Development of precise chemical biology tools for imaging the oxytocin receptor within the central nervous system

The oxytocin system is linked with numerous neurological disorders but suffers from a lack of available tools to elucidate its role. To overcome these limitations, this thesis describes the manufacture of a positron emission tomography (PET) probe for the OT receptor using optimised Al18F chemistry. The tracer is validated through in vitro binding assays that demonstrate its avidity, selectivity and specificity. However, in spite of its favourable profile, in vivo biodistribution and nanoPET scans show limited brain uptake. As such, the utility of the tracer for brain imaging will not be realised unless the highly discriminative aspects of the blood-­brain barrier are overcome. Consequently, the secondary aim of this thesis focuses on novel approaches for improving macromolecular delivery to the brain. To achieve this feat, two pathways are typically exploited: (i) Absorptive-­ (AMT) or (ii) Receptor mediated transcytosis (RMT). While numerous ligands for these routes exist, the underlying molecular factors governing sorting at the blood-­brain barrier are largely unknown and uptake remains modest. To uncover the optimal features for uptake and trafficking at the blood-­brain barrier this thesis reports the initial screening campaign of novel, chemically defined vehicles for precise presentation. A highly convergent synthesis route allowed rapid access of a diverse library, elaborated with defined arrays of targeting motifs, which retained their secondary structure following construction. Cross examination of the library’s performance in endocytosis and transcytosis assays showed a synergic effect of merging AMT and RMT motifs on a single platform, whereby the ligand, valency and position of the targeting modalities influenced uptake and sorting. Overall this thesis serves to guide the design and approach for selecting optimal brain delivery vehicles. The utility of these can be readily validated in vivo through attachment of the OT receptor tracer as molecular cargo.Open Acces