Synthesis and in vivo evaluation of a new PET radioligand for studying sigma-2 receptors

The cyclohexyl piperazine 1 (1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-propyl]-piperazine) has been shown to be a potent and selective sigma-2 receptor ligand. In the present study, we prepared [11C]1 by O-alkylation of the phenolic precursor 2 with [11C]CH3I. [11C]1 was obtained in a 29% non-decay corrected yield and specific activity of 9299 mCi/μmol calculated at end-of-synthesis. The biodistribution of [11C]1 in mouse brain demonstrated rapid and homogenous concentration in all brain structures, which included the cortex, thalamus, cerebellum and striatum. Co-administration of unlabelled 1 (1 mg/kg) or the sigma-2 selective ligand SM-21 (1 mg/kg) failed to show any significant inhibition of [11C]1 uptake in the mouse brain. The evaluation of this radioligand in vivo in the mouse clearly indicates that it does not possess the required properties for studying sigma-2 receptors in the brain using PET.

1-Cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-propyl]-piperazine 1 is a high affinity sigma-2 ligand, which has been labelled with carbon-11 (t1/2: 20.4 min) and evaluated in vivo in the mouse brain as a potential positron-emission-tomography (PET) radioligand.Figure optionsDownload as PowerPoint slide