- Synthesis of [11C]2β-Carbomethoxy-3β-(3'-iodo-4'-methyl, -ethyl and isopropyl Phenyl)Nortropane as Potential Radiotracers for Examination of the Serotonin Transporter with Positron Emission Tomography
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Research on depression and anxiety disorders would benefit from the development of suitable radioligands for PET-imaging of the serotonin transporter. Three cocaine analogues, 2β-carbomethoxy-3β-(3'-iodo-4'-methyl, -ethyl and isopropyl phenyl)nortropane (LBT-14, EINT and LBT-44), were prepared in a three-step synthesis by 1-4 addition of the appropriate Grignard reagent to anhydroecgonine methyl ester as first step. lodination of the phenyl ring was accomplished with a mixture of yellow mercuric oxide, perchloric acid and acetic acid followed by a solution of iodine in dichloromethane. N-desmethylation was performed by using 2,2,2-trichloroethylchloroformiate followed by treatment of zinc in acetic acid. Acidic hydrolysis of the ester functions gave the carboxylic acid analogues of LBT-14, EINT and LBT-44. The precursors were labelled with 11C using [11C]methyl iodide or [11C]methyl triflate in dimethyl formamide (DMF) and tetrabutyl ammonium hydroxide (TBAH) as base. [11C]LBT-14, [11C]EINT and [11C]LBT-44 were all examined in Cynomolgus monkey with PET. All three compounds entered the monkey brain to a high degree (ca. 5-10 percent of injected dose). There was a marked uptake of radioactivity in the thalamus and the brainstem, regions known to contain serotonin transporters. Pre-treatment with the selective serotonin transporter inhibitor citalopram had minor effect on the binding ratios, suggesting that none of the three examined radioligands are preferable to the previously examined non-iodinated 4'-isopropenyl analogue [11C]RTI-357 for the study of the serotonin reuptake system with PET.
- Sandell, Johan,Halldin, Christer,Helfenbein, Julie,Chou, Yuan-Hwa,Vercouillce, Johnny,Emond, Patrick,Swahn, Carl-Gunnar,Guilloteau, Denis,Farde, Lars
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p. 1033 - 1046
(2007/10/03)
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