Development of fluorine-18 radiolabelled peptides for targeted imaging of the CXCR4 chemokine receptor

Plater, Jarrad

Abstract

The chemokine receptor CXCR4 has been shown to be over-expressed in multiple cancer types and is often linked to a poor prognosis, making it a significant target of interest for both imaging and therapeutics. Early diagnosis, imaging and identification of this receptor, along with others shown to be over-expressed, can inform treatment selection and lead to improved outcomes for patients.
The development of a fluorine-18 based CXCR4 targeting tracer is intended to facilitate an increase in clinical availability due to the longer half-life than the more commonly used gallium-68 tracers such as Pentixafor. A range of novel tracers were synthesised with different length PEG chain spacers, building on previous work by the Archibald group. Competition binding assays and calcium mobilisation assays showed the length of these spacers did not appear to impact on the binding properties of the tracer, with CPCR4-PEG2-PEG3-F and CPCR4-PEG4-PEG4-F having very similar IC50 values (198.95 ± 4.75 nM and 199 ± 48.6 nM respectively, by competition binding assay).
Multiple synthetic routes were developed to increase yields and ease of purification before CPCR4- PEG4-PEG4-18F was progressed to in vivo testing, with final formulated yields of 37 % ± 15 % (decay corrected) delivering 103 ± 53 MBq (n = 5).
Imaging and in vivo studies show significant tumour uptake, with a tumour: muscle ratio of 2.9 at 50 minutes after tracer’s administration. Analysis by HPLC also showed a reasonable average tracer stability in the tumour, urine and liver (59, 69 and 78% respectively), with metabolites almost undetectable in the plasma.
In vivo studies showed that, while the lipophilicity of this novel tracer is lower than the previous derivatives produced by the Archibald group (-1.13 ± 0.01 compared to the previous value of -0.14 ± 0.02), the excretion route is primarily via the biliary system and gut, rather than the renal system. It is still a significant improvement on the previous attempt and shows promise for future development of this tracer class for fluorine-18.

Citation

Plater, J. Development of fluorine-18 radiolabelled peptides for targeted imaging of the CXCR4 chemokine receptor. (Thesis). University of Hull. https://hull-repository.worktribe.com/output/4223832

• Thesis Type: Thesis
• Deposit Date: Jan 17, 2022
• Publicly Available Date: Feb 24, 2023
• Keywords: Health sciences
• Public URL: https://hull-repository.worktribe.com/output/4223832
• Additional Information: Department of Health Science, The University of Hull
• Award Date: Nov 1, 2021