Synthesis and evaluation of imaging probes for prolyl oligopeptidase (PREP)

Abstract

PREP in an endopeptridase member of the serine peptidase family that has a selective mechanism: it cleaves peptides with no more than amino acid residues at the carboxyl side of proline residues. It has a high expression in brain and central nervous system (CNS) and has been found to be related to some neurodegenerative pathologies like Alzheimer's disease, Parkinson, Schizophrenia, mania, depression and epilepsy. The main goal for this project was to synthesise molecular imaging probes to follow the evolution of PREP expression during epiletogenesis. This imaging probes consist of three main parts: a PREP inhibitor as a targeting moiety biotin and rhodamine B piperazine anaolgues as signal agents and a linker that connects both parts. Tqo different signat agents have been synthesised in order to know wich is the best option. The generic structure for PREP inhibitor has been divided in the building blocks: (S)-pyrrolidine -2- carbozamide hydrochloride, (2S, 4S)-4-azido-1-(tert-butoxycarbonyl) pyrrolidine-2-carboxylic acid and 4-phenybutanoyl chloride, wich were synthesised separately and coupled in the end following the synthesis pathway reported before in 2012 by Van der Veken et al. Finally, a dehydration ot the primary amide group was done in order to obtain a carbonitrile warhead that reduces the proximity between the imaging probe and the target, PREP