C-11-labeling of N-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl]arylcarboxamide derivatives and evaluation as potential radioligands for PET imaging of dopamine D-3 receptors

摘要

The selective dopamine D-3 receptor ligands N-4-[4-[(2,3-dichlorophenyl)piperazin-1-yl]butyl]1-methoxy-2-naphthalencarboxamide (1) and N-4-[4-[(2,3-dichlorophenyl)piperazin-1-yl]butyl]-7-methoxy-2-benzofurancarboxamide (2) were labeled with C-11 (t(1/2) = 20.4 min) as potential radioligands for the noninvasive assessment of the dopamine D-3 neurotransmission system in vivo with positron emission tomography (PET). The radiosynthesis consisted in an O-methylation of the des-methyl precursors N-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl]-1-hydroxy-2-naphthalenecarboxamide (3) and N- [4- [4-(2,3-dichlorophenyl)piperazin-1-yl]butyl]-7-hydroxy-2-benzofurancarboxamide (4) with [C-11]methyl iodide using tBuOK/HMPA and KOH/DMSO, respectively. The radiotracers [C-11]1 and [C-11]2 were obtained in 35 min with over 99% radiochemical purity, 74 +/- 37 GBq/mu mol of specific radioactivity, 13% and 26% radiochemical yield (EOB, decay-corrected). Distribution studies in rats demonstrated that the new tracers [C-11]1 and [C-11]2 cross the blood-brain barrier and localize in the brain. However, the kinetics of cerebral uptake did not reflect the regional expression of the D3 receptors. Despite their in vitro pharmacological profile, [C-11]1 and [C-11]2 do not display an in vivo behavior suitable to image D-3 receptor expression using PET.