Abstract by Natasha Shalina Rajani Bidesi

Parkinson’s Disease (PD) is the second most neurodegenerative disease after Alzheimer’s Disease (AD), with prevalence numbers of 10 million and 47 million people relatively suffering from these diseases. The hallmark proteins associated with AD are Amyloid-β (Aβ) and tau, whereas for PD this is alpha-synyclein (α-Syn).

Positron Emission Tomography (PET) is a nuclear imaging technique that holds the power to non-invasively investigate, among other things, pathogenesis of brain disorders, localize and quantify drug targets and monitor treatment effect, when suitable tracers are available. The development of a PET tracer for any disease requires an extensive process in which several criteria must be met, such as the feasibility for the radiochemistry, specificity and affinity for the drug target, and Blood-Brain Barrier (BBB) penetration. To develop estimations of the specificity and affinity for the target, K_D and B_max are parameters that are often used, and can be determined by for example autoradiography. In autoradiography, the most commonly used radionuclides are long-lived such as tritium (³H, t_1/2 = 12.3 y) and iodine-125 (¹²⁵I, t_1/2 = 58 d), which allows for more flexibility in regard to performing the studies.

The search for finding a PET tracer targeting α-syn comes with additional hurdles, such as low target density, and similarity between AD proteins. Currently, there is no α-Syn PET tracer on the market. This thesis aims to get closer to develop a PET tracer that can image α-Syn deposition in PD patients using mAbs or peptides. However, many hurdles must be overcome to develop such a tracer targeting α-Syn. For this reason, we first focused on easier targets to establish proof-of-concept. In part A of the thesis, an extensive introduction is given with important principles on the role of neuroimaging in PD and the current efforts towards development of an α-Syn-PET tracer. In part B pretargeted imaging is introduced, which could be used as an important tool in neuroimaging. In this part is described the research towards developing tritiated and radioiodinated pretargeting tools, and their evaluation by autoradiography and biodistribution is established. Part C attempts in opening the BBB is shown for a somatostatin ligand based on the honeybee venom melittin. In part D, novel small molecules that are potential selective and strong α-syn binders are tritiated with the purpose of evaluating on α-syn fibrils and human PD post-mortem brain slices.