RADIOLABELLED PEPTIDES TARGETING CXCR4 FOR CANCER IMAGING AND TREATMENT

Abstract

Overexpressed cell surface receptors such as CXCR4 (a G-protein-coupled receptor) play critical roles in tumour metastasis and represent significant molecular targets for cancer imaging and therapy. Cyclic pentapeptides, including FC131 and its analogues, exhibit high affinity and specificity for CXCR4; however, the inherent lipophilicity of 124I-FC131 results in significant retention in the liver and spleen, thereby limiting its effectiveness as a PET imaging agent. To address this challenge, tyrosine sulfonation has been explored as a strategy to reduce lipophilicity while preserving receptor binding affinity, ultimately improving biodistribution and clearance profiles. In parallel, systematic modifications at the naphthylalanine residue have been investigated to further fine-tune physicochemical properties and minimise non-specific uptake. This study focuses on the design, synthesis, and evaluation of sulfonated FC131 analogues and their conjugation with diagnostic and therapeutic radionuclides such as [18F, 86Ga, 177Lu, and 213Bi] for enhanced cancer imaging and therapy. CXCR4-targeting ligands were synthesised using a combination of solid-phase peptide synthesis and solution-phase chemistry, with an emphasis on optimising lead peptide structures. Biological evaluations included competitive binding assays using CXCR4-positive Jurkat cells (hCXCR4), alongside studies of internalisation, externalisation, lipophilicity, and metabolic stability. nat/177Lu-pentixather was employed as a reference compound, with receptor affinity and selectivity assessed using the monoclonal antibody UMB-2. Preclinical PET imaging studies conducted by our group demonstrated that sulfonated peptides, such as 18F-labelled sulfonated RGD peptides, achieved high tumour uptake with minimal retention in non-target tissues. The combined strategies of tyrosine sulfonation and targeted residue modification are expected to optimise pharmacokinetic profiles, improve biodistribution, and enhance the therapeutic and imaging potential of CXCR4-targeting peptides.