[O-METHYL-C-11]BETA-CIT-FP, A POTENTIAL RADIOLIGAND FOR QUANTITATION OF THE DOPAMINE TRANSPORTER - PREPARATION, AUTORADIOGRAPHY, METABOLITE STUDIES, AND POSITRON EMISSION TOMOGRAPHY EXAMINATIONS

beta-CIT-FP [N-(3-fluoropropyl)-2 beta-carbomethoxy-3 beta-(4-iodophenyl)nortropane] is a cocaine analogue with a high affinity for the dopamine transporter. [O-methyl-C-11]beta-CIT-FP ([C-11]beta-CIT-FP) was prepared by O-alkylation of the free acid with [C-11]methyl iodide. The total radiochemical yield of [C-11]beta-CIT-FP was 50 to 60% with an overall synthesis time of 30 min. The radiochemical purity was >99%, and the specific radioactivity at time of injection was about 37 GBq/mu mol (1000 Ci/mmol). Autoradiographic examination of [C-11]beta-CIT-FP binding in human brain postmortem demonstrated specific binding in the caudate nucleus and putamen. Positron emission tomography (PET) examination of [C-11]beta-CIT-FP in a Cynomolgus monkey demonstrated accumulation in the striatum with a striatum-to-cerebellum ratio of about 8 after 60 min. Equilibrium in the striatum was attained within 70 to 90 min, The radioactivity ratios of thalamus/cerebellum and neocortex/cerebellum were about 2 and 1.5, respectively. In a displacement experiment, radioactivity in the striatum but not in the cerebellum was reduced after injection of beta-CIT, indicating that striatal radioactivity following injection of [C-11]beta-CIT-FP is associated with dopamine transporter sites and that the binding is reversible. The fraction of the total radioactivity in plasma representing [C-11]beta-CIT-FP determined by high-performance liquid chromatography (HPLC) was 84% at 15 min and 50% at 95 min. [C-11]beta-CIT-FP should be a useful PET radioligand for the quantitation of dopamine transporters in the human brain in vivo.