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Purpose: Radiation-induced pulmonary fibrosis (RIPF) is a potentially serious and disabling late complication of radiation therapy. Monitoring RIPF progression is challenging due to the absence of early detection tools and the difficulty in distinguishing RIPF from other lung diseases using standard imaging methods. In the lungs, integrin αvβ6 is crucial in the development of RIPF, acting as a significant activator of transforming growth factor β after radiation injury. This study aimed to investigate integrin α v β 6 -targeted positron emission tomography (PET) imaging ([ 64 Cu]Cu-α v β 6 -BP) to study RIPF development in vivo., Methods and Materials: We used a focal RIPF model (70 Gy delivered focally to a 3 mm spot in the lung) and a whole lung RIPF model (14 Gy delivered to the whole lung) in adult C57BL/6J mice. Small animal PET/computed tomography images were acquired 1 hour postinjection of 11.1 MBq of [ 64 Cu]Cu-α v β 6 -BP. Animals were imaged for 8 weeks in the focal RIPF model and 6 months in the whole lung RIPF model. Immunohistochemistry for integrin α v β 6 and trichrome staining were performed., Results: In the focal RIPF model, there was focal uptake of [ 64 Cu]Cu-α v β 6 -BP in the irradiated region at week 4 that progressively increased at weeks 6 and 8. In the whole lung RIPF model, minimal uptake of the probe was observed at 4 months post-radiation therapy, which significantly increased at months 5 and 6. Expression of integrin α v β 6 was validated histologically by immunohistochemistry in both models., Conclusions: Integrin α v β 6 -targeted PET imaging using [ 64 Cu]Cu-α v β 6 -BP can serve as a useful tool to identify RIPF in vivo., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)