O-methyl- 11C]β-CIT-FP, a potential radioligand for quantitation of the dopamine transporter: Preparation, autoradiography, metabolite studies, and positron emission tomography examinations

Abstract

β-CIT-FP [ N-(3-fluoropropyl)-2β-carbomethoxy-3β-(4-iodophenyl)nortropane] is a cocaine analogue with a high affinity for the dopamine transporter. [ O-methyl- 11C]β-CIT-FP ([ 11C]β-CIT-FP) was prepared by O-alkylation of the free acid with [ 11C]methyl iodide. The total radiochemical yield of [ 11C]β-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/μmol (1000 Ci/mmol). Autoradiographic examination of [ 11C]β-CIT-FP binding in human brain postmortem demonstrated specific binding in the caudate nucleus and putamen. Positron emission tomography (PET) examination of [ 11C]β-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 β-CIT, indicating that striatal radioactivity following injection of [ 11C]β-CIT-FP is associated with dopamine transporter sites and that the binding is reversible. The fraction of the total radioactivity in plasma representing [ 11C]β-CIT-FP determined by high-performance liquid chromatography (HPLC) was 84% at 15 min and 50% at 95 min. [ 11C]β-CIT-FP should be a useful PET radioligand for the quantitation of dopamine transporters in the human brain in vivo.