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

We have discovered and synthesized a series of indole-based derivatives as novel sigma-2 (sigma(2)) receptor ligands. Two ligands with high sigma(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 [F-18]9, or 1-(4-(5,6-dimethoxyisoindolin-2-yl)butyl)-4-(2 [F-18] fluoroethoxy)-1H-indole, was found to display high brain uptake and high brain-to-blood ratio. Pretreatment of animals with the selective sigma(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 [F-18]9 to sigma(2) receptors in the brain. Further, ex vivo autoradiography in male ICR mice demonstrated regionally heterogeneous specific binding of [F-18]9 in the brain that is consistent with the distribution pattern of sigma(2) receptors. Dynamic positron emission tomography imaging confirmed regionally distinct distribution and high levels of specific binding for [F-18]9 in the rat brain, along with appropriate tissue kinetics. Taken together, results from our current study indicated the novel radioligand [F-18]9 as the first highly specific and promising imaging agent for sigma(2) receptors in the brain. (C) 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.