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Synthesis of BVD15 analogues as models for radioligands in tumour imaging
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posted on 09.02.2017by Liu, Mengjie
Breast carcinomas have been found highly prevalent in females of both Australia and worldwide, causing significant mortality and heavy healthcare expenditure. However, current diagnostic and therapeutic measures are limited by low sensitivity and specificity. Breast tumours are found to over-express neuropeptide Y (NPY) Y1 receptors, whose important functional roles in tumour growth and metastasis have been well demonstrated. This thesis describes the synthesis of 38 truncated NPY analogues as models for Y1-specific radio imaging agents used in positron emission tomography (PET). These peptides are based on the previously reported BVD15 scaffold. Different strategies to improve Y1 affinity and plasma metabolic stability were investigated. It was found that a basic amino acid residue at position 4 significantly improved Y1 receptor affinity, and Arg4 substituted analogues possessed excellent tolerability to N-terminal aryl capping groups. While various conjugations at Lys4 ɛ-amine were well tolerated, a further N-terminal aryl group sacrificed affinity. Replacing Asn2 by a Lys residue was found to retain affinity, and a NOTA conjugation at its ɛ-amine was well tolerated. Modifications to position 5 were limited to small prosthetic groups. Finally, incorporation of D-amino acids for analogue stability enhancement resulted in loss of Y1 affinity.