Translational PET imaging of inflammation

Abstract: Inflammation is our body’s sophisticated defense mechanism against invading pathogens, traumas, and tumors. Repeatable and non-invasive monitoring of inflammation process would open opportunities to improve our knowledge of several diseases and enable assessment of personalized treatments. Positron emission tomography (PET) combined with computed tomography (CT) has sufficient sensitivity to visualize the location of inflamed tissue in minimally invasive way. Paper I focused utilizing an already clinically available radiotracer [68Ga]Ga-DOTA-TATE as a macrophage marker for PET imaging in porcine and rodent models of pulmonary inflammation. In Paper II novel radiotracer [11C]GW457427 was evaluated as marker for neutrophil elastase expression in a large animal model of acute respiratory distress syndrome. In Paper III the most favorable Affibody molecule conjugate for SPECT and PET imaging of CD69 expression of activated immune cells was selected. Paper IV followed the results from Paper III and compared the uptake of [68Ga]Ga-DOTA-ZCAM241with a negative control Affibody molecule conjugate [68Ga]Ga-DOTA-ZAM106 in rheumatoid arthritis mouse model.[68Ga]Ga-DOTA-TATE had increased SUV uptake in the most damaged parts of the lungs in porcine lavage model, that corresponded with the results from CT images and quantification, histology staining and [18F]FDG uptake in Paper I . On the rat lung inflammation model the [68Ga]Ga-DOTA-TATE uptake was significantly increased in the damaged lungs compared with healthy control group. The uptake could also be blocked in vivo. Paper II demonstrated that the binding of the neutrophil elastase radiotracer [11C]GW457427 was specific and selective in vivo. SUV were especially elevated in damaged lung regions and neutrophil rich tissues bone marrow and spleen. Paper III indicated that the Affibody molecule variant ZCAM241 had the highest affinity for human and murine CD69 as well as the lowest background binding in SPECT images and was chosen as the most favorable to continue with. Paper IV followed paper III and demonstrated that the optimized Affibody molecule-based radiotracer [68Ga]Ga-DOTA-ZCAM241 uptake in the inflamed joints increased gradually over time as the clinical symptoms got worse and were in line with the images from immunostaining. However, also the uptake of the negative control [68Ga]Ga-DOTA-ZAM106 increased over time, raising questions about the specificity and selectivity of [68Ga]Ga-DOTA-ZCAM241.In conclusion, this thesis presents the preclinical evaluation of several PET-imaging radiotracers targeting different inflammatory cells and their processes in small and large animal models.