Brain mGluR5 in mice with amyloid beta pathology studied with in vivo [11C]ABP688 PET imaging and ex vivo immunoblotting.

Alzheimer's disease (AD) is characterized by aggregation of amyloid beta (Aß) into insoluble plaques. Intermediates, Aß oligomers (Aßo), appear to be the mechanistic cause of disease. The de facto PET AD ligand, [11C]PIB, binds and visualizes Aß plaque load, which does not correlate well with disease severity. Therefore, finding a dynamic target that changes with pathology progression in AD is of great interest. Aßo alter synaptic plasticity, inhibit long-term potentiation, and facilitate long-term depression; key mechanisms involved in memory and learning. In order to convey these neurotoxic effects, Aßo requires interaction with the metabotropic glutamate 5 receptor (mGluR5). The aim was to investigate in vivo mGluR5 changes in an Aß pathology model using PET. Wild type C57/BL6 (wt) and AßPP transgenic mice (tg-ArcSwe), 4, 8, and 16 months old, were PET scanned with [11C]ABP688, which is highly specific to mGluR5, to investigate changes in mGluR5. Mouse brains were extracted postscan and mGluR5 and Aß protofibril levels were assessed with immunoblotting and ELISA respectively. Receptor-dense brain regions (hippocampus, thalamus, and striatum) displayed higher [11C]ABP688 concentrations corresponding to mGluR5 expression pattern. Mice had similar uptake levels of [11C]ABP688 regardless of genotype or age. Immunoblotting revealed general decline in mGluR5 expression and elevated levels of mGluR5 in 16 months old tg-ArcSwe compared with wt mice. [11C]ABP688 could visualize mGluR5 in the mouse brain. In conclusion, mGluR5 levels were found to decrease with age and tended to be higher in tg-ArcSwe compared with wt mice, however these changes could not be quantified with PET.

Antibody-based PET imaging of amyloid beta in mouse models of Alzheimer's disease.

Owing to their specificity and high-affinity binding, monoclonal antibodies have potential as positron emission tomography (PET) radioligands and are currently used to image various targets in peripheral organs. However, in the central nervous system, antibody uptake is limited by the blood-brain barrier (BBB). Here we present a PET ligand to be used for diagnosis and evaluation of treatment effects in Alzheimer's disease. The amyloid ß (Aß) antibody mAb158 is radiolabelled and conjugated to a transferrin receptor antibody to enable receptor-mediated transcytosis across the BBB. PET imaging of two different mouse models with Aß pathology clearly visualize Aß in the brain. The PET signal increases with age and correlates closely with brain Aß levels. Thus, we demonstrate that antibody-based PET ligands can be successfully used for brain imaging.