title: Preclinical Kinetic Analysis of the Caspase-3/7 PET Tracer 18F-C-SNAT: Quantifying the Changes in Blood Flow and Tumor Retention After Chemotherapy.
abstract: Early detection of tumor response to therapy is crucial to the timely identification of the most efficacious treatments. We recently developed a novel apoptosis imaging tracer, (18)F-C-SNAT (C-SNAT is caspase-sensitive nanoaggregation tracer), that undergoes an intramolecular cyclization reaction after cleavage by caspase-3/7, a biomarker of apoptosis. This caspase-3/7-dependent reaction leads to an enhanced accumulation and retention of (18)F activity in apoptotic tumors. This study aimed to fully examine in vivo pharmacokinetics of the tracer through PET imaging and kinetic modeling in a preclinical mouse model of tumor response to systemic anticancer chemotherapy.
  
  
  METHODS
  Tumor-bearing nude mice were treated 3 times with intravenous injections of doxorubicin before undergoing a 120-min dynamic (18)F-C-SNAT PET/CT scan. Time-activity curves were extracted from the tumor and selected organs. A 2-tissue-compartment model was fitted to the time-activity curves from tumor and muscle, using the left ventricle of the heart as input function, and the pharmacokinetic rate constants were calculated.
  
  
  RESULTS
  Both tumor uptake (percentage injected dose per gram) and the tumor-to-muscle activity ratio were significantly higher in the treated mice than untreated mice. Pharmacokinetic rate constants calculated by the 2-tissue-compartment model showed a significant increase in delivery and accumulation of the tracer after the systemic chemotherapeutic treatment. Delivery of (18)F-C-SNAT to the tumor tissue, quantified as K1, increased from 0.31 g⋅(mL⋅min)(-1) in untreated mice to 1.03 g⋅(mL⋅min)(-1) in treated mice, a measurement closely related to changes in blood flow. Accumulation of (18)F-C-SNAT, quantified as k3, increased from 0.03 to 0.12 min(-1), proving a higher retention of (18)F-C-SNAT in treated tumors independent from changes in blood flow. An increase in delivery was also found in the muscular tissue of treated mice without increasing accumulation.
  
  
  CONCLUSIONS
  (18)F-C-SNAT has significantly increased tumor uptake and significantly increased tumor-to-muscle ratio in a preclinical mouse model of tumor therapy. Furthermore, our kinetic modeling of (18)F-C-SNAT shows that chemotherapeutic treatment increased accumulation (k3) in the treated tumors, independent of increased delivery (K1).
authors.affiliation: Department of Radiology, Molecular Imaging Program at Stanford, Stanford University School of Medicine, Stanford, California; and.
authors.forename: Mikael
authors.initials: M
authors.lastname: Palner
authors.affiliation: Department of Radiology, Molecular Imaging Program at Stanford, Stanford University School of Medicine, Stanford, California; and.
authors.forename: Bin
authors.initials: B
authors.lastname: Shen
authors.affiliation: Department of Radiology, Molecular Imaging Program at Stanford, Stanford University School of Medicine, Stanford, California; and.
authors.forename: Jongho
authors.initials: J
authors.lastname: Jeon
authors.affiliation: Department of Radiology, Molecular Imaging Program at Stanford, Stanford University School of Medicine, Stanford, California; and Key Laboratory of Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, China.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Lin
authors.affiliation: Department of Radiology, Molecular Imaging Program at Stanford, Stanford University School of Medicine, Stanford, California; and.
authors.forename: Frederick T
authors.initials: FT
authors.lastname: Chin
authors.affiliation: Department of Radiology, Molecular Imaging Program at Stanford, Stanford University School of Medicine, Stanford, California; and jrao@stanford.edu.
authors.forename: Jianghong
authors.initials: J
authors.lastname: Rao
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D052160:Benzothiazoles / Q000493:pharmacokinetics*; D001783:Blood Flow Velocity; D053148:Caspase 3 / Q000378:metabolism*; D053179:Caspase 7 / Q000378:metabolism*; D004317:Doxorubicin / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D008657:Metabolic Clearance Rate; D051379:Mice; D057054:Molecular Imaging / Q000379:methods; D018365:Neoplasm, Residual; D009374:Neoplasms, Experimental / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology*; D009842:Oligopeptides / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D014018:Tissue Distribution; D016896:Treatment Outcome
chemical_list: D000903:Antibiotics, Antineoplastic; D052160:Benzothiazoles; C000602832:C-SNAT compound; D009842:Oligopeptides; D019275:Radiopharmaceuticals; D004317:Doxorubicin; D053148:Caspase 3; D053179:Caspase 7
keywords: apoptosis; caspase-3/7; preclinical PET; systemic chemotherapy; tumor therapy response