Synthesis and evaluation of [18F]fluoroethyl SA4503 as a PET ligand for the sigma receptor.

The sigma receptor might be involved in several diseases in the central nervous system. It occurs in the endocrine, immune, and other peripheral organ systems and is expressed in a variety of human tumors. The [18F]fluoroethyl analog of the sigma1-selective ligand SA4503 ([18F]FE-SA4503) was prepared and evaluated in animals to investigate its suitability for in vivo measurement of sigma receptors with positron emission tomography (PET). [18F]FE-SA4503 was synthesized by [18F]fluoroethylation of the corresponding O-demethyl precursor in an overall radiochemical yield of 4-7% (EOB) with a specific activity of >100 TBq/mmol. The radioligand had higher in vitro affinity for the sigma receptor than SA4503 (IC(50) sigma1 6.48 nM, IC50 sigma2 2.11 nM). [18F]FE-SA4503 was injected into mice. Uptake could be blocked by co-injection of the sigma receptor ligands haloperidol, pentazocine, and cold SA4503, but not with other receptor ligands. Ex vivo autoradiography studies in rats showed regional distribution in the brain similar to [11C]SA4503. Hippocampus, thalamus, and cortical areas were clearly delineated by [18F]FE-SA4503. The uptake was blocked by SA4503 treatment. In the rat brain, only a small portion of metabolites (6.6% of brain radioactivity) was detected at 30 min postinjection, whereas in plasma the fraction of metabolites amounted to 51.3% of plasma radioactivity. The kinetics of [18F]FE-SA4503 was measured with PET in the conscious monkey brain. High uptake values were found in the cortex, thalamus, cerebellum, and striatum, reaching a plateau value at 30 min postinjection. It is concluded that [18F]FE-SA4503 showed specific binding to sigma receptors in three animal species.