A Novel FAPI-Based Radiopharmaceutical for SPECT Imaging of Fibrotic Interstitial Lung Disease

<b>Objectives</b>: Early and noninvasive detection of fibrotic interstitial lung disease (fILD) is a critical but unmet clinical necessity. This study aimed to evaluate the feasibility of using ^99mTc-HYNIC-Glu(PEG₄-oncoFAPi)₂ (denoted as ^99mTc-H-PoFP₂), a novel ^99mTc-labeled radiopharmaceutical that targets fibroblast activation protein (FAP), for single-photon emission computed tomography (SPECT) imaging of pulmonary fibrosis in a mouse model and preliminary clinical studies. <b>Methods:</b>^99mTc-H-PoFP₂ could be conveniently afforded using a kit formula with high radiochemical purity and stability. The binding specificity and affinity of ^99mTc-H-PoFP₂ for FAP were validated by an in vitro binding assay. The in vivo characteristics of ^99mTc-H-PoFP₂ were also determined. <b>Results:</b>^99mTc-H-PoFP₂ was eliminated quickly via the urinary system, leading to low normal tissue uptake and a high target/background ratio. SPECT imaging demonstrated significantly enhanced uptake of the ^99mTc-H-PoFP₂ in bleomycin-induced fibrotic lung tissues, with visual effects superior to those of normal mice. Thus, a pilot clinical study of ^99mTc-H-PoFP₂ SPECT/CT imaging was conducted in 12 patients diagnosed with fILD. The physiological biodistribution of ^99mTc-H-PoFP₂ in patients was predominantly observed in the kidneys, bladder, liver, and pancreas, with relatively minor accumulation in the thyroid, salivary glands, and spleen. fILD patients exhibited elevated pulmonary ^99mTc-H-PoFP₂ uptake in the affected lung regions. Furthermore, the uptake of ^99mTc-HPoFP₂ demonstrated moderate correlations with the results of pulmonary function tests (PFTs). A higher gender-age-physiology (GAP) index was associated with elevated standardized uptake value maximum (SUVmax) and target-to-background ratio (TBR) values. <b>Conclusions:</b> Collectively, this study demonstrates the potential of ^99mTc-HPoFP₂ for SPECT imaging and assessing fILD by targeting FAP overexpressed in fibrotic lung tissues. This strategy offers new possibilities for noninvasive and precise assessment of pulmonary fibrosis.