title: Imaging integrin αvβ 3 and NRP-1 positive gliomas with a novel fluorine-18 labeled RGD-ATWLPPR heterodimeric peptide probe.
abstract: OBJECTIVE
  Radiolabeled Arg-Gly-Asp (RGD) and Ala-Thr-Trp-Leu-Pro-Pro-Arg (ATWLPPR) peptide analogs have received interests for their capability to serve as radiopharmaceuticals for imaging integrin αvβ3 and Neuropilin-1 (NRP-1) positive tumors, respectively. In this study, we developed a RGD-ATWLPPR heterodimeric peptide which contained both RGD and ATWLPPR motifs in one molecular probe. The aim of this study was to investigate the dual receptor-targeting property and tumor diagnostic value of RGD-ATWLPPR heterodimeric peptide labeled with fluorine-18 (F-18).
  
  
  METHODS
  A RGD-ATWLPPR heterodimer was synthesized from c(RGDyK) and ATWLPPR through a glutamate linker. The peptide was radiolabeled by reacting the [(18)F]fluoride-aluminum complex with the cyclic chelator, 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA). The receptor-binding characteristics and tumor-targeting efficacy of [(18)F]FAl-NOTA-RGD-ATWLPPR were tested in vitro and in vivo.
  
  
  RESULTS
  RGD-ATWLPPR had affinity for both integrin αvβ3 and NRP-1 in vitro. [(18)F]FAl-NOTA-RGD-ATWLPPR displayed significantly higher tumor uptake than [(18)F]FAl-NOTA-RGD and [(18)F]FAl-NOTA-ATWLPPR, both in vitro and in vivo. The uptake of the F-18 labeled heterodimer by an U87MG tumor was inhibited only partially in the presence of an excess amount of unlabeled RGD or ATWLPPR but was blocked completely in the presence of both RGD and ATWLPPR. Compared with the monomeric RGD and ATWLPPR peptides, [(18)F]FAl-NOTA-RGD-ATWLPPR showed improved in vivo pharmacokinetics, resulting in a more preferable imaging quality.
  
  
  CONCLUSIONS
  [(18)F]FAl-NOTA-RGD-ATWLPPR exhibited significantly improved receptor-targeting properties both in vitro and in vivo compared with the F-18 labeled RGD or ATWLPPR monomers. The improved targeting and localization exhibited by the RGD-ATWLPPR heterodimer provide a foundation for further investigations of its applicability in clinical tumor imaging.
authors.affiliation: Department of Nuclear Medicine, Xiamen Cancer Center, The First Affiliated Hospital of Xiamen University, 55 Zhenhai Rd., Xiamen, 361003, China, wuhua1025@163.com.
authors.forename: Hua
authors.initials: H
authors.lastname: Wu
authors.forename: Haojun
authors.initials: H
authors.lastname: Chen
authors.forename: Dongfeng
authors.initials: D
authors.lastname: Pan
authors.forename: Yufei
authors.initials: Y
authors.lastname: Ma
authors.forename: Sheng
authors.initials: S
authors.lastname: Liang
authors.forename: Ying
authors.initials: Y
authors.lastname: Wan
authors.forename: Ya
authors.initials: Y
authors.lastname: Fang
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000737:chemistry / Q000000981:diagnostic imaging* / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D005462:Fluorine Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics; D005910:Glioma / Q000737:chemistry / Q000000981:diagnostic imaging / Q000378:metabolism*; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D064847:Multimodal Imaging / Q000379:methods*; D039942:Neuropilin-1 / Q000378:metabolism*; D009842:Oligopeptides / Q000737:chemistry / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D055114:X-Ray Microtomography
chemical_list: D005462:Fluorine Radioisotopes; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D019275:Radiopharmaceuticals; D039942:Neuropilin-1; C047981:arginyl-glycyl-aspartic acid