title: Synthesis and in vitro evaluation of [18F]FECIMBI-36: A potential agonist PET ligand for 5-HT2A/2C receptors.
abstract: Radiosynthesis and in vitro evaluation of [(18)F]-2-(4-bromo-2,5-dimethoxyphenyl)-N-(2-(2-fluoroethoxy)benzyl)ethanamine, ([(18)F]FECIMBI-36) or ([(18)F]1), a potential agonist PET imaging agent for 5-HT2A/2C receptors is described. Syntheses of reference standard 1 and the corresponding des-fluoroethyl radiolabeling precursor (2) were achieved with 75% and 65% yields, respectively. In vitro pharmacology assay of FECIMBI-36 by [(3)H]-ketanserin competition binding assay obtained from NIMH-PDSP showed high affinities to 5-HT2AR (Ki = 1nM) and 5-HT2CR (Ki=1.7 nM). Radiolabeling of FECIMBI-36 was achieved from the boc-protected precursor 2 using [(18)F]-fluoroethyltosylate in presence of Cs2CO3 in DMSO followed by removal of the protective group. [(18)F]1 was isolated using RP-HPLC in 25 ± 5% yield, purity > 95% and specific activity 1-2Ci/μmol (N = 6). In vitro autoradiography studies demonstrate that [(18)F]1 selectively label 5-HT2A and 5-HT2C receptors in slide-mounted sections of postmortem human brain using phosphor imaging. Our results indicate the potential of [(18)F]1 for imaging 5-HT2A/2C receptors in the high affinity state in vivo using PET imaging.
authors.affiliation: Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY, USA. Electronic address: jp2155@cumc.columbia.edu.
authors.forename: Jaya
authors.initials: J
authors.lastname: Prabhakaran
authors.affiliation: Molecular Imaging and Neuropathology Division, New York State Psychiatric Institute, New York, NY, USA; Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY, USA.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Underwood
authors.affiliation: Molecular Imaging and Neuropathology Division, New York State Psychiatric Institute, New York, NY, USA.
authors.forename: J S Dileep
authors.initials: JS
authors.lastname: Kumar
authors.affiliation: Molecular Imaging and Neuropathology Division, New York State Psychiatric Institute, New York, NY, USA.
authors.forename: Norman R
authors.initials: NR
authors.lastname: Simpson
authors.affiliation: Molecular Imaging and Neuropathology Division, New York State Psychiatric Institute, New York, NY, USA.
authors.forename: Suham A
authors.initials: SA
authors.lastname: Kassir
authors.affiliation: Molecular Imaging and Neuropathology Division, New York State Psychiatric Institute, New York, NY, USA.
authors.forename: Mihran J
authors.initials: MJ
authors.lastname: Bakalian
authors.affiliation: Molecular Imaging and Neuropathology Division, New York State Psychiatric Institute, New York, NY, USA; Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY, USA.
authors.forename: J John
authors.initials: JJ
authors.lastname: Mann
authors.affiliation: Molecular Imaging and Neuropathology Division, New York State Psychiatric Institute, New York, NY, USA; Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY, USA.
authors.forename: Victoria
authors.initials: V
authors.lastname: Arango
mesh_terms: D004305:Dose-Response Relationship, Drug; D005021:Ethylamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005462:Fluorine Radioisotopes / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D049268:Positron-Emission Tomography; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism*; D058826:Serotonin 5-HT2 Receptor Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: C000607832:((18)F)-2-(4-bromo-2,5-dimethoxyphenyl)-N-(2-(2-fluoroethoxy)benzyl)ethanamine; D005021:Ethylamines; D005462:Fluorine Radioisotopes; D008024:Ligands; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D058826:Serotonin 5-HT2 Receptor Agonists
keywords: 5-HT; 5HT(2A/2C)R; Agonist; PET; Radiotracer