Validation of a CD206-targeted PET imaging probe for pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive disease with limited treatment options, poor prognosis, and a median survival of only 3-4 years after diagnosis. Current clinical diagnostic techniques are limited in early detection, patient stratification, and treatment effect monitoring. Invasive biopsy remains the gold standard to obtain pathological information for IPF diagnosis and prognosis. Pulmonary macrophages, including alveolar macrophages and monocyte-derived macrophages, are essential to the innate immune response in the pathogenesis of IPF. CD206-positive (CD206+) macrophages have been found to be pro-fibrotic and secret pro-fibrotic cytokines, interact with and support myofibroblasts, and promote extracellular matrix (ECM) accumulation. Elevated CD206 expression has been found during the fibrotic stage in bleomycin-induced mouse models and in the alveolar macrophages of IPF patients. Therefore, CD206+ macrophages have emerged as a promising target for both diagnostic and therapeutic interventions. However, current imaging agents targeting CD206, either use single-mannose based agents that are not specific or nanobody/antibody-based PET probes that might cause prolonged exposure to radiation or undesired pathologic effects to the lungs. We have developed CD206-targeted MRI agents and demonstrated that they are specific and able to map CD206+ macrophage changes in cutaneous injury, glioma, and stroke. Histopathological studies showed that the fluorescent analog of the MRI agent correlates well with CD206 and collagen and is markedly increased at week 3 compared to week 1 in bleomycin-induced lung fibrosis. However, MRI is often unsuitable for imaging pulmonary diseases, especially in ventilated patients. The goal of this proposal is to validate a PET imaging probe that shares the specific binding moiety with the CD206-targeted MRI agent to track CD206+ macrophages in pulmonary fibrosis. We will validate the specificity and efficacy of the probe both in vitro and in vivo, in a bleomycin-induced mouse model of lung fibrosis. We will demonstrate the ability of the validated probe in detecting CD206+ macrophages and correlate imaging data with biochemical, flow cytometric, and immunopathological findings. The results from this proposal will provide critical preliminary data for a forthcoming R01 application. Project Number: 1R03HL180811-01 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Cuihua Wang | Institution: MASSACHUSETTS GENERAL HOSPITAL, BOSTON, MA | Award Amount: $247,500 | Activity Code: R03 | Study Section: Special Emphasis Panel[ZHL1 CSR-Y (M1)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R03HL18081101