title: Synthesis and evaluation of (18)F-labeled 5-HT2A receptor agonists as PET ligands.
abstract: The serotonin 2A receptor (5-HT2AR) is the most abundant excitatory 5-HT receptor in the human brain and implicated in various brain disorders such as schizophrenia, depression, and Alzheimer's disease. Positron emission tomography (PET) can be used to image specific proteins and processes in the human brain and several 5-HT2AR PET antagonist radioligands are available. In contrast to an antagonist radioligand, an agonist radioligand should be able to image the population of functional receptors, i.e., those capable of inducing neuroreceptor signaling. Recently, we successfully developed and validated the first 5-HT2AR agonist PET tracer, [(11)C]Cimbi-36, for neuroimaging in humans and herein disclose some of our efforts to develop an (18)F-labeled 5-HT2AR agonist PET-ligand.
  
  
  
  Three fluorine containing derivatives of Cimbi-36 were synthesized and found to be potent 5-HT2A agonists. (18)F-labeling of the appropriate precursors was performed using [(18)F]FETos, typically yielding 0.2-2.0GBq and specific activities of 40-120GBq/μmol. PET studies in Danish landrace pigs revealed that [(18)F]1 displayed brain uptake in 5-HT2AR rich regions. However, high uptake in bone was also observed. No blocking effect was detected during a competition experiment with a 5-HT2AR selective antagonist. [(18)F]2 and [(18)F]3 showed very low brain uptake.
  
  
  
  None of the investigated (18)F-labeled Cimbi-36 derivatives [(18)F]1, [(18)F]2 and [(18)F]3 show suitable tracer characteristics for in vivo PET neuroimaging of the 5-HT2AR. Although for [(18)F]1 there was reasonable brain uptake, we suggest that a large proportion radioactivity in the brain was due to radiometabolites, which would explain why it could not be displaced by a 5-HT2AR antagonist.
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100, Copenhagen, Denmark; Neurobiology Research Unit and Center for Integrated Molecular Brain Imaging, Rigshospitalet, Blegdamsvej 9, DK-2100, Copenhagen, Denmark; Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, Blegdamsvej 9, DK-2100, Copenhagen, Denmark.
authors.forename: Matthias M
authors.initials: MM
authors.lastname: Herth
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100, Copenhagen, Denmark.
authors.forename: Ida Nymann
authors.initials: IN
authors.lastname: Petersen
authors.affiliation: Neurobiology Research Unit and Center for Integrated Molecular Brain Imaging, Rigshospitalet, Blegdamsvej 9, DK-2100, Copenhagen, Denmark.
authors.forename: Hanne Demant
authors.initials: HD
authors.lastname: Hansen
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100, Copenhagen, Denmark.
authors.forename: Martin
authors.initials: M
authors.lastname: Hansen
authors.affiliation: Neurobiology Research Unit and Center for Integrated Molecular Brain Imaging, Rigshospitalet, Blegdamsvej 9, DK-2100, Copenhagen, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Ettrup
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100, Copenhagen, Denmark.
authors.forename: Anders A
authors.initials: AA
authors.lastname: Jensen
authors.affiliation: Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, Blegdamsvej 9, DK-2100, Copenhagen, Denmark.
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Lehel
authors.affiliation: Neurobiology Research Unit and Center for Integrated Molecular Brain Imaging, Rigshospitalet, Blegdamsvej 9, DK-2100, Copenhagen, Denmark.
authors.forename: Agnete
authors.initials: A
authors.lastname: Dyssegaard
authors.affiliation: Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, Blegdamsvej 9, DK-2100, Copenhagen, Denmark.
authors.forename: Nic
authors.initials: N
authors.lastname: Gillings
authors.affiliation: Neurobiology Research Unit and Center for Integrated Molecular Brain Imaging, Rigshospitalet, Blegdamsvej 9, DK-2100, Copenhagen, Denmark.
authors.forename: Gitte M
authors.initials: GM
authors.lastname: Knudsen
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100, Copenhagen, Denmark. Electronic address: jesper.kristensen@sund.ku.dk.
authors.forename: Jesper L
authors.initials: JL
authors.lastname: Kristensen
mesh_terms: D000818:Animals; D001596:Benzylamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D001692:Biological Transport; D060326:Chemistry Techniques, Synthetic; D005260:Female; D005462:Fluorine Radioisotopes; D007553:Isotope Labeling; D008024:Ligands; D010627:Phenethylamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods*; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D058826:Serotonin 5-HT2 Receptor Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D013552:Swine
chemical_list: D001596:Benzylamines; C586246:Cimbi-36; D005462:Fluorine Radioisotopes; D008024:Ligands; D010627:Phenethylamines; D044402:Receptor, Serotonin, 5-HT2A; D058826:Serotonin 5-HT2 Receptor Agonists
keywords: 5-HT(2A)R; Agonist; Cimbi-36; Fluorine-18; PET