Atheroma is ubiquitous in man and rupture of the plaque is the principal cause of most heart attacks and stroke. Initiating early in life, development of the plaque is protracted and progress is dependent upon a variety of genetic and extrinsic factors. The pathogenesis of atheroma is poorly elucidated, although it is becoming increasingly apparent that inflammation, driven by the accumulation of macrophages at the lesion site, is the principal cause of instability and rupture. Previously, we have demonstrated the potential of positron emission tomography (PET) to image inflammatory activity in both carotid atheroma in humans (1) and aortic atheroma in a rabbit model using [¹⁸F]-fluorodeoxyglucose (FDG), a marker of elevated metabolic activity (2). However, FDG accumulates in all living cells including vascular smooth muscle cells, reducing the specificity of PET signal for the inflammatory component of the plaque. A PET-labelled marker specific to macrophages would enable more accurate quantification of macrophage presence. The peripheral benzodiazepine receptor (PBR) is a unique class of diazepine receptor which is functionally distinct from the central diazepine receptor and performs a number of context-dependent functions including cholesterol transport. It is highly expressed in a number of tissues and cell types, including immune cells such as the macrophage. In vivo imaging of the PBR is possible by PET using recently developed radioligands including [¹⁸F]-FEDAA1106; N-(5-fluoro-2-phenoxyphenyl)-N-(2-[¹⁸F]-fluoroethyloxy-5-methoxybenzyl)acetamide (3). Confirmation of the specificity of [¹⁸F]-FEDAA1106 for PBR expressed in activated macrophages in the atherosclerotic plaque is a necessary prequel to evaluating the efficacy of this PET radioligand in a rabbit model of atheroma. We have evaluated the binding of [¹⁸F]-FEDAA1106 to human and rabbit tissues known to express PBR and have shown specific binding (Kd ≈ 1.0nM) in both species. Analysis of [¹⁸F]-FEDAA binding in human carotid and rabbit aortic atheroma ex vivo indicates that this radioligand preferentially binds to sites within the plaque (Fig. 1), correlating with macrophage presence (CD68) and PBR expression (determined by immunohistochemistry). The successful conclusion of these experiments will generate an efficacious clinical tool for determining atheroma instability.