Project Summary Acute lung injury (ALI), clinically known as acute respiratory distress syndrome (ARDS), is a severe and potentially life-threatening condition with different sub-phenotypes leading to distinct clinical outcomes. In particular, patients with non-resolving pulmonary inflammation who survive the acute phase of ARDS are a subpopulation at increased risk for poor outcomes, including long term lung damage and significantly decreased quality of life. Therefore, developing strategies to monitor ongoing lung inflammation based on inflammatory signatures (i.e. specific inflammatory mediators and individual immune cell populations) represents a Precision Medicine approach, especially relevant given the growing development and applications of immunomodulatory therapies. Molecular imaging using positron emission tomography (PET) is emerging as a promising non- invasive approach that can used to visualize inflammatory processes and provide prognostic information. Current PET tracers, primarily 18F-FDG, for lung inflammation suffer from a lack of specificity and poor kinetics. We propose developing PET tracers targeting the receptor/chemokine ChemR23/chemerin, a newly established biomarker for imaging lung inflammation. We have designed two classes of PET tracers, an “active” probe imaging the expression of ChemR23 and an “activatable” probe imaging the inflammatory-protease bioactivation of the ChemR23-chemerin axis. Our central hypothesis is that modification of the “active” tracer into an “activatable” tracer through addition of a cleavable C-terminal tail will enhance the specificity of imaging the ChemR23-chemerin axis by mimicking the local bioactivation and ultimately uptake of chemerin in the inflammatory environment. We propose two specific aims: SPECIFIC AIM 1: To synthesize and biologically characterize active and protease-activatable chemerin-derived radiotracers. SPECIFIC AIM 2: To determine the biological, biochemical, and histological correlates of ChemR23-targeted PET by “active” and “activatable” tracers in a mouse model of ALI. Our ultimate goal is to develop bioactivatable PET tracers for precision medicine imaging of ongoing lung injury and inflammation along the ChemR23-chemerin axis to improve research and clinical prognostic tools.