PET-based imaging of chemokine receptor 2 in experimental and Disease-related lung inflammation

Yongjian Liu, Sean P. Gunsten, Deborah H. Sultan, Hannah P. Luehmann, Yongfeng Zhao, T. Scott Blackwell, Zachary Bollermann-Nowlis, Jie Hong Pan, Derek E. Byers, Jeffrey J. Atkinson, Daniel Kreisel, Michael J. Holtzman, Robert J. Gropler, Christophe Combadiere, Steven L. Brody

Research output: Contribution to journalArticle

13 Scopus citations

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 The study was approved by institutional animal and human Methods: studies committees. Informed consent was obtained from patients. A 7-amino acid CCR2 binding peptide (extracellular loop 1 inverso [ECL1i]) was conjugated to tetraazacy-clododecane tetraacetic acid (DOTA) and labeled with copper 64 ( 64 Cu) 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 of 64 Cu-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) with 64 Cu-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 with 64 Cu-DOTA-ECL1i by using autoradiography. Conclusion: 64 Cu-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.

Original languageEnglish
Pages (from-to)758-768
Number of pages11
JournalRadiology
Volume283
Issue number3
DOIs
StatePublished - Jun 2017

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