Protein engineering for better PET radioligands

An approved method for visualization of Amyloid β (Aβ) plaques in patients suffering from Alzheimer's disease is Positron Emission Tomography (PET). This method requires a radiolabeled amyloid ligand. A frequently used molecule is Pittsburgh Compound B (PIB) which is a derivative of Thioflavin T. Radiolabeled PIB is well-suited to visualize insoluble Aβ plaques and has been used for differential diagnosis of AD. However, the PIB signal, giving an estimate of total plaque load becomes saturated early in the disease progression. To being able to diagnose Alzheimer's disease early-on, soluble forms of aggregated Aβ like oligomers and protofibrils need to be visualized

Generally, monoclonal antibodies have been extremely successful in determining biological target structures and are a well-known diagnostic and therapeutic tool. Yet, transport of antibodies through the blood brain barrier is restricted. Previously, it has been reported that the brain uptake of antibodies can be increased significantly by adding specificity to the Transferrin Receptor (TfR).

In the current study, presented by a team of scientist from Uppsala University a monoclonal antibody against Aβ is coupled to and antibody against the transferrin receptor. When radiolabeled, this construct can be used as a PET probe. In the study, transgenic mice were used as a model for Alzheimer's disease. PET imaging using the new probe was performed in these mice and it was shown that the amount of probe increased with the degree of Aβ pahology to detect soluble forms of Aβ. Amytracker was used in this study for histopathological analysis in tissue sections from transgenic mice.

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