PET imaging of inflammation and fibrosis

When the body faces an injury, the immune system triggers inflammation to initiate tissue repair. However, dysregulation of this process can lead to chronic inflammation, driving persistent scar formation and resulting in fibrosis. Fibrosis, characterised by pathological scar tissue accumulation, impairs organ function which could ultimately lead to death. Despite its clinical significance, treatment options remain limited. Positron Emission Tomography (PET) imaging, a highly sensitive and quantitative technique, offers significant potential for the non-invasive assessment of inflammatory and fibrotic processes. Papers I and II investigate the Affibody molecule Z09591, which targets platelet-derived growth factor receptor β (PDGFR β), as a PET tracer for assessing liver fibrogenesis in a murine model of toxin-induced fibrosis (the CCl 4 model). PDGFRβ, expressed on fibrogenic cells such as activated hepatic stellate cells, is absent in quiescent cells. Two radiolabeling techniques were compared: the TCO-TZ conjugation method ([ 18 F]TZ-Z09591, Paper I) and the Al 18 F-RESCA method ([ 18 F]AlF-RESCA-Z09591, Paper II). Both tracers demonstrated specific uptake in fibrotic regions with low liver background, highlighting their potential for non-invasive assessment of fibrogenic activity. These findings have supported the initiation of a first-in-human clinical trial evaluating a Z09591-based PET tracer. Papers III and IV focus on two PET tracers, [¹¹C]NES and [ 68 Ga]Ga-FAPI-46, targeting neutrophil elastase (NE) and fibroblast activation protein (FAP), respectively, in pulmonary fibrosis. NE is a protease released by activated neutrophils, while FAP is expressed on activated fibroblasts. Sequential PET scans were performed in patients with long COVID-19 (Paper III) and interstitial lung disease (Paper IV), with [¹¹C]NES assessing neutrophil-mediated inflammation and [ 68 Ga]Ga-FAPI-46 imaging tissue remodeling activity. Tracer uptake correlated with lung abnormalities seen on computed tomography scans, underscoring their potential in imaging inflammation and tissue remodeling activity processes. Given the complex pathogenesis of fibrosis and the lack of curative treatments, PET tracers that enable earlier diagnosis and disease monitoring may improve patient management and support the development of anti-fibrotic therapies.