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In this study, a panel of 46 compounds containing five different scaffolds known to have high σ 2 receptor affinity were screened. 6,7-Dimethoxy-2-[4-(4-methoxyphenyl)butan-2-yl]-1,2,3,4-tetrahydroisoquinoline [(±)- 7 ] ( K i for σ 1 = 48.4 ± 7.7 nM, and K i for σ 2 = 0.59 ± 0.02 nM) and its desmethyl analogue, (±)- 8 ( K i for σ 1 = 108 ± 35 nM, and K i for σ 2 = 4.92 ± 0.59 nM), showed excellent binding affinity and subtype selectivity for σ 2 receptors. In vitro cell binding indicated that σ 2 receptor binding of [ 11 C]-(±)- 7 and [ 11 C]-(±)- 8 was dependent on TMEM97 protein expression. In PET studies, the peak brain uptake of [ 11 C]-(±)- 7 (8.28 ± 2.52%ID/cc) was higher than that of [ 11 C]-(±)- 8 (4.25 ± 0.97%ID/cc) with specific distribution in the cortex and hypothalamus. Brain uptake or tissue binding was selectively inhibited by ligands with different σ 2 receptor binding affinities. The results suggest [ 11 C]-(±)- 7 can be used as a PET radiotracer for imaging the function of σ 2 receptors in central nervous system disorders.

An unbiased phenotypic neuronal assay was developed to measure the synaptotoxic effects of soluble Aβ oligomers. A collection of CNS druglike small molecules prepared by conditioned extraction was screened. Compounds that prevented and reversed synaptotoxic effects of Aβ oligomers in neurons were discovered to bind to the sigma-2 receptor complex. Select development compounds displaced receptor-bound Aβ oligomers, rescued synapses, and restored cognitive function in transgenic hAPP Swe/Ldn mice. Our first-in-class orally administered small molecule investigational drug 7 ( CT1812 ) has been advanced to Phase II clinical studies for Alzheimer's disease., Competing Interests: The authors declare the following competing financial interest(s): Gilbert M. Rishton, Gary C. Look, Nicholas J. Izzo, Kelsie M. LaBarbera, Colleen S. Limegrover, Courtney Rehak, Raymond Yurko, and Susan M. Catalano are current or former employees of Cognition Therapeutics, Inc., (© 2021 American Chemical Society.)