The synthesis of biologically active heterocycles: development of novel imaging agents for the translocator protein (18 kDa) and poly(ADP-ribose)polymerase 1

Blair, Adele (2014) The synthesis of biologically active heterocycles: development of novel imaging agents for the translocator protein (18 kDa) and poly(ADP-ribose)polymerase 1. PhD thesis, University of Glasgow.

Abstract

The Translocator Protein (18 kDa) (TSPO) resides mainly in microglia and is upregulated in response to neuronal injury and inflammation, rendering it an interesting target for imaging focal neuroinflammation in a range of diseases. A library of TSPO ligands based on PK11195 with positions suitable for [11C]-, [18F]- and [123I]-labelling was prepared using three synthetic approaches. Implementation of a physicochemical study enabled selection of compounds most likely to be brain penetrant, and biological evaluation identified those with high binding affinities for the TSPO. From this, a lead candidate (compound 170) was identified. Radiofluorination and in vitro autoradiography revealed the ability of this compound to image tumour tissue in a mouse model of glioblastoma.

Poly(ADP-ribose) polymerase-1 (PARP-1) is an enzyme involved in the repair of DNA strand breaks, and widely regarded as a therapeutic target for cancer treatment. Many inhibitors of PARP-1 activity exist, e.g. olaparib. A programme of research focussing on the preparation of a potential PET imaging agent for measurement of PARP-1 activity, based on olaparib, was initiated. An expeditious seven step synthetic route was used to prepare a small library of compounds. Preliminary cell-free biological screening of these compounds indicated PARP-1 inhibitory potencies in the low nanomolar range demonstrating potential leads for development of a PET imaging agent, e.g. compound 223.

Extracts of Carduus crispus linn., traditionally used in Chinese folk medicine, yield a family of isoquinoline alkaloid natural products (Crispine A–E). Upon commencement of this project no reported synthesis of Crispine C existed in the literature. As such, a facile route utilising a key Pictet-Gams modification of the Bischler-Napieralski reaction for isoquinoline core formation was developed, enabling the first total synthesis of Crispine C to be achieved in seven steps and with an overall product yield of 25%.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: molecular imaging, positron emission tomography, single photon emission computed tomography, translocator protein, neuroinflammation, poly(ADP-ribose)polymerase 1, heterocyclic chemistry
• Subjects: Q Science > QD Chemistry
• Colleges/Schools: College of Science and Engineering > School of Chemistry
• Supervisor's Name: Sutherland, Dr. Andrew
• Date of Award: 2014
• Depositing User: Mrs Adele Blair
• Unique ID: glathesis:2014-5810
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 05 Dec 2014 09:45
• Last Modified: 15 Mar 2016 08:34
• URI: https://theses.gla.ac.uk/id/eprint/5810