Alzheimer’s disease (AD) pathological cascade is characterised by the formation of β-amyloid peptide (Aβ) plaques and neurofibrillary tangles of hyperphosphorylated tau (p-tau) in association with neuroinflammation. Positron emission tomography (PET) provides the possibility for in vivo imaging of these neuropathological changes in living subjects using PET tracers. This opens applications for PET in AD diagnosis, drug development. However, the availability of clinically-approved PET tracers has been a challenge. Imaging rodent models of AD with novel PET tracers is a valuable translational approach in the development process of PET tracers.

The aim of this thesis work was to conduct preclinical development of the PET tracers (S)-[18F]THK5117 and [11C]SMW139 in the APP/PS1-21 mouse model of AD. In vivo PET and ex vivo autoradiography were used to image p-tau aggregates with (S)-[18F]THK5117 and reactive glia P2X7 receptor with [11C]SMW139. Immunohistochemical staining was used to assess imaging targets in the brain. In addition, ex vivo methods were used to investigate tracers pharmacokinetics profile.

In the APP/PS1-21 mice, (S)-[18F]THK5117 brain uptake associated with Aβ plaques and MAO-B enzyme, but not p-tau aggregates. [11C]SMW139 longitudinal uptake did not increase with aging despite the ongoing neuroinflammation in APP/PS1-21 mice. Histological assessment of imaging targets associated well with imaging findings. (S)-[18F]THK5117 showed suitable pharmacokinetic properties, whereas [11C]SMW139 presented unfavoured metabolism for in vivo imaging.

In conclusion, tracer preclinical evaluation performed in the APP/PS1-21 mouse model of AD showed that (S)-[18F]THK5117 binding in the brain is predominantly non-specific, and [11C]SMW139 binding is low. Collectively, findings of this thesis work revealed that in vivo PET imaging of tau pathology with (S)-[18F]THK5117 and neuroinflammation with [11C]SMW139 are associated with major limitations, suggesting limited clinical application of both tracers.