title: Monitoring tumor response to antiangiogenic sunitinib therapy with 18F-fluciclatide, an 18F-labeled αVbeta3-integrin and αV beta5-integrin imaging agent.
abstract: Arginine-glycine-aspartate (RGD)-binding α(V)β(3)-integrin and α(V)β(5)-integrin play key roles in tumor angiogenesis. We examined an (18)F-labeled small peptide (fluciclatide [United States Adopted Name (ASAN)-approved, International Nonproprietary Name (INN)-proposed name], previously referred to as AH111585) containing an RGD sequence. Fluciclatide binds with a high (nM) affinity to α(V)β(3)-integrin and α(V)β(5)-integrin, which are highly expressed on tumors and the tumor neovasculature. In this study, (18)F-fluciclatide was used to examine the response of human glioblastoma xenografts to treatment with the antiangiogenic agent sunitinib.
  
  
  METHODS
  U87-MG tumor uptake of (18)F-fluciclatide was determined by small-animal PET after longitudinal administration of the antiangiogenic agent sunitinib (a 2-wk dosing regimen). Tumor sizes were measured throughout the study, and tumor volumes were calculated. Tumor microvessel density (MVD) after therapy was also analyzed.
  
  
  RESULTS
  Dynamic small-animal PET of (18)F-fluciclatide uptake after administration of the clinically relevant antiangiogenic agent sunitinib revealed a reduction in the tumor uptake of (18)F-fluciclatide compared with that in vehicle-treated controls over the 2-wk dosing regimen. Skeletal muscle, used as a reference tissue, showed equivalent (18)F-fluciclatide uptake in both therapy and control groups. A reduction in tumor MVD was also observed after treatment with the antiangiogenic agent. No significant changes in tumor volume were observed in the 2 groups.
  
  
  CONCLUSIONS
  The data demonstrated that (18)F-fluciclatide detected changes in tumor uptake after acute antiangiogenic therapy markedly earlier than any significant volumetric changes were observable. These results suggest that this imaging agent may provide clinically important information for guiding patient care and monitoring the response to antiangiogenic therapy.
authors.affiliation: GE Healthcare MDx Research, The Grove Centre, Amersham, UK. mark.battle@ge.com
authors.forename: Mark R
authors.initials: MR
authors.lastname: Battle
authors.forename: Julian L
authors.initials: JL
authors.lastname: Goggi
authors.forename: Lucy
authors.initials: L
authors.lastname: Allen
authors.forename: Jon
authors.initials: J
authors.lastname: Barnett
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Morrison
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000818:Animals; D045744:Cell Line, Tumor; D005909:Glioblastoma / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010455:Peptides / Q000493:pharmacokinetics*; D011092:Polyethylene Glycols / Q000493:pharmacokinetics*; D011758:Pyrroles / Q000627:therapeutic use*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D019030:Receptors, Vitronectin / Q000378:metabolism*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D000077210:Sunitinib
chemical_list: C530281:AH 111585; D020533:Angiogenesis Inhibitors; D007211:Indoles; D039302:Integrin alphaVbeta3; D010455:Peptides; D011758:Pyrroles; D019275:Radiopharmaceuticals; D019030:Receptors, Vitronectin; C064660:integrin alphaVbeta5; D011092:Polyethylene Glycols; D000077210:Sunitinib