Quantification of macrophage activity in knee synovial tissue using [¹⁸F]FEPPA positron emission tomography

Inflammation in knee osteoarthritis (OA) is mediated primarily by synovial tissue macrophages, but non-invasive measurement of macrophage activity in vivo is a challenge. Activated macrophages markedly increase expression of the translocator protein (TSPO). In the context of other diseases TSPO-PET using the [¹⁸F]FEPPA tracer (binding to TSPO) has been reported to be an effective method for imaging macrophages in vivo. The goal of this study was to validate the use of [¹⁸F]FEPPA PET radiotracer to accurately measure macrophage activation in knee synovial tissue.

Ten participants with late-stage OA scheduled for knee replacement surgery were recruited. Prior to surgery, 5 of the participants underwent a clinical [¹⁸F]FEPPA PET/MRI scan and the standard uptake value (SUV) in the suprapatellar synovial region was calculated. Suprapatellar synovial tissue samples were collected from all participants at the time of surgery and were imaged ex vivo with [¹⁸F]FEPPA autoradiography. Tracer uptake was compared to TSPO antibody immunostaining in serial tissue sections. The correlation between the [¹⁸F]FEPPA uptake and gold standard TSPO fluorescent intensity was measured.

The autoradiography [¹⁸F]FEPPA signal in the synovial lining was correlated with the TSPO signal in the. lining macrophages measured by immunohistochemistry (r = 0.81, p = 0.0040, CI [0.37, 0.95]). Similarly, PET/MRI scans demonstrated similar correlation between SUV in synovial tissues in vivo and in situ TSPO signal in lining macrophages {r = 0.90, p = 0.083, CI [0.086, 0.99]).

[¹⁸F]FEPPA uptake in knee synovial tissue is strongly correlated to the expression of TSPO in synovial lining macrophages, suggesting that clinical [¹⁸F]FEPPA PET/MRI may be a valid measure of true macrophage activity in synovial tissues in knee OA. [¹⁸F]FEPPA may be an effective tool to assess macrophage activation both ex vivo and in vivo, and should be investigated further to assess its performance and measurement properties in different clinical contexts of knee OA including disease states and responses to treatment.