Novel approaches for PET imaging of endometriosis

INTRODUCTION: Endometriosis, affecting up to 10% of women, is a chronic estrogen dependent disorder where ectopic endometrial-like tissue causes pelvic pain and infertility. Endometriosis is challenging to diagnose due to symptom overlap and limited imaging accuracy, often requiring surgical visualization. Positron emission tomography (PET) potentially offers a non-invasive, molecular-based approach for highly specific diagnosis and monitoring of endometriosis. Aromatase, typically low in normal endometrial tissue, is elevated in endometriotic lesions, while neutrophils, which are scarce in normal tissue, are increased in these lesions. Fibrosis, resulting from activated platelet-derived growth factor receptor β (PDGFR-β)-expressing myofibroblasts, has been observed in endometriosis lesions. In this study, three PET tracers; [11C]cetrozole ([11C]CET), [11C]GW457427 ([11C]NES), and [68Ga]Ga-ATH001, targeting aromatase, neutrophil elastase (NE), and PDGFR-β, respectively, were tested in endometriosis patient biopsies through autoradiography (ARG) combined with histological examinations. A pilot PET/Magnetic resonance imaging (PET/MR) study was performed in endometriosis patients with [11C]NES. METHODS: Ten biopsies from patients with endometriosis were collected. Frozen tissue was sectioned at 20 μm for ARG and 4 μm for immunohistochemistry (IHC). Total binding and non-specific binding, with quantification using ImageJ (fmol/mm3) was determined. Specific binding was calculated as total minus non-specific binding and expressed as a percentage. Sections were stained with Hematoxylin and Eosin (H/E) and Cytokeratin7 (CK7) for morphology, Sirius Red (SIR) for fibrosis, antibodies against PDGFR-β and NE. Neutrophil extracellular traps (NETs) were identified by combined staining for NE and Histone H3. Three endometriosis patients were scanned with [11C]NES by PET/MR. RESULTS: All three tracers showed high in vitro binding to endometriotic tissue in ARG. [11C]NES and [68Ga]Ga-ATH001 had high degree of specific binding to elastase and PDGFR-β, respectively, whereas no specific binding could be shown for [11C]CET. ARG results were validated by IHC: CK7 confirmed epithelial lesions, NE and Histone H3 verified neutrophils and NETs, and PDGFR-β/SIR indicated fibrosis. However, in vivo, no [11C]NES uptake was detected on the PET/MR scans of the three endometriosis patients. CONCLUSION: In ARG on endometriotic tissue samples, [68Ga]Ga-ATH001 and [11C]NES showed specific binding to their respective targets. However, tracer delivery potentially forms a challenge in visualizing fibrotic endometriosis lesions in vivo, as seen by [11C]NES PET/MR in patients.