Synthesis and evaluation of ¹⁸F-labeled indole-based analogs as highly selective sigma-2 receptor probes

Objectives: The sigma-2 (σ₂) receptors are overexpressed in a wide variety of human and rodent tumor cells and play a pivotal role in cancer biology. Moreover, they showed an approximately 10-fold higher expression in proliferating tumor cells compared to that in quiescent tumor cells. And thus, they proved to be a unique receptor-based biomarker of cell proliferation in solid tumors. Herein we report the synthesis and evaluate of a series of indole-based analogs with 5,6-dimethoxyisoindoline or 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline moiety as highly selective σ₂ receptor ligands.

Results and discussion: The newly synthesized indole-based analogs showed low nanomolar affinity for σ₂ receptors (K_i(σ₂) = 1.79-5.23 nM ) and excellent subtype selectivity (K_i(σ₁)/K_i(σ₂) = 56-708 folds). The carbon chain length of the linker between the indole group and 5,6-dimethoxyisoindoline or 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline moiety displayed significant influence on the subtype selectivity. The compounds with a butyl linker exhibited highest subtype selectivity. We synthesized 2-(4-(4-(2-[¹⁸F]fluoroethoxy)-1H-indol-1-yl)butyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 1-(4-(5,6-dimethoxyisoindolin-2-yl)butyl)-4-(2-[¹⁸F]fluoroethoxy)-1H-indole. The log D values of the above radioligands are 2.17 ± 0.13 and 2.14 ± 0.02, respectively. The in vivo biological evaluations are in progress.

Conclusions: These findings suggest that ¹⁸F-labeled indole-based ligands warrant further evaluation as potential PET radiotracers for σ₂ receptor imaging.

Acknowledgements: Supported by NSFC (21471019).

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