Radiolabeled Albumin Bound Fibroblast Activation Protein (FAP) Inhibitor-04 Enhances Precision in Renal Fibrosis Diagnosis via PET Imaging

Renal fibrosis is a critical pathological feature of both acute kidney injury (AKI) and chronic kidney disease (CKD), yet noninvasive methods for early detection remain limited. Current imaging tracers, such as ¹⁸F-FDG and ⁶⁸Ga-FAPI-04, suffer from poor specificity and renal clearance, hindering accurate fibrosis assessment. This study aimed to evaluate the ⁶⁸Ga-TE-FAPI-04 tracer as a promising tool for precise characterization of renal fibrosis across disease stages. ⁶⁸Ga-TE-FAPI-04 was synthesized by conjugating a FAP inhibitor with an albumin-binding moiety. Its performance was systematically evaluated in murine unilateral (early stage) and bilateral (advanced-stage) ischemia-reperfusion injury (IRI) models using longitudinal PET/CT imaging, biodistribution studies, histopathological correlations, and functional examinations. Comparative assessments with ⁶⁸Ga-FAPI-04 and ¹⁸F-FDG were performed. ⁶⁸Ga-TE-FAPI-04 demonstrated superior sensitivity for detecting active fibrogenesis in unilateral IRI models, with significantly higher uptake in injured kidneys than control kidneys during the critical window of days 7-14 postinjury (day 7, 0.79 ± 0.12 vs 0.51 ± 0.09, <i>P</i> < 0.001; day 10, 0.93 ± 0.17 vs 0.70 ± 0.14, <i>P</i> = 0.001). In bilateral IRI models, it effectively characterized advanced fibrosis, showing strong correlations with functional impairment (serum creatinine: <i>R</i> = 0.857, <i>P</i> = 0.007). The tracer's albumin-binding design enabled prolonged circulation and enhanced target accumulation, overcoming the rapid washout limitations of current FAPI tracers. Histopathological validation confirmed robust correlations between tracer uptake and both interstitial fibrosis (<i>R</i> = 0.847, <i>P</i> < 0.001) and FAP expression (<i>R</i> = 0.755, <i>P</i> < 0.001). ⁶⁸Ga-TE-FAPI-04 PET/CT represents a paradigm shift in renal fibrosis management, enabling early detection of active fibrogenesis before functional decline, and comprehensive assessment of advanced disease. Its dual capacity to quantify structural changes and reflect functional severity positions it as a precision medicine tool for revolutionizing nephrology practice. Further validation in clinical cohorts will be essential to confirm these preclinical findings.