Use this URL to cite or link to this record in EThOS:
Title: The synthesis of biologically active heterocycles : development of novel imaging agents for the translocator protein (18 kDa) and poly(ADP-ribose)polymerase 1
Author: Blair, Adele
ISNI:       0000 0004 5355 4816
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 2014
Availability of Full Text:
Access from EThOS:
Access from Institution:
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%.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QD Chemistry