In vivo validation of 68Ga-labeled AMD3100 conjugates for PET imaging of CXCR4

Introduction: The chemokine receptor CXCR4 has been shown to be over-expressed in multiple types of cancer and is usually associated with aggressive phenotypes and poor prognosis. Successfully targeting and imaging the expression level of this receptor in tumours could inform treatment selection and facilitate patient stratification. Methods: Known conjugates of AMD3100 that are specific to CXCR4 have been radiolabelled with gallium-68 and evaluated in naive and tumour-bearing mice. Tumour uptake of the radiotracers was compared to the known CXCR4-specific PET imaging agent, [68Ga]Pentixafor. Results: Ex vivo biodistribution in naive animals showed CXCR4-mediated uptake in the liver with both radio-tracers, confirmed by blocking experiments with the high affinity CXCR4 antagonist Cu2CB-Bicyclam (IC50 = 3 nM). PET/CT imaging studies revealed one tracer to have a higher accumulation in the tumour (SUVMean of 0.89 +/- 0.14 vs 0.32 +/- 0.11). CXCR4-specificity of the best performing tracer was confirmed by administration of a blocking dose of Cu2CB-Bicyclam, showing a 3-and 6-fold decrease in tumour and liver uptake, respectively. Conclusion and advances in knowledge: This initial study offers some interesting insights on the impact of some structural features on the pharmacokinetics and metabolic stability of the radiotracer. Additionally, as Pentixafor only binds to human CXCR4, the development of CXCR4-targeted imaging agents that bind to the receptor across different species could significantly help with preclinical evaluation of new CXCR4-specific therapeutics.

Automated summary

The CXCR4 chemokine receptor is over-expressed in many cancers, indicating aggressive behavior and poor prognosis. Targeting and imaging CXCR4 expression in tumors can guide treatment selection and patient stratification. Radiolabeled conjugates of AMD3100, a CXCR4-specific agent, were evaluated in mice and compared to the known PET imaging agent [68Ga]Pentixafor. One radiotracer showed higher accumulation in the tumor, indicating potential for CXCR4-targeted imaging in cancer patients.