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Evaluation of [18F]fluorinated sigma receptor ligands in the conscious monkey brain

PET‐imaging of the sigma receptors is very helpful to understand processes, e.g., several central nervous system (CNS)‐diseases in which the sigma receptors are involved. The [18F]fluoroethylated analogs of SA4503 and SA5845 ([18F]FE‐SA4503 and [18F]FE‐SA5845) were evaluated in conscious monkeys to estimate its suitability for human application for PET. Conscious monkeys (Macaca Mulatta) were either scanned with [18F]FE‐SA4503 or [18F]FE‐SA5845 (n = 3 for both groups, 220–802 MBq). After a dynamic study of 120 min, radioactivity was displaced by intravenous (i.v.) injection of haloperidol (1 mg/kg). One month later the same set of three monkeys were scanned with [18F]FE‐SA4503 for 120 min and “cold” SA4503 (1 mg/kg) was infused to displace the radioactivity, and the other three monkeys were pretreated with haloperidol (1 mg/kg) before the 120‐min PET‐scan with [18F]FE‐SA5845. Cortical areas (cingulate, frontal, occipital, parietal, temporal), striatum, and thalamus showed high radioactivity uptake. Infusion of haloperidol displaced the radioactivity levels of the two radioligands. The same effect was found for [18F]FE‐SA4503 after SA4503 displacement. Pretreatment with haloperidol blocked the [18F]FE‐SA5845 binding to give PET‐images with low and uniform uptake in the brain. The findings demonstrated the reversible binding of the two radioligands. Metabolite analysis showed that 14% and 23% parent compound of [18F]FE‐SA5845 and [18F]FE‐SA4503, respectively, at 120 min postinjection was present in plasma. Kinetic analysis showed that the binding potential of [18F]FE‐SA5845 was higher in all brain regions than that of [18F]FE‐SA4503 (4.75–8.79 vs. 1.65–4.04). The highest binding potential was found in the hippocampus, followed by the cortical regions, thalamus, cerebellar hemisphere, striatum and vermis. Both [18F]FE‐SA compounds bound specifically to cerebral sigma receptors of the monkey and have potential for mapping sigma receptors in the human brain. Synapse 52:29–37, 2004. © 2004 Wiley‐Liss, Inc.