title: Evaluation of a mitochondrial voltage sensor, (18F-fluoropentyl)triphenylphosphonium cation, in a rat myocardial infarction model.
abstract: Radiolabeled lipophilic cationic compounds, such as (18)F-labeled phosphonium salt, accumulate in the mitochondria through a negative inner transmembrane potential. The purpose of this study was to develop and evaluate ((18)F-fluoropentyl)triphenylphosphonium salt ((18)F-FPTP) as a myocardial PET agent.
  
  
  METHODS
  A reference compound of (18)F-FPTP was synthesized via 3-step nucleophilic substitution reactions and was radiolabeled via 2-step nucleophilic substitution reactions of no-carrier-added (18)F-fluoride. Accumulations of (18)F-FPTP, (3)H-tetraphenylphosphonium, and (99m)Tc-sestamibi were compared in a cultured embryonic cardiomyoblast cell line (H9c2). The biodistribution of (18)F-FPTP was assessed using BALB/c mice. The (18)F-FPTP small-animal PET study was performed in Sprague-Dawley rats with or without left coronary artery (LCA) ligation.
  
  
  RESULTS
  (18)F-FPTP was synthesized with a radiochemical yield of 15%-20% and radiochemical purity of greater than 98%. Specific activity was greater than 6.3 TBq/μmol. Cell uptake of (18)F-FPTP was more than 15-fold higher in H9c2 than in normal fibroblasts (human normal foreskin fibroblasts). Selective collapse of mitochondrial membrane potential substantially decreased cellular uptake for (18)F-FPTP and (3)H-tetraphenylphosphonium, compared with that for (99m)Tc-sestamibi. The biodistribution data in mice (n = 24) showed rapid blood clearance and high accumulation in the heart. Heart-to-blood ratios at 10 and 30 min were 54 and 133, respectively. Heart-to-lung and heart-to-liver ratios at 10, 30, and 60 min were 4, 4, and 7 and 4, 5, and 7, respectively. Dynamic small-animal PET for 60 min after injection of (18)F-FPTP showed an initial spike of radioactivity, followed by retention in the myocardium and rapid clearance from the background. (18)F-FPTP small-animal PET images in LCA-occluded rats demonstrated sharply defined myocardial defects in the corresponding area of the myocardium. The myocardial defect size measured by (18)F-FPTP small-animal PET correlated closely with the hypoperfused area measured by quantitative 2,3,5-triphenyltetrazolium chloride staining (r(2) = 0.92, P < 0.001).
  
  
  CONCLUSIONS
  The excellent pharmacokinetics of (18)F-FPTP and its correlation with 2,3,5-triphenyltetrazolium chloride staining in normal and LCA-occluded rats suggest that this molecular probe may have a high potential as a mitochondrial voltage sensor for PET. This probe may also allow high throughput, with multiple daily studies and a wide distribution of PET myocardial imaging in the clinic.
authors.affiliation: Department of Nuclear Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Dong-Yeon
authors.initials: DY
authors.lastname: Kim
authors.forename: Hyeon-Sik
authors.initials: HS
authors.lastname: Kim
authors.forename: Uyenchi Nguyen
authors.initials: UN
authors.lastname: Le
authors.forename: Sheng Nan
authors.initials: SN
authors.lastname: Jiang
authors.forename: Hee-Jung
authors.initials: HJ
authors.lastname: Kim
authors.forename: Kyo-Chul
authors.initials: KC
authors.lastname: Lee
authors.forename: Sang-Keun
authors.initials: SK
authors.lastname: Woo
authors.forename: Jihwa
authors.initials: J
authors.lastname: Chung
authors.forename: Hyung-Seok
authors.initials: HS
authors.lastname: Kim
authors.forename: Hee-Seung
authors.initials: HS
authors.lastname: Bom
authors.forename: Kook-Hyun
authors.initials: KH
authors.lastname: Yu
authors.forename: Jung-Joon
authors.initials: JJ
authors.lastname: Min
mesh_terms: D000818:Animals; D001692:Biological Transport; D002460:Cell Line; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008928:Mitochondria / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology*; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000473:pathology*; D009943:Organophosphorus Compounds / Q000138:chemical synthesis / Q000378:metabolism* / Q000493:pharmacokinetics; D010720:Phosphines / Q000138:chemical synthesis / Q000378:metabolism* / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D011854:Radiochemistry; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C577321:(5-fluoropentyl)triphenylphosphonium; D009943:Organophosphorus Compounds; D010720:Phosphines