Evaluation and Late-Stage Fluorination of Small Molecule GnRH-R Antagonists

Abstract

Alzheimer’s disease is the most common type of dementia; causing problems with memory, thinking and behaviour. The seemingly protective effect of hormone replacement therapy against Alzheimer’s disease sparked an interest in the role of the sex hormone system. Sex steroid production is dependent on gonadotropins released in the pituitary. The gonadotropin level is controlled by gonadotropin releasing hormone and its receptor (GnRH-R) is dispersed throughout the body, but is interestingly expressed on neurons in the same brain regions affected by Alzheimer’s disease. Positron emission tomography (PET) is a non-invasive imaging technique which utilises radioactively labeled molecules. A radioactively labelled GnRH-R antagonist allows for the observation and quantification of GnRH-R density which may reflect early pathological changes in Alzheimer’s disease. This thesis includes the synthesis, fluorination and biological in vitro evaluation by human serum stability of four piperazine tert-butyl benzimidazole GnRH-R antagonist analogues via direct halide exchange from chloroalkyl precursors. Three compounds were successfully fluorinated in the last reaction step. The reactions all had reaction times less than 30 minutes, suitable for radioactive labelling where a short reaction time is essential. In the last part of this thesis, the three fluorinated compounds were tested for stability in human serum and incubated for 22 hours. All of the fluorinated compounds showed good stability and were found to be suitable for future experiments with radiolabellnig in vitro and in vivo.