Abstract
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.