Pomper
authors.forename: Robert
authors.initials: R
authors.lastname: Dannals
authors.forename: James J
authors.initials: JJ
authors.lastname: Frost
mesh_terms: D000818:Animals; D018288:Carcinoma, Small Cell / Q000000981:diagnostic imaging* / Q000503:physiopathology*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000000981:diagnostic imaging* / Q000378:metabolism*; D006801:Humans; D008564:Membrane Potentials; D008657:Metabolic Clearance Rate; D051379:Mice; D009928:Organ Specificity; D009943:Organophosphorus Compounds / Q000493:pharmacokinetics*; D011877:Radionuclide Imaging; D014018:Tissue Distribution