18F-FDG Versus Tissue Factor-Targeted PET/CT in Longitudinal Evaluation of the Formation of DEN-Induced Rat Hepatocellular Carcinoma

Tissue factor (TF) has emerged as a promising target for the diagnosis and treatment of hepatocellular carcinoma (HCC). However, there is limited data available on TF-related PET imaging for longitudinal monitoring of the pathophysiological changes during HCC formation. Herein, we aimed to explore the TF-expression feature and compare a novel TF-targeted PET probe with ¹⁸F-FDG through longitudinal imaging in diethylnitrosamine (DEN)-induced rat HCC. Wistar rats were randomly allocated to three groups receiving DEN: intragastric administration (10 mg/kg, i.g.); intragastric administration (80 mg/kg, i.g.); intraperitoneal administration (80 mg/kg, i.p.) for 12 consecutive weeks. Longitudinal Al¹⁸F-NOTA-tTF and ¹⁸F-FDG (∼3.7 MBq) PET/CT were performed at weeks 7, 15, and 21. Terminal histopathological evaluation included hematoxylin-eosin staining and immunohistochemical analysis of Ki-67, AFP, and TF expression. In DEN-induced HCC rats (80 mg/kg, i.p. and i.g.), longitudinal ¹⁸F-FDG PET/CT revealed temporal metabolic progression, with no detectable lesions at week 7 but distinct hypermetabolic foci appearing by week 15 (4 lesions/group) and increasing to 12 lesions/group at week 21. Quantitative analysis demonstrated significant SUVmax increases in both models from weeks 15 to 21 (i.p.: 1.53 ± 0.54 to 1.87 ± 0.53; i.g.: 1.34 ± 0.37 to 1.77 ± 1.08), though notable heterogeneity emerged with 33.3% of i.p. lesions showing paradoxical SUVmax reduction. In contrast, the Al¹⁸F-NOTA-tTF demonstrated superior early detection, identifying lesions as early as week 7 (2 lesions/group) with progressive detection rates reaching 5 lesions by week 15 and 21 (i.p.)/12 (i.g.) lesions at week 21. From weeks 15 to 21, the Al¹⁸F-NOTA-tTF exhibited consistently increasing SUVmax (i.p.: 0.56 ± 0.23 to 0.76 ± 0.30; i.g.: 0.47 ± 0.13 to 0.58 ± 0.13), with sustained uptake in 90% (i.p.) and 83% (i.g.) of lesions. Immunohistochemistry demonstrated overexpression of Ki-67, AFP, and TF in PET-positive regions. The longitudinal ¹⁸F-FDG PET imaging exhibits significant spatial, temporal, and quantitative heterogeneity in detecting lesions during hepatocarcinogenesis, while TF-targeted PET imaging shows superior capabilities in early and advanced HCC detection. This complementary information highlights the complexity of hepatocarcinogenesis and supports the potential clinical translation of TF-targeted PET for improved HCC detection and characterization.