Targeting activated macrophages to identify the vulnerable atherosclerotic plaque

Excerpt

Hellberg and co-workers report the results of a preclinical study in mice designed to test the feasibility of targeting translocator protein (TSPO) with ¹⁸F-FEMPA for the detection of atherosclerotic plaque inflammation. TSPO (formerly called peripheral benzodiazepine receptor) is a translocator protein that is ubiquitously expressed in mammalian tissue, localized to the outer mitochondrial membrane involved in cholesterol transport and expressed in activated macrophages. Because it targets activated macrophages, this radioligand is in theory a specific probe for inflammation imaging in atherosclerotic plaque. The investigators performed in vivo dynamic PET/CT in 3 LDLR^−/−ApoB^100/100 mice and 4 C57BL/6N (wild-type) mice to document whole-body biodistribution and kinetics. Additional mice (10 athero mice and 7 WT) were injected with radiotracer and sacrificed at 20 minutes and the thoracic aorta was removed for autoradiography and subsequently for immunohistology. Carotid endarterectomy tissue from 4 patients with recent cerebral ischemic events was also analyzed by in vitro autoradiography. While radioactive uptake as count density correlated with plaque macrophage density on ex vivo autoradiography for mouse tissue, ¹⁸F-FEMPA was also taken up in normal arterial walls adjacent to the plaque and diffusely in the walls of large arteries of non-atherosclerotic WT mice, and consequently, there was no difference in radioactive uptake in plaque vs normal vessel. These findings were explained by high constitutive expression of TSPO in endothelial cells and VSMCs in rodents. For the human autoradiographic and histological analysis, ¹⁸F-FEMPA uptake was also highest in macrophage-rich plaques with uptake also seen at lower levels in α-SMA-positive areas but in vitro autoradiography was limited to the plaque region removed at endarterectomy, and therefore, adjacent non-atherosclerotic or remote vessel tissue was not available for study. While these preliminary studies do not stand as a positive proof of principle for the further development of this agent for in vivo PET imaging of inflamed atherosclerotic plaque in human subjects it is important to consider experimental and biological factors that may have affected the results and should be discussed before deciding on any possible future directions for this imaging ligand. The thoughtful study design and careful experimental approach carried out by Dr Hellberg and her co-investigators are instructive to considering the development or a targeted radiotracer to identify vulnerable atherosclerotic plaques. …