title: PET imaging of apoptosis with (64)Cu-labeled streptavidin following pretargeting of phosphatidylserine with biotinylated annexin-V.
abstract: OBJECTIVE
  In vivo detection of apoptosis is a diagnostic tool with potential clinical applications in cardiology and oncology. Radiolabeled annexin-V (anxV) is an ideal probe for in vivo apoptosis detection owing to its strong affinity for phosphatidylserine (PS), the molecular flag on the surface of apoptotic cells. Most clinical studies performed to visualize apoptosis have used (99m)Tc-anxV; however, its poor distribution profile often compromises image quality. In this study, tumor apoptosis after therapy was visualized by positron emission tomography (PET) using (64)Cu-labeled streptavidin (SAv), following pre-targeting of apoptotic cells with biotinylated anxV.
  
  
  METHODS
  Apoptosis was induced in tumor-bearing mice by photodynamic therapy (PDT) using phthalocyanine dyes as photosensitizers, and red light. After PDT, mice were injected i.v. with biotinylated anxV, followed 2 h later by an avidin chase, and after another 2 h with (64)Cu-DOTA-biotin-SAv. PET images were subsequently recorded up to 13 h after PDT.
  
  
  RESULTS
  PET images delineated apoptosis in treated tumors as early as 30 min after (64)Cu-DOTA-biotin-SAv administration, with tumor-to-background ratios reaching a maximum at 3 h post-injection, i.e., 7 h post-PDT. Omitting the administration of biotinylated anxV or the avidin chase failed to provide a clear PET image, confirming that all three steps are essential for adequate visualization of apoptosis. Furthermore, differences in action mechanisms between photosensitizers that target tumor cells directly or via initial vascular stasis were clearly recognized through differences in tracer uptake patterns detecting early or delayed apoptosis.
  
  
  CONCLUSIONS
  This study demonstrates the efficacy of a three-step (64)Cu pretargeting procedure for PET imaging of apoptosis. Our data also confirm the usefulness of small animal PET to evaluate cancer treatment protocols.
authors.affiliation: Sherbrooke Molecular Imaging Centre and Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada.
authors.forename: Nicole
authors.initials: N
authors.lastname: Cauchon
authors.forename: Réjean
authors.initials: R
authors.lastname: Langlois
authors.forename: Jacques A
authors.initials: JA
authors.lastname: Rousseau
authors.forename: Guillaume
authors.initials: G
authors.lastname: Tessier
authors.forename: Jules
authors.initials: J
authors.lastname: Cadorette
authors.forename: Roger
authors.initials: R
authors.lastname: Lecomte
authors.forename: Darel J
authors.initials: DJ
authors.lastname: Hunting
authors.forename: Roberto A
authors.initials: RA
authors.lastname: Pavan
authors.forename: Stefan K
authors.initials: SK
authors.lastname: Zeisler
authors.forename: Johan E
authors.initials: JE
authors.lastname: van Lier
mesh_terms: D000818:Animals; D017304:Annexin A5 / Q000493:pharmacokinetics*; D017209:Apoptosis; D001710:Biotin / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D003301:Copper Radioisotopes / Q000493:pharmacokinetics; D016503:Drug Delivery Systems / Q000379:methods; D005260:Female; D008657:Metabolic Clearance Rate; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000000981:diagnostic imaging / Q000378:metabolism*; D009928:Organ Specificity; D010718:Phosphatidylserines / Q000378:metabolism*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D019809:Streptavidin / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: D017304:Annexin A5; D003301:Copper Radioisotopes; D010718:Phosphatidylserines; D019275:Radiopharmaceuticals; D001710:Biotin; D019809:Streptavidin