Discovery and development of brain-penetrant (18)F-labeled radioligands for neuroimaging of the sigma-2 receptors

We have discovered and synthesized a series of indole-based derivatives as novel sigma-2 (σ(2)) receptor ligands. Two ligands with high σ(2) receptor affinity and subtype selectivity were then radiolabeled with F-18 in good radiochemical yields and purities, and evaluated in rodents. In biodistribution studies in male ICR mice, radioligand [(18)F]9, or 1-(4-(5,6-dimethoxyisoindolin-2-yl)butyl)-4-(2-[(18)F]fluoroethoxy)-1H-indole, was found to display high brain uptake and high brain-to-blood ratio. Pretreatment of animals with the selective σ(2) receptor ligand CM398 led to significant reductions in both brain uptake (29%–54%) and brain-to-blood ratio (60%–88%) of the radioligand in a dose-dependent manner, indicating high and saturable specific binding of [(18)F]9 to σ(2) receptors in the brain. Further, ex vivo autoradiography in male ICR mice demonstrated regionally heterogeneous specific binding of [(18)F]9 in the brain that is consistent with the distribution pattern of σ(2) receptors. Dynamic positron emission tomography imaging confirmed regionally distinct distribution and high levels of specific binding for [(18)F]9 in the rat brain, along with appropriate tissue kinetics. Taken together, results from our current study indicated the novel radioligand [(18)F]9 as the first highly specific and promising imaging agent for σ(2) receptors in the brain.