Design and synthesis of CXCR4-specific tracers for positron emission tomography

Molecular imaging is an ideal platform for non-invasive detection and assessment of cancer. In recent years, the targeted imaging of CXCR4, a chemokine receptor that has been associated with tumour metastasis, has become an area of intensive research. CXCR4 is a GPCR whose interaction with its natural ligand SDF-1α is essential for embryo development and haematopoiesis. Over-expression of this receptor is associated with aggressive types of cancer and potentially metastatic tumours. Several classes of CXCR4 inhibitors have been reported in the literature, including TN14003-, FC131- and IT1t-derivatives. The aim of the research presented herein was to develop CXCR4-targeted probes for positron emission tomography. To this end, we designed and synthesised 20 new potential tracers belonging to those three classes of CXCR4 inhibitors, for labelling with fluorine-18 or gallium-68. In vitro and in vivo evaluation of these radiotracer candidates allowed for further understanding of the structure-activity relationship and pharmacokinetic properties of these types of compounds. In particular, our gallium-68-labelled tracer based on the structure of TN14003 displayed the essential features for the identification of CXCR4-expressing tumours in a clinical setting.