**2.3 Imaging amyloid-ß (Aß) plaque burden in Alzheimer's disease**

As Aβ deposition is considered a hallmark neuropathological sign of AD and is thought to be one of the primary events in the pathogenesis of AD (the "amyloid cascade hypothesis"), Aβ PET imaging agents are at the forefront of this expanding field (Haass and Selkoe, 2007). In AD patients, Aβ deposits are composed of Aβ1-40 and Aβ1-42, peptides that are 40 and 42 amino acids in length, respectively, generated from the sequential proteolytic cleavage of amyloid precursor protein (APP) by β- and γ-secretases (Beyreuther and Masters, 1991; Martins, et al., 1991). Whilst Aβ1-42 deposits have a higher propensity to oligomerize, both isoforms are found in fibrillar amyloid plaques (Tamaoka, et al., 1994), characteristic β-sheetrich structures that represent the target for Aβ PET ligands.

The ability to image and measure Aβ load *in vitro* has considerable implications for the future study of AD. As Aβ deposition commences long before the onset of cognitive deficits, Aβ-targeting probes may support earlier diagnoses and interventions in the pre-dementia stage of this disease (Pike, et al., 2007; Price and Morris, 1999; Thal, et al., 2002). Aβ PET imaging additionally has some utility in accurately differentiating AD from Aβ-negative forms of dementia and, thus, in increasing the specificity of a clinical diagnosis. Objectively monitoring treatments and selecting candidates for particular drugs and clinical trials are other potential uses for this imaging technology (Rafii and Aisen, 2009); for example, patients with low cortical Aβ load, as measured by Aβ PET, are unlikely to qualify for antiamyloid therapies.

Due to the large number of possible clinical applications, there has been a dramatic rise in the number of probes that target Aβ plaques over the last decade. The four Aβ PET imaging agents under active commercial development are [11C]PIB, [18F]flutemetamol, [18F]florbetaben, and [18F]florbetapir. Each imaging agent is currently undergoing FDAapproved Phase III clinical trials in the US, except [18F]Florbetapir, which is awaiting FDA approval. Each Aβ PET imaging agent will be discussed individually in further detail below.
