Visualising neurodegeneration in the living brain : Preclinical evaluation of PET radioligands

Abstract: With an ageing population, the number of people suffering from Alzheimer’s disease (AD) and Parkinson’s disease (PD) escalates yearly. Pathological hallmarks of AD and PD include aggregated proteins and synaptic dysfunction. Developing imaging probes targeting specific pathological hallmarks is highly valuable in aiding early diagnosis and treatment assessment.The thesis focused on evaluating positron emission tomography (PET) imaging probes that can visualise different pathological changes in preclinical models of neurodegeneration. Ligands targeting synaptic vesicle protein 2A (SV2A), alpha-synuclein (αSyn), and amyloid-beta (Aβ) are investigated.In paper I, we compared synaptic density in transgenic AD and PD mouse models to their wild-type age-matched controls using SV2A PET. In the hippocampus, lower synaptic density was found in the PD mice compared to the control. In paper II, we continued using SV2A PET and studied synaptic density in ageing mice. Synaptic density remained steady for most of the lifespan but slightly decreased in old age. In paper III, we developed and evaluated five antibody-based PET radioligands targeting αSyn aggregates. By conjugating anti-αSyn antibodies with the transferrin receptor (TfR) binder 8D3, we increased antibody brain entry significantly. These bispecific antibodies displayed high specificity and selectivity to αSyn aggregates. The most promising candidate successfully imaged brain-deposited αSyn but was unable to detect endogenously expressed αSyn in PD mouse models. In light of this, further investigation of antibody brain entry, distribution, and elimination is needed. Thus, in paper IV, we used microdialysis to compare the brain pharmacokinetics of a bispecific antibody targeting TfR and Aβ and its regular monospecific version that only binds to Aβ. The bispecific antibody showed distinct pharmacokinetics and entered the brain more efficiently than the regular antibody. Lastly, in paper V, we studied the impact of anti-Aβ antibody treatment on amyloid PET. AD mice were short-term treated with anti-Aβ antibody mAb158 and underwent [11C]PiB ex vivo autoradiography. We found a trend indicating that the treatment reduced the [11C]PiB signal despite no reduction in total Aβ levels.Our results contribute to an increased understanding of PET radioligands imaging neurodegeneration. Furthermore, it provides valuable information for designing and developing new PET radioligands.