Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.700658
Title: Novel imaging targets in inflammation
Author: Cheong, Poh Yue
ISNI:       0000 0004 5994 1673
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2014
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Abstract:
Over the last two decades, research into the imaging of inflammation has been thoroughly investigated as it presents a promising therapeutic target for many diseases, including neurodegenerative and cardiovascular diseases. There are only a few radiopharmaceuticals which are currently in general use for imaging inflammation, e.g. 18F-FDG, nuclear labelled autologous white blood cells, 67Ga-citrate etc. However, none is specific for inflammation thus there is a need to investigate novel imaging agents for distinguishing sterile inflammation from infection. Formyl peptide receptors (FPRs) were originally identified as chemoattractant receptors, which have been shown to be implicated with potential therapeutic benefits for inflammatory diseases. Highly specific hexapeptides, cFLFLFK (cinnamoyl-Phe-D-Leu-Phe-D-Leu-Phe-Lys-NH2) and WKYMVm (Trp-Lys-Tyr-Met-Val-D-Met-NH2), which are selective antagonist and agonist for FPR1 and FPR2 respectively, have been modified by conjugating to a cyclen based chelate for metal ions, allowing for specific imaging of inflammation using non-invasive imaging techniques such as MRI, PET and SPECT. This thesis depicts the synthesis of a bifunctional chelate, DOTAGA containing five acetate arms. Ln.DOTAGA-conjugates were prepared by coupling the Ln(III) complexes of DOTAGA onto the desired peptides without a protection step as the four pendant acetate arms were involved in coordination. Their binding affinities and biological functions were assessed by various in vitro assays such as radioligand binding assays, chemotaxis and TNF-α induced cytokine release. In vivo imaging of inflammation using the synthesised compounds and a mu-rine model of inflammation was performed. Further to this, the DOTAGA was further modified to an anhydride analogue, which allows for post radiolabelling after conjugation to the peptides. Subsequent complexation with Cu(II) and Ga(III) ions indicated their potential use in nuclear imaging. Two organic chromophores based on Cy5 bearing two orthogonal functional groups have been synthesised. Successive conjugation with cFLFLFK and confocal microscopy indicated their potential use in optical imaging. Multimodal imaging agents featuring a Cy5 chromophore and a DOTAGA for inflammation have been designed and synthesised. Subsequent complexation with Gd(III) and Tb(III) resulted in MRI/optical and dual luminescent imaging agents, respectively.
Supervisor: Long, Nicholas ; Gavins, Felicity Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.700658  DOI: Not available
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