Discovery and development of brain-penetrant 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 ( ) receptor ligands. Two ligands with high 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 [F], or 1-(4-(5,6-dimethoxyisoindolin-2-yl)butyl)-4-(2-[F]fluoroethoxy)-1-indole, was found to display high brain uptake and high brain-to-blood ratio. Pretreatment of animals with the selective 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 [F] to receptors in the brain. Further, autoradiography in male ICR mice demonstrated regionally heterogeneous specific binding of [F] in the brain that is consistent with the distribution pattern of receptors. Dynamic positron emission tomography imaging confirmed regionally distinct distribution and high levels of specific binding for [F] in the rat brain, along with appropriate tissue kinetics. Taken together, results from our current study indicated the novel radioligand [F] as the first highly specific and promising imaging agent for receptors in the brain.