title: Imaging integrin alpha-v-beta-3 expression in tumors with an 18F-labeled dimeric RGD peptide.
abstract: Integrin αv β3 receptors are expressed on activated endothelial cells during neovascularization to maintain tumor growth. Many radiolabeled probes utilize the tight and specific association between the arginine-glycine-aspartatic acid (RGD) peptide and integrin αv β3 , but one main obstacle for any clinical application of these probes is the laborious multistep radiosynthesis of (18)F. In this study, the dimeric RGD peptide, E-[c(RGDfK)]2, was conjugated with NODAGA and radiolabeled with (18)F in a simple one-pot process with a radiolabeling yield of 20%, the whole process lasting only 45 min. NODAGA-E-[c(RGDfK)]2 labeled with (18)F at a specific activity of 1.8 MBq nmol(-1) and a radiochemical purity of 100% could be achieved. The logP value of (18)F-labeled NODAGA-E-[c(RGDfK)]2 was -4.26 ± 0.02. In biodistribution studies, (18)F-NODAGA-E-[c(RGDfK)]2 cleared rapidly from the blood with 0.03 ± 0.01 percentage injected dose per gram (%ID g(-1)) in the blood at 2 h p.i., mainly via the kidneys, and showed good in vivo stability. Tumor uptake of (18)F-NODAGA-E-[c(RGDfK)]2 (3.44 ± 0.20 %ID g(-1), 2 h p.i.) was significantly lower than that of reference compounds (68) Ga-labeled NODAGA-E-[c(RGDfK)]2 (6.26 ± 0.76 %ID g(-1) ; p <0.001) and (111) In-labeled NODAGA-E-[c(RGDfK)]2 (4.99 ± 0.64 %ID g(-1) ; p < 0.01). Co-injection of an excess of unlabeled NODAGA-E-[c(RGDfK)]2 along with (18)F-NODAGA-E-[c(RGDfK)]2 resulted in significantly reduced radioactivity concentrations in the tumor (0.85 ± 0.13 %ID g(-1)). The αv β3 integrin-expressing SK-RC-52 tumor could be successfully visualized by microPET with (18)F-labeled NODAGA-E-[c(RGDfK)]2 . In conclusion, NODAGA-E-[c(RGDfK)]2 could be labeled rapidly with (18)F using a direct aqueous, one-pot method and it accumulated specifically in αv β3 integrin-expressing SK-RC-52 tumors, allowing for visualization by microPET.
authors.affiliation: Department of Biochemistry, Cardiovascular Research Institute, Maastricht University, Maastricht, The Netherlands.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Dijkgraaf
authors.forename: Samantha Y A
authors.initials: SY
authors.lastname: Terry
authors.forename: William J
authors.initials: WJ
authors.lastname: McBride
authors.forename: David M
authors.initials: DM
authors.lastname: Goldenberg
authors.forename: Peter
authors.initials: P
authors.lastname: Laverman
authors.forename: Gerben M
authors.initials: GM
authors.lastname: Franssen
authors.forename: Wim J G
authors.initials: WJ
authors.lastname: Oyen
authors.forename: Otto C
authors.initials: OC
authors.lastname: Boerman
mesh_terms: D000818:Animals; D019281:Dimerization; D005260:Female; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics*; D015972:Gene Expression Regulation, Neoplastic; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D007553:Isotope Labeling / Q000379:methods; D008657:Metabolic Clearance Rate; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D057054:Molecular Imaging / Q000379:methods; D009374:Neoplasms, Experimental / Q000000981:diagnostic imaging* / Q000378:metabolism*; D009842:Oligopeptides / Q000737:chemistry / Q000493:pharmacokinetics*; D009928:Organ Specificity; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods
chemical_list: D005462:Fluorine Radioisotopes; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid