title: Evaluation of [18F]CP18 as a Substrate-Based Apoptosis Imaging Agent for the Assessment of Early Treatment Response in Oncology.
abstract: The substrate-based positron emission tomography (PET) tracer [18F]CP18 is capable of detecting the activity of caspase-3/7, two key executioner proteases in the apoptosis pathway, through selective cleavage of the ligand by the activated proteases and subsequent accumulation in apoptotic cells. Using an in vitro and in vivo model of colorectal cancer (CRC), we investigated whether [18F]CP18 tracer accumulation provides a measure for apoptosis and reliably reflects early treatment response to chemotherapeutics.
  
  
  
  [18F]CP18 cell uptake was assessed in treated Colo205 cells (saline, 5-fluorouracil (5-FU), irinotecan or their combination) and correlated with caspase-3/7 activity. [18F]CP18 imaging was performed in Colo205 xenografts, starting with a baseline μPET/micro X-ray computed tomography (​μCT) scan, followed by a 3-day treatment with saline (n = 5), 5-FU (low sensitivity, n = 4), irinotecan (high sensitivity, n = 5), or a combination of both (n = 7). The study was concluded with a second [18F]CP18 scan, 24 h after final treatment administration, followed by tumor removal for gamma counting (%ID/g) and for cleaved caspase-3 immunohistochemistry (apoptotic index/necrosis). Tumors were delineated on μCT images and, using the obtained volumes of interest, average percentage injected dose per cubic centimeter (%ID/cm3) was calculated from every μPET image.
  
  
  
  In vitro, [18F]CP18 cell uptake was positively correlated with caspase-3/7 activity (r = 0.59, p = 0.003). A drug-dependent increase in [18F]CP18 tumor uptake compared to baseline was observed in animals treated with 5-FU (+14 ± 25 %), irinotecan (+56 ± 54 %), and their combination (+158 ± 69 %, p = 0.002). %ID/cm3showed a positive relationship with both %ID/g (r = 0.83, p < 0.0001) and the apoptotic index (r = 0.60, p = 0.004), but not with tumor necrosis (r = 0.22, p = 0.36).
  
  
  
  Both our in vitro and in vivo findings have shown the ability of [18F]CP18-PET to visualize therapy-induced cancer cell apoptosis and possibly serve as a biomarker for early therapy response.
authors.affiliation: Molecular Imaging Center Antwerp (MICA), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium.
authors.forename: Sara
authors.initials: S
authors.lastname: Rapic
authors.affiliation: Molecular Imaging Center Antwerp (MICA), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium.|Department of Nuclear Medicine, Antwerp University Hospital, Edegem, Belgium.
authors.forename: Christel
authors.initials: C
authors.lastname: Vangestel
authors.affiliation: Molecular Imaging Center Antwerp (MICA), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium.|Department of Nuclear Medicine, Antwerp University Hospital, Edegem, Belgium.
authors.forename: Filipe
authors.initials: F
authors.lastname: Elvas
authors.affiliation: Molecular Imaging Center Antwerp (MICA), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Verhaeghe
authors.affiliation: Molecular Imaging Center Antwerp (MICA), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium.|Department of Nuclear Medicine, Antwerp University Hospital, Edegem, Belgium.
authors.forename: Tim Van
authors.initials: TV
authors.lastname: den Wyngaert
authors.affiliation: Molecular Imaging Center Antwerp (MICA), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium.|Department of Nuclear Medicine, Antwerp University Hospital, Edegem, Belgium.
authors.forename: Leonie
authors.initials: L
authors.lastname: Wyffels
authors.affiliation: Center for Oncological Research (CORE), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium.|Department of Pathology, Antwerp University Hospital, Edegem, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Pauwels
authors.affiliation: Molecular Imaging Center Antwerp (MICA), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium.
authors.forename: Steven
authors.initials: S
authors.lastname: Staelens
authors.affiliation: Molecular Imaging Center Antwerp (MICA), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium. Sigrid.Stroobants@uza.be.|Department of Nuclear Medicine, Antwerp University Hospital, Edegem, Belgium. Sigrid.Stroobants@uza.be.
authors.forename: Sigrid
authors.identifier: 0000-0002-1285-9117
authors.initials: S
authors.lastname: Stroobants
mesh_terms: D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000473:pathology; D004789:Enzyme Activation; D005260:Female; D005462:Fluorine Radioisotopes / Q000737:chemistry*; D006801:Humans; D007150:Immunohistochemistry; D008819:Mice, Nude; D015203:Reproducibility of Results; D016896:Treatment Outcome
chemical_list: D005462:Fluorine Radioisotopes; D053148:Caspase 3; D053179:Caspase 7
keywords: Apoptosis imaging; Caspase-3/7; Colorectal cancer; PET; [18F]CP18