title: Synthesis, radiolabeling and in vivo evaluation of [(11)C](R)-1-[4-[2-(4-methoxyphenyl)phenyl]piperazin-1-yl]-3-(2-pyrazinyloxy)-2-propanol, a potential PET radioligand for the 5-HT(7) receptor.
abstract: In the search for a novel serotonin 7 (5-HT7) receptor PET radioligand we synthesized and evaluated a new series of biphenylpiperazine derivatives in vitro. Among the studied compounds, (R)-1-[4-[2-(4-methoxyphenyl)phenyl]piperazin-1-yl]-3-(2-pyrazinyloxy)-2-propanol ((R)-16), showed the best combination of affinity, selectivity, and lipophilicity, and was thus chosen for carbon-11 labelling and evaluation in pigs. After intravenous injection, [(11)C](R)-16 entered the pig brain and displayed reversible tracer kinetics. Pretreatment with the 5-HT7 receptor selective antagonist SB-269970 (1) resulted in limited decrease in the binding of [(11)C](R)-16, suggesting that this radioligand is not optimal for imaging the brain 5-HT7 receptor in vivo but it may serve as a lead compound for the design of novel 5-HT7 receptor PET radioligands.
authors.affiliation: Center for Integrated Molecular Brain Imaging, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark; Neurobiology Research Unit, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark.
authors.forename: Hanne D
authors.initials: HD
authors.lastname: Hansen
authors.affiliation: Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari A. Moro, Via Orabona, 4, 70125 Bari, Italy.
authors.forename: Enza
authors.initials: E
authors.lastname: Lacivita
authors.affiliation: Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari A. Moro, Via Orabona, 4, 70125 Bari, Italy.
authors.forename: Pantaleo
authors.initials: P
authors.lastname: Di Pilato
authors.affiliation: Center for Integrated Molecular Brain Imaging, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark; Neurobiology Research Unit, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark; PET and Cyclotron Unit, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark.
authors.forename: Matthias M
authors.initials: MM
authors.lastname: Herth
authors.affiliation: PET and Cyclotron Unit, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark.
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Lehel
authors.affiliation: Center for Integrated Molecular Brain Imaging, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark; Neurobiology Research Unit, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Ettrup
authors.affiliation: Center for Integrated Molecular Brain Imaging, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark; Neurobiology Research Unit, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark; PET and Cyclotron Unit, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark.
authors.forename: Valdemar L
authors.initials: VL
authors.lastname: Andersen
authors.affiliation: Center for Integrated Molecular Brain Imaging, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark; Neurobiology Research Unit, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark.
authors.forename: Agnete
authors.initials: A
authors.lastname: Dyssegaard
authors.affiliation: Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari A. Moro, Via Orabona, 4, 70125 Bari, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: De Giorgio
authors.affiliation: Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari A. Moro, Via Orabona, 4, 70125 Bari, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Perrone
authors.affiliation: Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari A. Moro, Via Orabona, 4, 70125 Bari, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Berardi
authors.affiliation: Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari A. Moro, Via Orabona, 4, 70125 Bari, Italy.
authors.forename: Nicola Antonio
authors.initials: NA
authors.lastname: Colabufo
authors.affiliation: Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari A. Moro, Via Orabona, 4, 70125 Bari, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Niso
authors.affiliation: Center for Integrated Molecular Brain Imaging, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark; Neurobiology Research Unit, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark. Electronic address: gmk@nru.dk.
authors.forename: Gitte M
authors.initials: GM
authors.lastname: Knudsen
authors.affiliation: Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari A. Moro, Via Orabona, 4, 70125 Bari, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Leopoldo
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging; D016466:CHO Cells; D002247:Carbon Isotopes; D003412:Cricetulus; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D008024:Ligands; D015394:Molecular Structure; D010636:Phenols / Q000494:pharmacology; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry; D049268:Positron-Emission Tomography; D020005:Propanols / Q000138:chemical synthesis* / Q000737:chemistry; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D011985:Receptors, Serotonin / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D013552:Swine; D014018:Tissue Distribution
chemical_list: C000594237:((11)C)(R)-1-(4-(2-(4-methoxyphenyl)phenyl)piperazin-1-yl)-3-(2-pyrazinyloxy)-2-propanol; D002247:Carbon Isotopes; D008024:Ligands; D010636:Phenols; D010879:Piperazines; D020005:Propanols; D011719:Pyrazines; D019275:Radiopharmaceuticals; D011985:Receptors, Serotonin; C404922:SB 269970; D013449:Sulfonamides; C104425:serotonin 7 receptor
keywords: 5-HT(7) receptor; Arylpiperazine; PET; Radioligand; SB-269970