Low background and high contrast PET imaging of amyloid-β with [11C]AZD2995 and [11C]AZD2184 in Alzheimer's disease patients

The aim of this study was to evaluate AZD2995 side by side with AZD2184 as novel PET radioligands for imaging of amyloid-beta in Alzheimer's disease (AD). In vitro binding of tritium-labelled AZD2995 and AZD2184 was studied and compared with that of the established amyloid-beta PET radioligand PIB. Subsequently, a first-in-human in vivo PET study was performed using [C-11]AZD2995 and [C-11]AZD2184 in three healthy control subjects and seven AD patients. AZD2995, AZD2184 and PIB were found to share the same binding site to amyloid-beta. [H-3]AZD2995 had the highest signal-to-background ratio in brain tissue from patients with AD as well as in transgenic mice. However, [C-11]AZD2184 had superior imaging properties in PET, as shown by larger effect sizes comparing binding potential values in cortical regions of AD patients and healthy controls. Nevertheless, probably due to a lower amount of nonspecific binding, the group separation of the distribution volume ratio values of [C-11]AZD2995 was greater in areas with lower amyloid-beta load, e.g. the hippocampus. Both AZD2995 and AZD2184 detect amyloid-beta with high affinity and specificity and also display a lower degree of nonspecific binding than that reported for PIB. Overall [C-11]AZD2184 seems to be an amyloid-beta radioligand with higher uptake and better group separation when compared to [C-11]AZD2995. However, the very low nonspecific binding of [C-11]AZD2995 makes this radioligand potentially interesting as a tool to study minute levels of amyloid-beta. This sensitivity may be important in investigating, for example, early prodromal stages of AD or in the longitudinal study of a disease modifying therapy.