Skip to main content

Research Repository

Advanced Search

Towards the synthesis of multifunctional constructs : coupling PET and PDT for the targeted diagnosis and therapy of CXCR4 expressing tumours

Smith, Rachel


Rachel Smith


Stephen J. Archibald


To establish accurate and early stage tumour diagnosis, quantitative molecular imaging modalities such as positron emission tomography (PET) are being employed. Molecular probes containing a positron emitting isotope (e.g. ¹⁸F, ⁶⁴Cu) are designed to target biomarkers or metabolic processes within the tumour. A therapeutic molecule could then be conjugated to this diagnostic probe to create a multifunctional construct (MFC). MFCs are a new concept in drug design offering the potential for both diagnosis and therapy. This work exploits the chelating properties of saturated tetraazamacrocycles known herein as macrocycles as well as their known affinity for the chemokine receptor CXCR4, a cell surface receptor involved in embryonic development and cell migration known to be overexpressed in at least twenty three different tumour types, along with the photodynamic activity of porphyrin molecules to create novel MFCs with diagnostic and therapeutic properties.

A series of configurationally restricted copper(II), zinc(II) and nickel(II) mono-ring macrocycles bearing a methylamine pendant arm are presented. Monomacrocycles possess the potential for improved pharmacological properties. Biological studies assessing the affinity and potency of these macrocycles as CXCR4 antagonists demonstrated that zinc(II) monomacrocycles were the most potent in their class. A side bridged (SB) zinc(II) monocyclen compound; [Zn9]²⁺ synthesised in 64% yield, demonstrated the highest affinity for CXCR4 in its class showing a 2.5-fold higher affinity in comparison to the clinically licensed antagonist AMD3100 (IC₅₀ = 12 nM vs. 31 nM).

In response to the high affinity observed for a meta-substituted biscyclen ligand (L48) a novel cross bridged (CB) meta-substituted biscyclen compound bearing a methylamine pendant arm 20 was synthesised along with its copper(II), nickel(II) and zinc(II) complexes in 77%, 88% and 90% yields, respectively. These metal complexes displayed high affinity for CXCR4 when competed with a CXCR4 specific antibody (% inhibition >85%) and required sub-micromolar concentrations to reduce the ‘normal’ signalling of CXCR4 by 50%. [Cu₂20]⁴⁺ has the potential to be a targeted PET probe through the use of ⁶⁴Cu and so a detailed biological evaluation into its binding mode was undertaken. These assays concluded that [Cu₂20]⁴⁺ exerts its antagonistic effect by locking the receptor on the surface of the cell, stopping the internalisation and recycling processes, which would result in formation of a new receptor. An analogous meta-substituted biscyclam ligand (28) and its copper(II), zinc(II) and nickel(II) complexes were synthesised in 74%, 58% and 46% yields, respectively. These metal complexes also demonstrated high affinity for CXCR4 (IC₅₀ <0.1 μM). In fact [Cu₂28]⁴+ showed unexpectedly high affinity for CXCR4 demonstrating almost a 3-fold higher affinity than AMD3100 (IC₅₀ = 11nM vs. 31 nM), the potential of [Cu₂28]⁴⁺ as a targeted PET probe should also be considered.

Various organic spacer arms were attached to bismacrocycle 20, to produce a CXCR4 targeting probe with a functional arm for further conjugation which would also act to prevent steric hindrance. An acidic terminating chain was successfully attached to bismacrocycle 20 in quantitative yield, via ring-opening of diglycolic anhydride as well as an amine terminating variant (93% yield). A biotin tag was also attached to bimacrocycle 20 and its copper(II) complex was successfully isolated in a 94% yield. Addition of a spacer arm was found to have no significantly detrimental effect on binding affinity to CXCR4.

A series of known water and organic soluble metalloporphyrins were synthesised. Subsequent conjugation to macrocyclic compounds proved challenging but analytical data for the conjugation of bismacrocycle 20 and metalloporphyrin [Zn59] indicated a successful reaction had occurred. This reaction represents important steps towards the synthesis of MFCs with diagnostic and therapeutic properties.


Smith, R. (2012). Towards the synthesis of multifunctional constructs : coupling PET and PDT for the targeted diagnosis and therapy of CXCR4 expressing tumours. (Thesis). University of Hull. Retrieved from

Thesis Type Thesis
Deposit Date Feb 13, 2018
Publicly Available Date Feb 23, 2023
Keywords Chemistry
Public URL
Additional Information Department of Chemistry, The University of Hull
Award Date Dec 1, 2012


Thesis (8.5 Mb)

Copyright Statement
© 2012 Smith, Rachel. All rights reserved. No part of this publication may be reproduced without the written permission of the copyright holder.

You might also like

Downloadable Citations