title: PET-based Imaging of Chemokine Receptor 2 in Experimental and Disease-related Lung Inflammation.
abstract: Purpose To characterize a chemokine receptor type 2 (CCR2)-binding peptide adapted for use as a positron emission tomography (PET) radiotracer for noninvasive detection of lung inflammation in a mouse model of lung injury and in human tissues from subjects with lung disease. Materials and Methods The study was approved by institutional animal and human studies committees. Informed consent was obtained from patients. A 7-amino acid CCR2 binding peptide (extracellular loop 1 inverso [ECL1i]) was conjugated to tetraazacyclododecane tetraacetic acid (DOTA) and labeled with copper 64 (64Cu) or fluorescent dye. Lung inflammation was induced with intratracheal administration of lipopolysaccharide (LPS) in wild-type (n = 19) and CCR2-deficient (n = 4) mice, and these mice were compared with wild-type mice given control saline (n = 5) by using PET performed after intravenous injection of64Cu-DOTA-ECL1i. Lung immune cells and those binding fluorescently labeled ECL1i in vivo were detected with flow cytometry. Lung inflammation in tissue from subjects with nondiseased lungs donated for lung transplantation (n = 11) and those with chronic obstructive pulmonary disease (COPD) who were undergoing lung transplantation (n = 16) was evaluated for CCR2 with immunostaining and autoradiography (n = 6, COPD) with64Cu-DOTA-ECL1i. Groups were compared with analysis of variance, the Mann-Whitney U test, or the t test. Results Signal on PET images obtained in mouse lungs after injury with LPS was significantly greater than that in the saline control group (mean = 4.43% of injected dose [ID] per gram of tissue vs 0.99% of injected dose per gram of tissue; P < .001). PET signal was significantly diminished with blocking studies using nonradiolabeled ECL1i in excess (mean = 0.63% ID per gram of tissue; P < .001) and in CCR2-deficient mice (mean = 0.39% ID per gram of tissue; P < .001). The ECL1i signal was associated with an elevated level of mouse lung monocytes. COPD lung tissue displayed significantly elevated CCR2 levels compared with nondiseased tissue (median = 12.8% vs 1.2% cells per sample; P = .002), which was detected with64Cu-DOTA-ECL1i by using autoradiography. Conclusion64Cu-DOTA-ECL1i is a promising tool for PET-based detection of CCR2-directed inflammation in an animal model and in human tissues as a step toward clinical translation.©RSNA, 2017 Online supplemental material is available for this article.
authors.affiliation: From the Mallinckrodt Institute of Radiology (Y.L., D.H.S., H.P.L., Y.Z., R.J.G., S.L.B.) and Departments of Medicine (S.P.G., T.S.B., Z.B.N., J.H.P., D.E.B., J.J.A., M.J.H., R.J.G., S.L.B.), Surgery (D.K.), Pathology and Immunology (D.K.), and Cell Biology (M.J.H.), Washington University School of Medicine, 660 S Euclid Ave, Box 8052, St Louis, MO 63110; and Centre d'Immunologie et des Maladies Infectieuses, CIMI-Paris, Faculté de Médecine Pitié-Salpêtrière, Paris INSERM, Paris, France (C.C.).
authors.forename: Yongjian
authors.initials: Y
authors.lastname: Liu
authors.affiliation: From the Mallinckrodt Institute of Radiology (Y.L., D.H.S., H.P.L., Y.Z., R.J.G., S.L.B.) and Departments of Medicine (S.P.G., T.S.B., Z.B.N., J.H.P., D.E.B., J.J.A., M.J.H., R.J.G., S.L.B.), Surgery (D.K.), Pathology and Immunology (D.K.), and Cell Biology (M.J.H.), Washington University School of Medicine, 660 S Euclid Ave, Box 8052, St Louis, MO 63110; and Centre d'Immunologie et des Maladies Infectieuses, CIMI-Paris, Faculté de Médecine Pitié-Salpêtrière, Paris INSERM, Paris, France (C.C.).
authors.forename: Sean P
authors.initials: SP
authors.lastname: Gunsten
authors.affiliation: From the Mallinckrodt Institute of Radiology (Y.L., D.H.S., H.P.L., Y.Z., R.J.G., S.L.B.) and Departments of Medicine (S.P.G., T.S.B., Z.B.N., J.H.P., D.E.B., J.J.A., M.J.H., R.J.G., S.L.B.), Surgery (D.K.), Pathology and Immunology (D.K.), and Cell Biology (M.J.H.), Washington University School of Medicine, 660 S Euclid Ave, Box 8052, St Louis, MO 63110; and Centre d'Immunologie et des Maladies Infectieuses, CIMI-Paris, Faculté de Médecine Pitié-Salpêtrière, Paris INSERM, Paris, France (C.C.).
authors.forename: Deborah H
authors.initials: DH
authors.lastname: Sultan
authors.affiliation: From the Mallinckrodt Institute of Radiology (Y.L., D.H.S., H.P.L., Y.Z., R.J.G., S.L.B.) and Departments of Medicine (S.P.G., T.S.B., Z.B.N., J.H.P., D.E.B., J.J.A., M.J.H., R.J.G., S.L.B.), Surgery (D.K.), Pathology and Immunology (D.K.), and Cell Biology (M.J.H.), Washington University School of Medicine, 660 S Euclid Ave, Box 8052, St Louis, MO 63110; and Centre d'Immunologie et des Maladies Infectieuses, CIMI-Paris, Faculté de Médecine Pitié-Salpêtrière, Paris INSERM, Paris, France (C.C.).
authors.forename: Hannah P
authors.initials: HP
authors.lastname: Luehmann
authors.affiliation: From the Mallinckrodt Institute of Radiology (Y.L., D.H.S., H.P.L., Y.Z., R.J.G., S.L.B.) and Departments of Medicine (S.P.G., T.S.B., Z.B.N., J.H.P., D.E.B., J.J.A., M.J.H., R.J.G., S.L.B.), Surgery (D.K.), Pathology and Immunology (D.K.), and Cell Biology (M.J.H.), Washington University School of Medicine, 660 S Euclid Ave, Box 8052, St Louis, MO 63110; and Centre d'Immunologie et des Maladies Infectieuses, CIMI-Paris, Faculté de Médecine Pitié-Salpêtrière, Paris INSERM, Paris, France (C.C.).
authors.forename: Yongfeng
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: From the Mallinckrodt Institute of Radiology (Y.L., D.H.S., H.P.L., Y.Z., R.J.G., S.L.B.) and Departments of Medicine (S.P.G., T.S.B., Z.B.N., J.H.P., D.E.B., J.J.A., M.J.H., R.J.G., S.L.B.), Surgery (D.K.), Pathology and Immunology (D.K.), and Cell Biology (M.J.H.), Washington University School of Medicine, 660 S Euclid Ave, Box 8052, St Louis, MO 63110; and Centre d'Immunologie et des Maladies Infectieuses, CIMI-Paris, Faculté de Médecine Pitié-Salpêtrière, Paris INSERM, Paris, France (C.C.).
authors.forename: T Scott
authors.initials: TS
authors.lastname: Blackwell
authors.affiliation: From the Mallinckrodt Institute of Radiology (Y.L., D.H.S., H.P.L., Y.Z., R.J.G., S.L.B.) and Departments of Medicine (S.P.G., T.S.B., Z.B.N., J.H.P., D.E.B., J.J.A., M.J.H., R.J.G., S.L.B.), Surgery (D.K.), Pathology and Immunology (D.K.), and Cell Biology (M.J.H.), Washington University School of Medicine, 660 S Euclid Ave, Box 8052, St Louis, MO 63110; and Centre d'Immunologie et des Maladies Infectieuses, CIMI-Paris, Faculté de Médecine Pitié-Salpêtrière, Paris INSERM, Paris, France (C.C.).
authors.forename: Zachary
authors.initials: Z
authors.lastname: Bollermann-Nowlis
authors.affiliation: From the Mallinckrodt Institute of Radiology (Y.L., D.H.S., H.P.L., Y.Z., R.J.G., S.L.B.) and Departments of Medicine (S.P.G., T.S.B., Z.B.N., J.H.P., D.E.B., J.J.A., M.J.H., R.J.G., S.L.B.), Surgery (D.K.), Pathology and Immunology (D.K.), and Cell Biology (M.J.H.), Washington University School of Medicine, 660 S Euclid Ave, Box 8052, St Louis, MO 63110; and Centre d'Immunologie et des Maladies Infectieuses, CIMI-Paris, Faculté de Médecine Pitié-Salpêtrière, Paris INSERM, Paris, France (C.C.).
authors.forename: Jie-Hong
authors.initials: JH
authors.lastname: Pan
authors.affiliation: From the Mallinckrodt Institute of Radiology (Y.L., D.H.S., H.P.L., Y.Z., R.J.G., S.L.B.) and Departments of Medicine (S.P.G., T.S.B., Z.B.N., J.H.P., D.E.B., J.J.A., M.J.H., R.J.G., S.L.B.), Surgery (D.K.), Pathology and Immunology (D.K.), and Cell Biology (M.J.H.), Washington University School of Medicine, 660 S Euclid Ave, Box 8052, St Louis, MO 63110; and Centre d'Immunologie et des Maladies Infectieuses, CIMI-Paris, Faculté de Médecine Pitié-Salpêtrière, Paris INSERM, Paris, France (C.C.).
authors.forename: Derek E
authors.initials: DE
authors.lastname: Byers
authors.affiliation: From the Mallinckrodt Institute of Radiology (Y.L., D.H.S., H.P.L., Y.Z., R.J.G., S.L.B.) and Departments of Medicine (S.P.G., T.S.B., Z.B.N., J.H.P., D.E.B., J.J.A., M.J.H., R.J.G., S.L.B.), Surgery (D.K.), Pathology and Immunology (D.K.), and Cell Biology (M.J.H.), Washington University School of Medicine, 660 S Euclid Ave, Box 8052, St Louis, MO 63110; and Centre d'Immunologie et des Maladies Infectieuses, CIMI-Paris, Faculté de Médecine Pitié-Salpêtrière, Paris INSERM, Paris, France (C.C.).
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Atkinson
authors.affiliation: From the Mallinckrodt Institute of Radiology (Y.L., D.H.S., H.P.L., Y.Z., R.J.G., S.L.B.) and Departments of Medicine (S.P.G., T.S.B., Z.B.N., J.H.P., D.E.B., J.J.A., M.J.H., R.J.G., S.L.B.), Surgery (D.K.), Pathology and Immunology (D.K.), and Cell Biology (M.J.H.), Washington University School of Medicine, 660 S Euclid Ave, Box 8052, St Louis, MO 63110; and Centre d'Immunologie et des Maladies Infectieuses, CIMI-Paris, Faculté de Médecine Pitié-Salpêtrière, Paris INSERM, Paris, France (C.C.).
authors.forename: Daniel
authors.initials: D
authors.lastname: Kreisel
authors.affiliation: From the Mallinckrodt Institute of Radiology (Y.L., D.H.S., H.P.L., Y.Z., R.J.G., S.L.B.) and Departments of Medicine (S.P.G., T.S.B., Z.B.N., J.H.P., D.E.B., J.J.A., M.J.H., R.J.G., S.L.B.), Surgery (D.K.), Pathology and Immunology (D.K.), and Cell Biology (M.J.H.), Washington University School of Medicine, 660 S Euclid Ave, Box 8052, St Louis, MO 63110; and Centre d'Immunologie et des Maladies Infectieuses, CIMI-Paris, Faculté de Médecine Pitié-Salpêtrière, Paris INSERM, Paris, France (C.C.).
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Holtzman
authors.affiliation: From the Mallinckrodt Institute of Radiology (Y.L., D.H.S., H.P.L., Y.Z., R.J.G., S.L.B.) and Departments of Medicine (S.P.G., T.S.B., Z.B.N., J.H.P., D.E.B., J.J.A., M.J.H., R.J.G., S.L.B.), Surgery (D.K.), Pathology and Immunology (D.K.), and Cell Biology (M.J.H.), Washington University School of Medicine, 660 S Euclid Ave, Box 8052, St Louis, MO 63110; and Centre d'Immunologie et des Maladies Infectieuses, CIMI-Paris, Faculté de Médecine Pitié-Salpêtrière, Paris INSERM, Paris, France (C.C.).
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Gropler
authors.affiliation: From the Mallinckrodt Institute of Radiology (Y.L., D.H.S., H.P.L., Y.Z., R.J.G., S.L.B.) and Departments of Medicine (S.P.G., T.S.B., Z.B.N., J.H.P., D.E.B., J.J.A., M.J.H., R.J.G., S.L.B.), Surgery (D.K.), Pathology and Immunology (D.K.), and Cell Biology (M.J.H.), Washington University School of Medicine, 660 S Euclid Ave, Box 8052, St Louis, MO 63110; and Centre d'Immunologie et des Maladies Infectieuses, CIMI-Paris, Faculté de Médecine Pitié-Salpêtrière, Paris INSERM, Paris, France (C.C.).
authors.forename: Christophe
authors.initials: C
authors.lastname: Combadiere
authors.affiliation: From the Mallinckrodt Institute of Radiology (Y.L., D.H.S., H.P.L., Y.Z., R.J.G., S.L.B.) and Departments of Medicine (S.P.G., T.S.B., Z.B.N., J.H.P., D.E.B., J.J.A., M.J.H., R.J.G., S.L.B.), Surgery (D.K.), Pathology and Immunology (D.K.), and Cell Biology (M.J.H.), Washington University School of Medicine, 660 S Euclid Ave, Box 8052, St Louis, MO 63110; and Centre d'Immunologie et des Maladies Infectieuses, CIMI-Paris, Faculté de Médecine Pitié-Salpêtrière, Paris INSERM, Paris, France (C.C.).
authors.forename: Steven L
authors.initials: SL
authors.lastname: Brody
mesh_terms: D000818:Animals; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D011014:Pneumonia / Q000000981:diagnostic imaging* / Q000276:immunology*; D049268:Positron-Emission Tomography / Q000379:methods; D054390:Receptors, CCR2 / Q000032:analysis*
chemical_list: D054390:Receptors, CCR2