Development of PET tracers for M2-macrophages

Macrophages dysregulation can lead to a chronic inflammatory state which is also observed in many age-related diseases such as cancer. The assessment of macrophages using positron emission tomography (PET) could be of benefit of early tumor characterization, treatment monitoring, and a better understanding of the role of M2-like macrophages in inflammatory diseases and cancer where this macrophage phenotype is presented. Therefore, we evaluated novel PET tracers for CD163 receptor and arginase for imaging of M2-like macrophages. The CD163-tracer NODA-MP-C6-CTHRSSVVC was labeled with aluminum [18F]fluoride and showed approximately 50% of specific receptor-mediated binding in vitro using human CD163-expressing tissue homogenates and enabled clear visualization of the tumor with PET. [18F]AlF-NODA-MP-C6-CTHRSSVVC was not able to detect the subtle differences in CD163 levels in the tumor caused by different treatments, however, a positive correlation between tracer uptake and CD163 levels in the tumor was found. The arginase tracer [18F]FBMARS was synthesized using a Cu-mediated oxidative 18F-fluorination technique. The tracer production was successfully automated using Synthra synthesis module generating sufficient amounts for preclinical and clinical studies. Non-displaceable binding potential derived from the 2-tissue compartment model demonstrated to be the most suitable parameter to express arginase activity in rats with an arginase-overexpressing macrophage xenograft. The initial preclinical evaluation of [18F]AlF-NODA-MP-C6-CTHRSSVVC and [18F]FBMARS demonstrated satisfactory outcomes to be further studied in more suitable preclinical models and these tracers might open a door to mapping M2-macrophages in PET imaging in oncology.