PET examination of three potent cocaine derivatives as specific radioligands for the serotonin transporter

Several positron emission tomography (PET) radioligands based on the aryl tropane structure have been used for studies on monoamine reuptake sites. RTI-364, RTI-330, and RTI-357 (3-beta-(4'-n-propyl-, 4'-iso-propyl-, and 4'-iso-propenyl-phenyl)nortropane-2-beta-carboxylic acid methyl ester) are three recently synthesized cocaine analogues with higher affinity for the serotonin (5-HTT) than the dopamine transporter (DAT). Unlabelled RTI-364 and RTI-330 were prepared in a two-step synthesis. The key step was the addition of the appropriate propyl Grignard reagent to anhydroecgonine methyl ester. RTI-357 was prepared in a three-step synthesis with a palladium-catalyzed coupling reaction of beta-CIT and isopropenylzinc bromide as key step. Hydrolysis of the ester functions gave the carboxylic acid analogues of RTI-364, RTI-330, and RTI-357, which were labelled with C-11 using [C-11]methyl iodide in dimethyl formamide (DMF) and tetrabutylammonium hydroxide (TBAH) as base. All three compounds entered the monkey brain in a high degree (similar to 5-10%). There was a low uptake of [C-11]RTI-364 in serotonin-rich brain areas, whereas [C-11]RTI-330 and [C-11]RTI-357 showed a marked uptake of radioactivity in the thalamus and the brainstem, regions known to contain serotonin transporters, Transient equilibrium was reached at 15 and 40 min for [C-11]RTI-330 and [C-11]RTI-357, respectively. After pretreatment with citalopram, the ratio of radioactivity in the thalamus and the brainstem to the cerebellum were markedly reduced for [C-11]RTI-357 but not for [C-11]RTI-330. The results indicate that [C-11]RTI-357 is a potential PET radioligand for quantitation of the serotonin reuptake site. (C) 1999 Elsevier Science Inc. All rights reserved.