Abstract
302
Objectives: Localized inflammation in myocardium and vasculature has emerged as a therapeutic and imaging target for cardiovascular disease. A range of different radiotracers have been evaluated for assessment of inflammatory cell infiltration, but the precise cell populations responsible for the in vivo signal remain elusive. We aimed to characterize the cellular binding profiles of five candidate inflammation radiotracers.
Methods: Radiotracers evaluated were: 18F-deoxyglucose (FDG), labeled amino acids 18F-fluoroethyltyrosine (FET) and 11C-methionine (MET), mitochondrial translocator protein (TSPO)-targeted 18F-GE180, and leukocyte-expressed chemokine receptor type 4 (CXCR4) targeted 68Ga-pentixafor. All tracers were previously shown to be useful for imaging of myocardial inflammation in preclinical and/or clinical models. Uptake assays were performed in THP-1 derived macrophages with classical polarization, and in peripheral blood leukocyte subpopulations purified by magnetic immunoseparation.
Results: All tracers demonstrated specific uptake by polarized macrophages. FDG uptake was consistently higher than for other tracers, with intermediate uptake of GE180, and comparatively low accumulation of MET, FET, and pentixafor, reflecting slower transport rates of amino acids and lower expression of CXCR4, respectively. Most tracers showed higher accumulation in proinflammatory M1 macrophages over M2. FDG uptake was 20-fold higher in M1 compared to M2 (p<0.001), FET was 13-fold higher (p<0.001), MET was 10-fold higher (p=0.03), and GE180 was 7-fold higher (p<0.001). By contrast, pentixafor showed comparable accumulation in M1 and M2 polarized macrophages, suggesting similar expression of CXCR4 in these cells (p=NS). In peripheral blood leukocytes, CD177-positive neutrophils tended to have the highest uptake of FDG, MET, and FET, reflecting high metabolic activity. By contrast, T- and B-lymphocytes showed relatively low uptake of metabolic tracers. Both GE180 and pentixafor displayed greater selectivity for CD11b-positive monocytes over other subtypes, supporting higher selectivity of TSPO and CXCR4 molecular targets (Fig).
Conclusion: Inflammation-targeted tracers show subtle differences with regard to the identified leukocyte subpopulations. Whereas metabolic markers are characterized by high accumulation in neutrophils, more specific molecular markers TSPO and CXCR4 target different subsets of leukocytes. These differences in tracer uptake parameters should be considered when interpreting inflammation imaging data. Research Support: N/A