Oral Presentation Royal Australian Chemical Institute National Congress 2026

Structure-Activity Relationship Investigation into P2X7 Analogues as Potential Radioligands (136628)

Joseph Hilton-Proctor 1 2 , Richard Sequeira 3 , Victor Pike 4 , Mastura Monif 3 5 , Mohammad Haskali 1 2
  1. Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  2. The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia
  3. Department of Neuroscience, Monash University, Melbourne, Victoria, Australia
  4. Molecular Imaging , National Institute of Mental Health, Bethesda, Maryland, United States of America
  5. Department of Neurology, The Alfred, Melbourne, Victoria, Australia

Introduction: P2X7 is a ligand-gated ion channel that belongs to the P2X subfamily of purinergic receptors. P2X7 overexpression has revealed numerous connections between signalling pathways and disease states, such as triggering the inflammasome NLRP3 – a connection associated with head and neck cancer cells1 – and promoting the proliferation of colorectal cancer cells via the PI3K/Akt/GSK3β pathway.2 A recent collaboration described a novel link between P2X7 activity and glioblastoma progression,3 highlighting the potential therapeutic benefit of P2X7 inhibition. In this project, we investigated modifications to a known P2X7 inhibitor, GSK1482160, via a structure-activity relationship analysis to lay the groundwork for a novel P2X7 radioligand labelled with fluorine-18 that can be used for positron emission tomography (PET).

Methods: GSK1482160 served as the starting point for our synthetic efforts. Modifications to GSK1482160 were carried out according to previous literature.4-6 Compounds were synthesised using established methods and analysed via HPLC-MS and NMR to confirm their structures. IC50s of P2X7 standards and candidates were determined using a P2X7 pore assay, utilising the YO-PRO-1 fluorescent dye and flow cytometry.

Results: Two reference compounds (GSK1482160 and IUR-1601) and seven candidates were synthesised and tested for inhibitory activity against P2X7. GSK1482160 and the fluorinated analogue IUR-1601 have benchmark IC50s of 53 nM and 153 nM, respectively. While our pyrrolidone candidates fell short (IC50 > 439 nM), our parent imidazolinone compound (IC50 < 10 nM) and one of its fluorinated derivatives (IC50 = 26 nM) surpassed both GSK1482160 and IUR-1601, respectively.

Conclusion: These results have revealed a potential radioligand candidate that has improved on the inhibitory activity of the pyrrolidone predecessors GSK1482160 and IUR-1601 and preserved the activity of the parent imidazolinone ligand against P2X7. A synthetic pathway will now be established to append fluorine-18 to our candidate and gauge its viability as a PET radioligand.

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