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

Several positron emission tomography (PET) radioligands based on the aryl t ropane structure have been used for studies on monoamine reuptake sites. RT I-364, RTI-330, and RTI-357 (3-beta-(4'-n-propyl-, 4'-iso-propyl-, and 4'-i so-propenyl-phenyl)nortropane-2-beta-carboxylic acid methyl ester) are thre e recently synthesized cocaine analogues with higher affinity for the serot onin (5-HTT) than the dopamine transporter (DAT). Unlabelled RTI-364 and RT I-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. Hydr olysis 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 io dide in dimethyl formamide (DMF) and tetrabutylammonium hydroxide (TBAH) as base. All three compounds entered the monkey brain in a high degree (simil ar to 5-10%). There was a low uptake of [C-11]RTI-364 in serotonin-rich bra in 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]R TI-330. The results indicate that [C-11]RTI-357 is a potential PET radiolig and for quantitation of the serotonin reuptake site. (C) 1999 Elsevier Scie nce Inc. All rights reserved.