Synthesis and radiolabeling of N-[4-[4-(2-[¹¹C]methoxyphenyl)piperazin-1-yl]butyl]benzo[b]thiophene-2-carboxamide — a potential radiotracer for D₃ receptor imaging with PET

Abstract 

FAUC346 (N-[4-[4-(2-methoxyphenyl)piperazin-1-yl]butyl]benzo[b]thiophene-2-carboxamide), an in vitro D₃-selective ligand, and its normethyl derivative have been synthesized from commercially available 1-(2-substituted-phenyl)piperazines. FAUC346 has been labeled using [¹¹C]methyl triflate in acetone containing aqueous NaOH (5 Eq) at −10 °C for 1 min, purified on semipreparative reverse-phase high-performance liquid chromatography (HPLC) and formulated as an intravenous injectable solution using a Sep-Pak Plus C₁₈ device. Up to 5.5 GBq of [¹¹C]FAUC346 (N-[4-[4-(2-[methyl-¹¹C]methoxyphenyl)piperazin-1-yl]butyl]benzo[b]thiophene-2-carboxamide), with a specific radioactivity of 45–75 GBq/μmol, could be obtained in 30–35 min, including HPLC purification and formulation starting from 44.4 GBq of [¹¹C]carbon dioxide. Preliminary pharmacological evaluation of [¹¹C]FAUC346 in rat brain clearly demonstrated in vivo selectivity for D₃ receptors and the absence of radiolabeled metabolite within the brain. These encouraging results, however, could not be confirmed in nonhuman primates; therefore, this radioligand does not appear to have the required pharmacological profile for a positron emission tomography probe for imaging D₃ receptors.

Keywords: Carbon-11, D₃ receptors, Positron emission tomography