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[18F]9,or 1-(4-(5,6-dimethoxyisoindolin-2-yl)butyl)-4-(2-[18F]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[18F]9 to σ_(2) receptors in the brain.Further,ex vivo autoradiography in male ICR mice demonstrated regionally heterogeneous specific binding of[18F]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[18F]9 in the rat brain,along with appropriate tissue kinetics.Taken together,results from our current study indicated the novel radioligand[18F]9 as the first highly specific and promising imaging agent for σ_(2) receptors in the brain.

Synthesis and characterization of the two enantiomers of a chiral sigma-1 receptor radioligand:(S)-(+)-and(R)-(-)-[^(18)F]FBFP

Racemic[^(18)F]FBFP([^(18)F]1)proved to be a potentσ_(1) receptor radiotracer with superior imaging properties.The pure enantiomers of unlabeled compounds(S)-and(R)-1 and the corresponding iodonium ylide precursors were synthesized and characterized.The two enantiomers(S)-1 and(R)-1 exhibited comparable high affinity forσ_(1) receptors and selectivity overσ_(2) receptors.The Ca^(2+) fluorescence assay indicated that(R)-1 behaved as an antagonist and(S)-1 as an agonist forσ_(1) receptors.The ^(18)F-labeled enantiomers(S)-and(R)-[^(18)F]1 were obtained in>99%enantiomeric purity from the corresponding enantiopure iodonium ylide precursors with radiochemical yield of 24.4%±2.6%and molar activity of 86–214 GBq/μmol.In ICR mice both(S)-and(R)-[^(18)F]1displayed comparable high brain uptake,brain-to-blood ratio,in vivo stability and binding specificity in the brain and peripheral organs.In micro-positron emission tomography(PET)imaging studies in rats,(S)-[^(18)F]1 exhibited faster clearance from the brain than(R)-[^(18)F]1,indicating different brain kinetics of the two enantiomers.Both(S)-and(R)-[^(18)F]1 warrant further evaluation in primates to translate a single enantiomer with more suitable kinetics for imaging theσ_(1) receptors in humans.