Application of [¹¹C]SA4503 to selection of novel σ₁ selective agonists

The σ₁ligands are considered to be a new class of potential therapeutic agents for several types of central nervous system disorder. Carbon-11-labeled 1-[2-(3,4-dimethoxyphenyl)ethyl]-4-(3-phenylpropyl)piperazine ([¹¹C]SA4503) was shown to be a promising PET ligand for mapping σ(1) receptors, and was applied to measure receptor occupancy with several therapeutic drugs in the living human brain. In this study, we applied this technique for preclinical in vivo screening of novel σ₁ selective agonists.

Six newly synthesized piperazine derivatives containing arylalkylamine groups and cyclohexylamine derivatives containing phenyl groups were selected and tested for their in vivo σ₁ receptor binding with [¹¹C]SA4503. The test compounds were administered by intravenous co-injection or oral administration. The in vivo receptor binding of [¹¹C]SA4503 was evaluated by a tissue dissection method at a single time point.

Our in vivo screen identified the most promising candidate of novel σ(1) agonist in the piperazine derivatives. Some correlations between in vitro affinity and in vivo receptor blocking rate were observed when considering oral bioavailability. In vivo receptor blocking of piperazine derivatives after oral administration may be predictable by simple co-injection study.

Ligand selection with [¹¹C]SA4503 by the in vivo receptor binding assay was performed successfully. This technique is a practical and high-throughput method that can directly evaluate blood-brain barrier permeability, receptor binding, and bioavailability of drug candidates at the same time.