PT  - JOURNAL ARTICLE
AU  - Debbie Sultan
AU  - Sean Gunsten
AU  - Hannah Luehmann
AU  - Michelle Hoelscher
AU  - Gyu Seong Heo
AU  - Pan Jiehong
AU  - Tao Huang
AU  - Richard Laforest
AU  - Robert Gropler
AU  - Delphine Chen
AU  - Jeffrey Atkinson
AU  - Steven Brody
AU  - Yongjian Liu
TI  - Chemokine receptor 2 targeted PET imaging in pulmonary fibrosis.
DP  - 2021 May 01
TA  - Journal of Nuclear Medicine
PG  - 1695--1695
VI  - 62
IP  - supplement 1
4099  - http://jnm.snmjournals.org/content/62/supplement_1/1695.short
4100  - http://jnm.snmjournals.org/content/62/supplement_1/1695.full
SO  - J Nucl Med2021 May 01; 62
AB  - 1695Objectives: The role of chemokine receptor 2 (CCR2) has been elucidated in the development of idiopathic pulmonary fibrosis (IPF). This inflammatory disease, with limited treatment options and a 5-year survival of 20-40%, has no effective molecular markers for monitoring disease progression or treatment response. CCR2+ cells are increased in pulmonary fibrosis with expression in both Ly6Chigh inflammatory monocytes and their progeny, profibrotic interstitial macrophages. Therefore, we developed a 64Cu-based radiotracer that targets the extracellular loop one (ECL1) of CCR2, 64Cu-DOTA-ECL1i, to track the CCR2 expression in mouse models of fibrosis along the progression of the disease and variation following treatment. Moreover, we have translated this radiotracer for human use in both healthy volunteers and patients with IPF. Methods: Pre-clinical evaluation of CCR2 expression in mice was evaluated using two mouse models of fibrosis, bleomycin- or radiation-induced, in wild-type and CCR2-knockout mice. In the bleomycin model, treatment response was assessed following administration of pirfenidone on days 10-28 after bleomycin. Dynamic PET-CT scans were performed on days 2, 14, and 28 following bleomycin and 14- and 26-weeks following irradiation. Tissues were harvested for immunostaining and autoradiography, and uptake was correlated with PET/CT signal. The CCR2 cell populations were localized relative to fibrotic regions in lung tissue and characterized using immunolocalization, mass cytometry, and CCR2 RNA in situ hybridization and correlated with parallel quantitation of lung uptake of 64Cu-DOTA-ECL1i. Following FDA approval, 64Cu-DOTA-ECL1i was evaluated in human healthy volunteers (n = 7) and patients with IPF (n = 4). Results: In the bleomycin mouse model, 64Cu-DOTA-ECL1i PET showed intensive lung uptake associated with perifibrotic regions which peaked at day 14. Competitive receptor blocking and imaging using CCR2 knock-out mice showed significantly decreased lung uptake. Mass cytometry showed markedly increased CCR2+ cells, supporting PET data. Following pirfenidone treatment, PET signals in lungs were reduced, which was consistent with decreased lung fibrosis, accumulation of CCR2+ cells, and interstitial macrophages. In ex vivo human fibrotic lung tissues, the expression profile of CCR2+ cells was comparable to 64Cu-DOTA-ECL1i autoradiography, suggesting the specific binding of as-developed tracer to CCR2. Human imaging in healthy volunteers revealed little lung uptake and reasonable dosimetry. In IPF patients, a close association between 64Cu-DOTA-ECL1i PET uptake and fibrotic activity was determined. Conclusion: Our data demonstrated the sensitivity and specificity of 64Cu-DOTA-ECL1i imaging CCR2 in both mouse and human. Our findings support a role for imaging CCR2 cells within the fibrogenic niche in IPF to provide a molecular target for personalized therapy and monitoring.