Screening of σ2Receptor Ligands and In VivoEvaluation of 11C-Labeled 6,7-Dimethoxy-2-[4-(4-methoxyphenyl)butan-2-yl]-1,2,3,4-tetrahydroisoquinoline for Potential Use as a σ2Receptor Brain PET Tracer

In this study, a panel of 46 compounds containing five different scaffolds known to have high σ2receptor affinity were screened. 6,7-Dimethoxy-2-[4-(4-methoxyphenyl)butan-2-yl]-1,2,3,4-tetrahydroisoquinoline [(±)-7] (Kifor σ1= 48.4 ± 7.7 nM, and Kifor σ2= 0.59 ± 0.02 nM) and its desmethyl analogue, (±)-8(Kifor σ1= 108 ± 35 nM, and Kifor σ2= 4.92 ± 0.59 nM), showed excellent binding affinity and subtype selectivity for σ2receptors. In vitrocell binding indicated that σ2receptor binding of [11C]-(±)-7and [11C]-(±)-8was dependent on TMEM97 protein expression. In PET studies, the peak brain uptake of [11C]-(±)-7(8.28 ± 2.52%ID/cc) was higher than that of [11C]-(±)-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 σ2receptor binding affinities. The results suggest [11C]-(±)-7can be used as a PET radiotracer for imaging the function of σ2receptors in central nervous system disorders.