Synthesis and radiolabelling of ackr3 binding peptides as positron emission tomography imaging probes

Cetin, Aynil

Abstract

Atypical chemokine receptor 3 (ACKR3) is an atypical chemokine receptor involved in a variety of physiological processes, including cardiac development and vascular function. The overexpression of ACKR3 is associated with metastatic progression and poor prognosis in cancer, therefore, it presents a promising target for diagnosis and therapy.
Positron emission tomography (PET) is a non-invasive nuclear medicine technique applying positron emitting radionuclides to visualize and quantify biological targets or biochemical processes at the cellular or molecular level. The ability to image ACKR3 expression in vivo could be used to better understand the physiological role of ACKR3 and assist in the development of ACKR3 targeted therapies.
Recently, multiple ACKR3 active small molecules have been disclosed, mainly in the patent literature. However, the only reported ACKR3 targeted PET probe is a 89Zr labelled antibody, which serves as a proof-of concept for imaging of this target in vivo, but does not offer an attractive pathway for further development and clinical use. Peptides are intermediate in size between small molecules and biologicals, such as affibodies or antibodies. An octapeptide LIH 383, identified from the literature, shows a high ACKR3 selective binding and, therefore, was selected as a targeting vector for ACKR3 targeted 68Ga and 18F labelled tracer development.
The original peptide, cold standards containing [natGa]gallium and [19F]fluorine and radiolabelling precursors were prepared by manual solid phase peptide synthesis, purified by semi-preparative HPLC, characterized by mass spectrometry, and tested for ACKR3 selective binding in competitive binding assay performed by collaborators of Archibald group. It has been confirmed that LIH 383 can be labelled with either [68Ga]gallium or [18F]fluorine without loss of the binding affinity of the parent peptide. However, further investigation revealed an unacceptably high metabolic instability preventing progression of the tracers to in vivo testing. The effort to increase the metabolic stability by introducing non-natural or sterically hindered amino acids whilst retaining activity is on-going.

Citation

Cetin, A. (2021). Synthesis and radiolabelling of ackr3 binding peptides as positron emission tomography imaging probes. (Thesis). University of Hull. https://hull-repository.worktribe.com/output/4922422

• Thesis Type: Thesis
• Deposit Date: Nov 22, 2024
• Publicly Available Date: Nov 4, 2025
• Keywords: Biomedical sciences
• Public URL: https://hull-repository.worktribe.com/output/4922422
• Additional Information: Biomedical sciences; Department of Biomedical Sciences; University of Hull
• Award Date: Nov 3, 2021