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

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