Preclinical PET imaging and therapy of Alzheimer's disease

Sammanfattning: The main histopathological hallmarks of Alzheimer’s disease are extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles, containing tau protein. Because of misfolded and aggregated proteins, activated microglia and astroglia react with a neuroinflammatory response, which may contribute to disease progression and severity. To date, there is no treatment available that stops the underlying mechanisms of the disease, but several new drug candidates entered clinical trials every year during the last decade. New treatments, aiming to clear Aβ from the brain parenchyma or to reduce Aβ production, are dependent on diagnostic tools to follow changes in brain Aβ pathology in vivo. The presence of brain amyloid, verified with positron emission tomography (PET), is a regularly used criterion for enrolling patients in clinical trials. However, current amyloid radioligands such as [11C]Pittsburgh Compound B ([11C]PiB) have some disadvantages, e.g. early saturation during disease progression and reduced binding to diffuse Aβ pathology. Currently available radioligands for imaging of neuroinflammation are also suboptimal. In this thesis, we investigated the potential of a brain-penetrating, bispecific Aβ antibody as a PET ligand to detect effects of treatment. In paper I and II, we demonstrated that this ligand can follow Aβ disease progression and that Aβ reduction due to treatment with a BACE-1 inhibitor can be quantified in a mouse model of AD. In paper II we also compared antibody-PET with [11C]PiB-PET and showed that the two ligands provided differing read-outs.In paper III we created and investigated an antibody-based radioligand against the triggering receptor expressed on myeloid cells 2. Compared to wild type mice, transgenic animals displayed higher total in vivo exposure, calculated as the area under the concentration curve based on PET at 24 h, 48 h and 72 h post injection. However, differences were not evident in single time point PET images.In paper IV we investigated brain delivery of a nanobody against GFAP with and without active transcytosis over the blood-brain barrier in vivo. Brain uptake with active transcytosis was two times higher. However, brain retention after 8 h, 24 h or 48 h did not differ between transgenic and wild type mice. In paper V we studied the potential of a hexavalent and bispecific antibody construct against soluble Aβ aggregates for PET or immunotherapy in vivo. Its brain retention increased with age when applied at tracer doses in genetically modified mice. However, when applied at therapeutic dose, it had no or very low impact on Aβ levels measured in brain homogenates.