Selective Imaging of Lung Macrophages Using [11C]PBR28-Based Positron Emission Tomography

Abstract

Purpose: We tested whether the translocator protein (TSPO)-targeted positron emission tomography (PET) tracer, N-acetyl-N-(2-[¹¹C]methoxybenzyl)-2-phenoxy-5-pyridinamine ([¹¹C]PBR28), could distinguish macrophage dominant from neutrophilic inflammation better than 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG) in mouse models of lung inflammation and assessed TSPO association with macrophages in lung tissue from the mouse models and in patients with chronic obstructive pulmonary disease (COPD).

Procedures: MicroPET imaging quantified [¹¹C]PBR28 and [¹⁸F]FDG lung uptake in wild-type (Wt) C57BL/6J or heterozygous transgenic monocyte-deficient Wt/opT mice at 49 days after Sendai virus (SeV) infection, during macrophage-dominant inflammation, and in Wt mice at 3 days after SeV infection or 24 h after endotoxin instillation during neutrophilic inflammation. Immunohistochemical staining for TSPO in macrophages and neutrophils was performed using Mac3 and Ly6G for cell identification in mouse lung sections and CD68 and neutrophil elastase (NE) in human lung sections taken from explanted lungs from patients with COPD undergoing lung transplantation and donor lungs rejected for transplantation. Differences in tracer uptake among SeV-infected, endotoxin-treated, and uninfected/untreated control mice and in TSPO staining between neutrophils and macrophage populations in human lung sections were tested using analysis of variance.

Results: In Wt mice, [¹¹C]PBR28 uptake (% injected dose/ml lung tissue) increased significantly with macrophage-dominant inflammation at 49 days (D49) after SeV infection compared to controls (p = <0.001) but not at 3 days (D49) after SeV infection (p = 0.167). [¹¹C]PBR28 uptake was unchanged at 24 h after endotoxin instillation (p = 0.958). [¹⁸F]FDG uptake increased to a similar degree in D3 and D49 SeV-infected and endotoxin-treated Wt mice compared to controls with no significant difference in the degree of increase among the tested conditions. [¹¹C]PBR28 but not [¹⁸F]FDG lung uptake at D49 post-SeV infection was attenuated in Wt/opT mice compared to Wt mice. TSPO localized predominantly to macrophages in mouse lung tissue by immunostaining, and TSPO staining intensity was significantly higher in CD68+ cells compared to neutrophils in the human lung sections.

Conclusions: PET imaging with [¹¹C]PBR28 can specifically detect macrophages versus neutrophils during lung inflammation and may be a useful biomarker of macrophage accumulation in lung disease.

Keywords: Chronic obstructive pulmonary disease; Lung inflammation; Macrophage; Macrophage polarization; Positron emission tomography; Translocator protein.