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 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.