New AMD3100 derivatives for CXCR4 chemokine receptor targeted molecular imaging studies: synthesis, anti-HIV-1 evaluation and binding affinities.

Sophie Poty,Thomas D‘Huys,Franck Denat,Dominique Schols,Frédéric Boschetti,Christine Goze,Helmut R Maëcke,Stephen J Archibald,Christopher Cawthorne,Pauline Désogère

doi:10.1039/c4dt02972k

Abstract

CXCR4 is a target of growing interest for the development of new therapeutic drugs and imaging agents as its role in multiple disease states has been demonstrated. AMD3100, a CXCR4 chemokine receptor antagonist that is in current clinical use as a haematopoietic stem cell mobilising drug, has been widely studied for its anti-HIV properties, potential to inhibit metastatic spread of certain cancers and, more recently, its ability to chelate radiometals for nuclear imaging. In this study, AMD3100 is functionalised on the phenyl moiety to investigate the influence of the structural modification on the anti-HIV-1 properties and receptor affinity in competition with anti-CXCR4 monoclonal antibodies and the natural ligand for CXCR4, CXCL12. The effect of complexation of nickel(II) in the cyclam cavities has been investigated. Two amino derivatives were obtained and are suitable intermediates for conjugation reactions to obtain CXCR4 molecular imaging agents. A fluorescent probe (BODIPY) and a precursor for (18)F (positron emitting isotope) radiolabelling were conjugated to validate this route to new CXCR4 imaging agents.

Highlights

The CXCR4 chemokine receptor is a seven transmembrane helix protein, and member of the G-protein-coupled receptor (GPCR) superfamily.[1]. It has only one naturally occurring endogenous ligand known as SDF-1 or CXCL12.2 Together with its natural ligand, CXCR4 is a central part of the signalling system in the human body that results in a variety of normal physiological responses, such as chemotaxis, cell survival and proliferation, intracellular calcium flux, and gene transcription
A cyclam ring protected with tosyl, mesityl, diethylphosphoramidate (Dep) or tert-butoxycarbonyle (Boc) groups is used as a starting material
To investigate the influence of a functionalisation of the phenyl moiety on AMD3100 properties, we considered the synthesis of a p-dibromoxylyl spacer substituted with an ester group

Summary

Introduction

Inhibition of the CXCR4-CXCL12 signalling was investigated as a therapeutic strategy using antagonists of the natural ligand. Several CXCR4-binding agents, including antibodies and peptide-based antagonists have been developed.[6] In the search for new anti-HIV agents, bicyclam compounds were discovered as CXCR4 antagonists with potent and selective antiHIV activities.[7] These molecules consist of two 14-member tetraaza macrocyclic rings, linked either by an aliphatic bridge or an aromatic bridge such as AMD3100 The latter, unlike many other existing HIV drugs that target the virus after it has infected a healthy cell, blocks the virus from entering the cell, inhibiting the replication of both HIV-1 and HIV-2.8 AMD3100 binds to the CXCR4 chemokine receptor mainly via electrostatic interaction between the positively charged protonated amino nitrogens of the cyclam moieties and the negatively charged carboxylates of the aspartate and glutamate residues of the receptor.[9] AMD3100 has been demonstrated to be a ligand for another chemokine receptor, CXCR7.

Synthetic procedures

Introduction of a precursor for radiofluorination

Conclusion