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

Objectives: 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 (99m)Tc-HYNIC-Glu(PEG(4)-oncoFAPi)(2) (denoted as (99m)Tc-H-PoFP(2)), a novel (99m)Tc-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. Methods:(99m)Tc-H-PoFP(2) could be conveniently afforded using a kit formula with high radiochemical purity and stability. The binding specificity and affinity of (99m)Tc-H-PoFP(2) for FAP were validated by an in vitro binding assay. The in vivo characteristics of (99m)Tc-H-PoFP(2) were also determined. Results:(99m)Tc-H-PoFP(2) 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 (99m)Tc-H-PoFP(2) in bleomycin-induced fibrotic lung tissues, with visual effects superior to those of normal mice. Thus, a pilot clinical study of (99m)Tc-H-PoFP(2) SPECT/CT imaging was conducted in 12 patients diagnosed with fILD. The physiological biodistribution of (99m)Tc-H-PoFP(2) 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 (99m)Tc-H-PoFP(2) uptake in the affected lung regions. Furthermore, the uptake of (99m)Tc-HPoFP(2) 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. Conclusions: Collectively, this study demonstrates the potential of (99m)Tc-HPoFP(2) 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.