title: Monitoring Mitochondrial Complex-I Activity Using Novel PET Probe 18F-BCPP-EF Allows Early Detection of Radiotherapy Effect in Murine Squamous Cell Carcinoma.
abstract: OBJECTIVE
  Aerobic glycolysis, the main pathway of energy production in tumors (Warburg effect) allows detection of tumors by positron emission tomography (PET) using 18F-fluoro-2-deoxy-D-glucose (18F-FDG). Since ionizing radiation (IR) is reported to switch aerobic glycolysis to mitochondrial oxidative phosphorylation, radiotherapeutic efficacy was monitored by the activity of mitochondrial complex I (MC-I), using a new PET probe 18F-BCPP-EF, 18F-2-tert-butyl-4-chloro-5-{6-[2-(2-fluoro-ethoxy)-ethoxy] -pyridine-3-ylmethoxy}-2H-pyridazin-3-one, compared with 18F-FDG uptake and the apoptosis index.
  
  
  METHODS
  Tumor uptake of 18F-BCPP-EF or 18F-FDG was examined in C3H/HeN mice inoculated with murine squamous cell carcinoma SCCVII at various time points after a single dose of x-ray irradiation at 0, 6, 15, or 30 Gy. Apoptosis incidence was determined by TUNEL staining in excised tumor tissue.
  
  
  RESULTS
  Tumor growth suppression was dose-dependent; tumor grew 10-fold (0 Gy), 5-fold (6 Gy), 2-fold (15 Gy), and reduced to half in its volume (30 Gy) 14 days after treatment. 18F-BCPP-EF uptake was significantly increased as early as 3 days after 15 Gy or 30 Gy, when tumor size and apoptosis index showed no difference among radiation doses. In contrast, 18F-FDG uptake was initially increased dose-dependently, remained elevated up to 7 days, and eventually decreased 10 days after 30 Gy and also 14 days after 15 Gy when tumor size was already reduced. Apoptosis index was increased after irradiation but failed to correlate with tumor response.
  
  
  CONCLUSIONS
  Tumor uptake of 18F-BCPP-EF was increased dose-dependently early after effective doses of IR when 18F-FDG uptake as well as apoptosis incidence were not indicative of tumor response. The results suggest that 18F-BCPP-EF is a promising "positive" MC-I imaging PET probe for early detection of efficacy of tumor radiotherapy.
authors.affiliation: Department of Clinical Pharmacology, Tokai University School of Medicine, Isehara, Japan.|Department of Radiation Oncology, Tokai University School of Medicine, Isehara, Japan.
authors.forename: Chieko
authors.initials: C
authors.lastname: Murayama
authors.affiliation: Department of Cell Transplantation and Regenerative Medicine, Tokai University School of Medicine, Isehara, Japan.
authors.forename: Akira T
authors.initials: AT
authors.lastname: Kawaguchi
authors.affiliation: Support Center for Medical Research and Education, Tokai University, Isehara, Japan.
authors.forename: Akemi
authors.initials: A
authors.lastname: Kamijo
authors.affiliation: Support Center for Medical Research and Education, Tokai University, Isehara, Japan.
authors.forename: Katsuko
authors.initials: K
authors.lastname: Naito
authors.affiliation: Central Research Laboratory, Hamamatsu Photonics K.K., Hamamatsu, Japan.
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Kanazawa
authors.affiliation: Central Research Laboratory, Hamamatsu Photonics K.K., Hamamatsu, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Tsukada
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects*; D002294:Carcinoma, Squamous Cell / Q000000981:diagnostic imaging / Q000378:metabolism / Q000532:radiotherapy*; D042967:Electron Transport Complex I / Q000378:metabolism*; D019788:Fluorodeoxyglucose F18; D051379:Mice; D008809:Mice, Inbred C3H; D009368:Neoplasm Transplantation; D049268:Positron-Emission Tomography; D011724:Pyridazines; D011725:Pyridines; D019275:Radiopharmaceuticals
chemical_list: C588084:2-tert-butyl-4-chloro-5-(6-(2-(2-fluoroethoxy)ethoxy)pyridin-3-ylmethoxy)-2H-pyridazin-3-one; D011724:Pyridazines; D011725:Pyridines; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; D042967:Electron Transport Complex I