title: Design, synthesis, radiolabeling and in vivo evaluation of potential positron emission tomography (PET) radioligands for brain imaging of the 5-HT₇ receptor.
abstract: Here we describe the design, synthesis, and pharmacological evaluation of a set of compounds structurally related to the high affinity serotonin 5-HT7 receptor agonist N-(4-cyanophenylmethyl)-4-(2-diphenyl)-1-piperazinehexanamide (6, LP-211). Specific structural modifications were performed in order to maintain affinity for the target receptor and to improve the selectivity over 5-HT1A and adrenergic α1 receptors. The synthesized compounds have chemical features that could enable labeling with a positron emitter radioisotope (carbon-11 or fluorine-18) and lipophilicity within the range considered optimal for brain penetration and low non-specific binding. 4-[2-(4-Methoxyphenyl)phenyl]-N-(pyridin-4-ylmethyl)piperazinehexanamide (23a) and N-pyridin-4-ylmethyl-3-[4-[2-(4-methoxyphenyl)phenyl]piperazin-1-yl]ethoxy]propanamide (26a) were radiolabeled on the methoxy group with carbon-11. Positron emission tomography (PET) analysis revealed that [(11)C]-23a and [(11)C]-26a were P-glycoprotein (P-gp) substrates and rapidly metabolized, resulting in poor brain uptake. These features were not predicted by in vitro tests.
authors: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari A. Moro, via Orabona 4, 70125 Bari, Italy.
authors: Enza
authors: E
authors: Lacivita
authors: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari A. Moro, via Orabona 4, 70125 Bari, Italy.
authors: Mauro
authors: M
authors: Niso
authors: Center for Integrated Molecular Brain Imaging, Copenhagen University Hospital Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark; Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, University of Copenhagen, Blegdamsvej 9, 2100 Copenhagen, Denmark.
authors: Hanne D
authors: HD
authors: Hansen
authors: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari A. Moro, via Orabona 4, 70125 Bari, Italy.
authors: Pantaleo
authors: P
authors: Di Pilato
authors: Center for Integrated Molecular Brain Imaging, Copenhagen University Hospital Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark; Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, University of Copenhagen, Blegdamsvej 9, 2100 Copenhagen, Denmark; PET and Cyclotron Unit, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark.
authors: Matthias M
authors: MM
authors: Herth
authors: PET and Cyclotron Unit, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark.
authors: Szabolcs
authors: S
authors: Lehel
authors: Center for Integrated Molecular Brain Imaging, Copenhagen University Hospital Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark; Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, University of Copenhagen, Blegdamsvej 9, 2100 Copenhagen, Denmark.
authors: Anders
authors: A
authors: Ettrup
authors: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari A. Moro, via Orabona 4, 70125 Bari, Italy.
authors: Lisa
authors: L
authors: Montenegro
authors: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari A. Moro, via Orabona 4, 70125 Bari, Italy.
authors: Roberto
authors: R
authors: Perrone
authors: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari A. Moro, via Orabona 4, 70125 Bari, Italy.
authors: Francesco
authors: F
authors: Berardi
authors: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari A. Moro, via Orabona 4, 70125 Bari, Italy.
authors: Nicola A
authors: NA
authors: Colabufo
authors: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari A. Moro, via Orabona 4, 70125 Bari, Italy. Electronic address: marcello.leopoldo@uniba.it.
authors: Marcello
authors: M
authors: Leopoldo
authors: Center for Integrated Molecular Brain Imaging, Copenhagen University Hospital Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark; Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, University of Copenhagen, Blegdamsvej 9, 2100 Copenhagen, Denmark.
authors: Gitte M
authors: GM
authors: Knudsen
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism; D003952:Diagnostic Imaging / Q000379:methods*; D015394:Molecular Structure; D049268:Positron-Emission Tomography / Q000379:methods*; D011859:Radiography; D011869:Radioligand Assay / Q000379:methods*; D019275:Radiopharmaceuticals; D051381:Rats; D011985:Receptors, Serotonin / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D019275:Radiopharmaceuticals; D011985:Receptors, Serotonin; C078730:serotonin 5 receptor
keywords: 5-HT(7) receptor; Arylpiperazine; PET; Radioligand