title: Radiosynthesis and in vivo evaluation of novel radioligands for PET imaging of cerebral 5-HT7 receptors.
abstract: The serotonin (5-hydroxytryptamine [5-ΗΤ]) 7 receptor (5-HT7R) is the most recently discovered 5-HT receptor, and its physiologic and possible pathophysiologic roles are not fully elucidated. So far, no suitable 5-HT7R PET radioligand is available, thus limiting the investigation of this receptor in the living brain. Here, we present the radiosynthesis and in vivo evaluation of Cimbi-712 (3-{4-[4-(4-methylphenyl)piperazine-1-yl]butyl}p-1,3-dihydro-2H-indol-2-one) and Cimbi-717 (3-{4-[4-(3-methoxyphenyl)piperazine-1-yl]butyl}-1,3-dihydro-2H-indol-2-one) as selective 5-HT7R PET radioligands in the pig brain. The 5-HT7R distribution in the postmortem pig brain is also assessed.
  
  
  METHODS
  In vitro autoradiography with the 5-HT7R selective radioligand (3)H-labeled (R)-3-(2-(2-(4-methylpiperidin-1-yl)ethyl)pyrrolidine-1-sulfonyl)phenol (SB-269970) was performed on pig brain sections to establish the 5-HT7R binding distribution. Radiolabeling of 5-HT7R selective compounds was performed in an automated synthesis module in which we conducted either palladium-mediated cross coupling ((11)C-Cimbi-712) or conventional O-methylation ((11)C-Cimbi-717) using (11)C-MeI and (11)C-MeOTf, respectively. After intravenous injection of the radioligands in Danish Landrace pigs, the in vivo brain distribution of the ligands was studied. Specific binding of (11)C-Cimbi-712 and (11)C-Cimbi717 to 5-HT7R was investigated by intravenous administration of SB-269970 before a second PET scan.
  
  
  RESULTS
  High 5-HT7R density was found in the thalamus and cortical regions of the pig brain by autoradiography. The radiosynthesis of both radioligands succeeded after optimization efforts (radiochemical yield, ∼20%-30% at the end of synthesis). Time-activity curves of (11)C-Cimbi-712 and (11)C-Cimbi-717 showed high brain uptake and distribution according to 5-HT7R distribution, but the tracer kinetics of (11)C-Cimbi-717 were faster than (11)C-Cimbi-712. Both radioligands were specific for 5-HT7R, as binding could be blocked by pretreatment with SB-269970 for (11)C-Cimbi-717 in a dose-dependent fashion. For (11)C-Cimbi-717, nondisplaceable binding potentials of 6.4 ± 1.2 (n = 6) were calculated in the thalamus.
  
  
  CONCLUSIONS
  Both (11)C-Cimbi-712 and (11)C-Cimbi-717 generated a specific binding in accordance with 5-HT7R distribution and are potential PET radioligands for 5-HT7R. (11)C-Cimbi-717 is the better candidate because of the more reversible tracer kinetics, and this radioligand showed a dose-dependent decline in cerebral binding after receptor blockade. Thus, (11)C-Cimbi-717 is currently the most promising radioligand for investigation of 5-HT7R binding in the living human brain.
authors.affiliation: Center for Integrated Molecular Brain Imaging, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
authors.forename: Hanne D
authors.initials: HD
authors.lastname: Hansen
authors.forename: Matthias M
authors.initials: MM
authors.lastname: Herth
authors.forename: Anders
authors.initials: A
authors.lastname: Ettrup
authors.forename: Valdemar L
authors.initials: VL
authors.lastname: Andersen
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Lehel
authors.forename: Agnete
authors.initials: A
authors.lastname: Dyssegaard
authors.forename: Jesper L
authors.initials: JL
authors.lastname: Kristensen
authors.forename: Gitte M
authors.initials: GM
authors.lastname: Knudsen
mesh_terms: D000818:Animals; D001345:Autoradiography; D001711:Biotransformation; D001921:Brain / Q000000981:diagnostic imaging*; D001923:Brain Chemistry; D002540:Cerebral Cortex / Q000000981:diagnostic imaging / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D005260:Female; D007211:Indoles / Q000138:chemical synthesis*; D007553:Isotope Labeling / Q000379:methods*; D008024:Ligands; D010636:Phenols; D010879:Piperazines / Q000138:chemical synthesis*; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis*; D011985:Receptors, Serotonin / Q000378:metabolism*; D018490:Serotonin Agents / Q000737:chemistry; D013449:Sulfonamides; D013552:Swine; D013788:Thalamus / Q000000981:diagnostic imaging / Q000378:metabolism
chemical_list: C000588666:3-(4-(4-(3-methoxyphenyl)piperazine-1-yl)butyl)-1,3-dihydro-2H-indol-2-one; D007211:Indoles; D008024:Ligands; D010636:Phenols; D010879:Piperazines; D019275:Radiopharmaceuticals; D011985:Receptors, Serotonin; C404922:SB 269970; D018490:Serotonin Agents; D013449:Sulfonamides; C104425:serotonin 7 receptor
keywords: 11C-Cimbi-712; 11C-Cimbi-717; 5-HT7 receptor; PET; novel radioligand