title: In Vivo PET Imaging of the Cancer Integrin αvβ6 Using68Ga-Labeled Cyclic RGD Nonapeptides.
abstract: Expression of the cellular transmembrane receptor αvβ6 integrin is essentially restricted to malignant epithelial cells in carcinomas of a broad variety of lineages, whereas it is virtually absent in normal adult tissues. Thus, it is a highly attractive target for tumor imaging and therapy. Furthermore, αvβ6 integrin plays an important role for the epithelial-mesenchymal interaction and the development of fibrosis.Methods:On the basis of the68Ga chelators TRAP (triazacyclononane-triphosphinate) and NODAGA, we synthesized mono-, di-, and trimeric conjugates of the αvβ6 integrin-selective peptide cyclo(FRGDLAFp(NMe)K) via click chemistry. These were labeled with68Ga and screened regarding their suitability for in vivo imaging of αvβ6 integrin expression by PET and ex vivo biodistribution in severe combined immunodeficiency mice bearing H2009 tumor (human lung adenocarcinoma) xenografts. For these, αvβ6 integrin expression in tumor and other tissues was determined by β6 immunohistochemistry.Results:Despite the multimers showing higher αvβ6 integrin affinities (23-120 pM) than the monomers (260 pM), the best results-that is, low background uptake and excellent tumor delineation-were obtained with the TRAP-based monomer68Ga-avebehexin. This compound showed the most favorable pharmacokinetics because of its high polarity (logD= -3.7) and presence of additional negative charges (carboxylates) on the chelator, promoting renal clearance. Although tumor uptake was low (0.65% ± 0.04% injected dose per gram tissue [%ID/g]), it was still higher than in all other organs except the kidneys, ranging from a maximum for the stomach (0.52 ± 0.04 %ID/g) to almost negligible for the pancreas (0.07 ± 0.01 %ID/g). A low but significant target expression in tumor, lung, and stomach was confirmed by immunohistochemistry.Conclusion:Because of highly sensitive PET imaging even of tissues with low αvβ6 integrin expression density, we anticipate clinical applicability of68Ga-avebehexin for imaging of αvβ6 tumors and fibrosis by PET.
authors.affiliation: Lehrstuhl für Pharmazeutische Radiochemie, Technische Universität München, Garching, Germany johannes.notni@tum.de.
authors.forename: Johannes
authors.initials: J
authors.lastname: Notni
authors.affiliation: Lehrstuhl für Pharmazeutische Radiochemie, Technische Universität München, Garching, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Reich
authors.affiliation: Institute for Advanced Study and Center of Integrated Protein Science (CIPSM), Department Chemie, Technische Universität München, Munich, Germany.
authors.forename: Oleg V
authors.initials: OV
authors.lastname: Maltsev
authors.affiliation: Institute for Advanced Study and Center of Integrated Protein Science (CIPSM), Department Chemie, Technische Universität München, Munich, Germany.
authors.forename: Tobias G
authors.initials: TG
authors.lastname: Kapp
authors.affiliation: Institute of Pathology, Technische Universität München, Munich, Germany; and.
authors.forename: Katja
authors.initials: K
authors.lastname: Steiger
authors.affiliation: Lehrstuhl für Pharmazeutische Radiochemie, Technische Universität München, Garching, Germany.
authors.forename: Frauke
authors.initials: F
authors.lastname: Hoffmann
authors.affiliation: Institute of Pathology, Universitätsklinikum Düsseldorf, Düsseldorf, Germany.
authors.forename: Irene
authors.initials: I
authors.lastname: Esposito
authors.affiliation: Institute of Pathology, Technische Universität München, Munich, Germany; and.
authors.forename: Wilko
authors.initials: W
authors.lastname: Weichert
authors.affiliation: Institute for Advanced Study and Center of Integrated Protein Science (CIPSM), Department Chemie, Technische Universität München, Munich, Germany.
authors.forename: Horst
authors.initials: H
authors.lastname: Kessler
authors.affiliation: Lehrstuhl für Pharmazeutische Radiochemie, Technische Universität München, Garching, Germany.
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Wester
mesh_terms: D000230:Adenocarcinoma / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000595:Amino Acid Sequence; D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism*; D002384:Catalysis; D045744:Cell Line, Tumor; D003300:Copper / Q000737:chemistry; D005260:Female; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D008175:Lung Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009842:Oligopeptides / Q000737:chemistry* / Q000493:pharmacokinetics; D010456:Peptides, Cyclic / Q000737:chemistry*; D049268:Positron-Emission Tomography; D014018:Tissue Distribution
chemical_list: D000951:Antigens, Neoplasm; D016023:Integrins; D009842:Oligopeptides; D010456:Peptides, Cyclic; C507169:cyclic arginine-glycine-aspartic acid peptide; C073878:integrin alphavbeta6; D003300:Copper
keywords: 68Ga; click chemistry; positron emission tomography; preclinical imaging