title: 11C-labeling of n-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl]arylcarboxamide derivatives and evaluation as potential radioligands for PET imaging of dopamine D3 receptors.
abstract: 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% radiochemical 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.
authors.affiliation: Institute of Molecular Bioimaging and Physiology-CNR, University of Milano/Bicocca, Institute San Raffaele, Via Olgettina 60, 20132 Milan, Italy.
authors.forename: Elia A
authors.initials: EA
authors.lastname: Turolla
authors.forename: Mario
authors.initials: M
authors.lastname: Matarrese
authors.forename: Sara
authors.initials: S
authors.lastname: Belloli
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Moresco
authors.forename: Pasquale
authors.initials: P
authors.lastname: Simonelli
authors.forename: Sergio
authors.initials: S
authors.lastname: Todde
authors.forename: Ferruccio
authors.initials: F
authors.lastname: Fazio
authors.forename: Fulvio
authors.initials: F
authors.lastname: Magni
authors.forename: Marzia Galli
authors.initials: MG
authors.lastname: Kienle
authors.forename: Marcello
authors.initials: M
authors.lastname: Leopoldo
authors.forename: Francesco
authors.initials: F
authors.lastname: Berardi
authors.forename: Nicola A
authors.initials: NA
authors.lastname: Colabufo
authors.forename: Enza
authors.initials: E
authors.lastname: Lacivita
authors.forename: Roberto
authors.initials: R
authors.lastname: Perrone
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D001345:Autoradiography; D001812:Blood-Brain Barrier / Q000000981:diagnostic imaging / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D002250:Carbon Radioisotopes; D008024:Ligands; D008297:Male; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D050637:Receptors, Dopamine D3 / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D000577:Amides; D002250:Carbon Radioisotopes; D008024:Ligands; D010879:Piperazines; D019275:Radiopharmaceuticals; D050637:Receptors, Dopamine D3