In Vivo Mapping of Vascular Inflammation Using the Translocator Protein Tracer ¹⁸F-FEDAA1106

Abstract

Noninvasive imaging methods are required to monitor the inflammatory content of atherosclerotic plaques. FEDAA1106 (N-(5-fluoro-2-phenoxyphenyl)-N-(2-(2-fluoroethoxy)-5-methoxybenzyl) acetamide) is a selective ligand for TSPO-18kDa (also known as peripheral benzodiazepine receptor), which is expressed by activated macrophages. We compared 18F-FEDAA1106 and 2-deoxy-2-[18F]fluoro-d-glucose (18F-FDG, a marker of glucose metabolism) for positron emission tomographic (PET) imaging of vascular inflammation. This was tested using a murine model in which focal inflammation was induced in the carotid artery via placement of a constrictive cuff. Immunostaining revealed CD68-positive cells (macrophages) at a disturbed flow site located downstream from the cuff. Dynamic PET imaging using 18F-FEDAA1106 or 18F-FDG was registered to anatomic data generated by computed tomographic (CT)/CT angiography. Standardized uptake values were significantly increased at cuffed compared to contralateral arteries using either 18F-FEDAA1106 (p < .01) or FDG (p < .05). However, the 18F-FEDAA1106 signal was significantly higher at the inflamed disturbed flow region compared to the noninflamed uniform flow regions, whereas differences in FDG uptake were less distinct. We conclude that 18F-FEDAA1106 can be used in vivo for detection of vascular inflammation. Moreover, the signal pattern of 18F-FEDAA1106 corresponded with vascular inflammation more specifically than FDG uptake.

TSPO: kaleidoscopic 18-kDa amid biochemical pharmacology, control and targeting of mitochondria

“…In stroke patients, TSPO expression and glial activation is increased in the peri-infarct zone for several weeks following insult (154) while bio-imaging has revealed elevated TSPO expression in inflamed atherosclerotic plaques of the vasculature (155,156). …”

Positron Emission Tomography Imaging of Macrophages in Atherosclerosis with 18F-GE-180, a Radiotracer for Translocator Protein (TSPO)

“…Novel TSPO-targeting tracers have been studied in preclinical settings to overcome this problem. For example, 18 F-FEDAA1106 has been evaluated in the imaging of the carotid artery cuff model in mice [ 23 ] and 11 C-PBR28 in a rat model of aortic aneurysm [ 24 ]. Both of these studies showed noticeable tracer uptake in lesion areas.…”

Mitochondrial regulation of macrophage cholesterol homeostasis

“…Expression of TSPO is upregulated by exposure to modified LDL in human macrophages [153] and in microglia by lipopolysaccharide (LPS) [154], and TSPO ligands have been used to image macrophage burden and intraplaque inflammation within human and murine atherosclerotic lesions [155][156][157]. Transient overexpression of TSPO in human macrophages enhanced efflux of cholesterol to apoA-I, HDL, and human serum, while knockdown of TSPO achieved the reverse [153].…”

“…Signaling via TSPO also reduced the production of reactive oxygen species, cytokines, and chemokines in microglia, and promoted phagocytic activity [158][159][160]; TSPO ligands have also proved useful in reducing inflammation and severity of disease in a murine model of multiple sclerosis [161]. Indeed, TSPO has been proposed as a novel target for Alzheimer's disease and neurologic disorders [162][163][164][165], pain [166], vascular disease [153,[155][156][157], and cancer [167], although it is not clear at present how many of the effects ascribed to TSPO are related to its proposed role in mitochondrial cholesterol trafficking. Further, caution is obviously needed in interpreting the reported effects of TSPO and its ligands, given the lack of phenotype recently reported in healthy TSPO(-/-) mice [111,132,133]: it remains to be seen whether loss of TSPO will contribute to macrophage dysfunction in the context of specific disease pathologies.…”