Synthesis of [C-11]2 beta-carbomethoxy-3 beta-(3 '-iodo-4 '-methyl, -ethyland isopropyl phenyl)nortropane as potential radiotracers for examination of the serotonin transporter with positron emission tomography

Research on depression and anxiety disorders would benefit from the develop ment of suitable radioligands for PET-imaging of the serotonin transporter. Three cocaine analogues, 2 beta-carbomethoxy-3 beta-(3'-iodo-4'-methyl, -e thyl and isopropyl phenyl)nortropane (LBT-14, EINT and LBT-44), were prepar ed in a three-step synthesis by 1-4 addition of the appropriate Grignard re agent to anhydroecgonine methyl ester as first step. Iodination of the phen yl ring was accomplished with a mixture of yellow mercuric oxide, perchlori c 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 est er functions gave the carboxylic acid analogues of LBT-14, EINT and LBT-44. The precursors were labelled with C-11 using [C-11]methyl iodide or [C-11] methyl triflate in dimethyl formamide (DMF) and tetrabutyl ammonmium hydrox ide (TBAH) as base. [C-11]LBT-14, [C-11]EINT and [C-11]LBT-44 were all exam ined in Cynomolgus monkey with PET. All three compounds entered the monkey brain to a high degree (similar to 5-10% of injected dose). There was a mar ked uptake of radioactivity in the thalamus and the brainstem, regions know n to contain serotonin transporters. Pre-treatment with the selective serot onin transporter inhibitor citalopram had minor effect on the binding ratio s, suggesting that none of the three examined radioligands are preferable t o the previously examined non-iodinated 4'-isopropenyl analogue [C-11]RTI-3 57 for the study of the serotonin reuptake system with PET.