~(11)C-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 ~(11)C(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 [~(11)C]methyl iodide using tBuOK/HMPA and KOH/ DMSO,respectively.The radiotracers [~(11)C]1 and [~(11)C]2 were obtained in 35 min with over 99% radiochemical purity,74 +-37 GBq/mumol of specific radioactivity,13% and 26% radio-chemical yield(EOB,decay-corrected).Distribution studies in rats demonstrated that the new tracers [~(11)C]1 and [~(11)C]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 D_3 receptors.Despite their in vitro pharmacological profile,[~(11)C]1 and [~(11)C]2 do not display an in vivo behavior suitable to image D_3 receptor expression using PET.