RATIONAL DESIGN AND SYNTHESIS OF POTENTIAL SINGLE PHOTON EMISSION COMPUTED TOMOGRAPHY (SPECT) RADIOLIGANDS FOR IN VIVO IMAGING OF P2X7 RECEPTORS

The purinergic P2X7 receptor (P2X7R) is an ion gated channel activated by ATP and is involved in microglial activation, proliferation, and apoptosis. Under physiological conditions, P2X7Rs expression in the CNS is rather limited. Following a brain injury, the expression of P2X7Rs increases substantially, thereby promoting inflammasome formation and the release of proinflammatory cytokines/chemokines.1 Several studies have highlighted a link between P2X7R expression and neurodegenerative disorders, such as sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease. For this reason, P2X7R has been proposed as a target for in vivo imaging of neuroinflammation as an alternative to the translocator protein (TSPO). Several P2X7R antagonists have been radiolabeled and studied during the last decade as potential PET radioligands, whereas no SPECT radioligand has been developed so far.2 SPECT radioligands offer several advantages over PET radioligands including longer half-life and ease of radiosynthesis.3 From a literature survey, we identified compound 1 and compound 2 as a valuable starting point for developing a potential SPECT radioligand for the in vivo imaging of P2X7R. In fact, both compounds had inhibitory activity in the nanomolar range and have functional groups amenable for further functionalization with a linker bearing the SPECT radionuclide. A preliminary docking study on compounds 1 and 2 evidenced that the benzamide moiety is oriented towards the extracellular part of the binding site. Therefore, the methoxy group on the benzamide moiety will be the anchoring point of the linker bearing the SPECT radionuclide. Different linker lengths will be studied, and technetium-99m (Tc-99m) will be selected as SPECT radionuclide. We will report the rational design and the synthesis of the potential SPECT P2X7R radioligands.