CXCR4 and ACKR3 binding agents for imaging applications in cancer

Renard, Isaline

Abstract

The chemokine receptors CXCR4 and ACKR3 have been shown to be over-expressed in multiple types of cancer and are usually associated with aggressive phenotypes and poor prognosis. Successfully targeting and imaging the expression levels of these receptors in tumours could allow earlier diagnosis of some cancers, inform treatment selection and lead to better outcome for the patients.
Previously reported AMD3100 conjugates (3 and 4) specific to CXCR4 have been radiolabelled with gallium-68 and evaluated in vivo in tumour-bearing animals. Tumour uptake of the radiotracers was compared to the known CXCR4-specific PET radiotracer, [68Ga]Pentixafor. Blocking with 5 mg/kg of the high affinity Cu2CB-Bicyclam led to a 3- and 6-fold decrease in tumour and liver uptake of [68Ga]Ga4, respectively.
Previous work in the Archibald group has identified a macrocycle derivative (13), that binds to both CXCR4 and ACKR3. Synthesis of 13 has been optimised and semi-preparative HPLC methods were developed for the purification of this compound and its corresponding copper(II) and zinc(II) metal complexes to yield high purity derivatives for the first time to allow biological evaluation. The SAR of these compounds is currently under investigation and preliminary results have already shown affinity below 1 nM for CXCR4 and of ca 100 nM for ACKR3. A synthetic route was developed for a novel compound (14) designed to optimise receptor binding.
As no small molecule or peptide ACKR3-specific PET imaging agent has been reported so far, the possibility of functionalising ACKR3-specific peptides, P20 (23) and FC313 (24), to introduce a chelator amenable to gallium-68 radiolabelling was investigated. The ACKR3 affinity of the several derivatives synthesised was evaluated in vitro with the lead compound showing an IC50 of 1.4 μM.

Citation

Renard, I. (2019). CXCR4 and ACKR3 binding agents for imaging applications in cancer. (Thesis). University of Hull. https://hull-repository.worktribe.com/output/4912463

• Thesis Type: Thesis
• Deposit Date: Nov 12, 2024
• Publicly Available Date: Nov 12, 2024
• Keywords: Chemistry
• Public URL: https://hull-repository.worktribe.com/output/4912463
• Additional Information: Department of Chemistry; University of Hull
• Award Date: Nov 1, 2019