title: [18F]FPhEP and [18F]F2PhEP, two new epibatidine-based radioligands: evaluation for imaging nicotinic acetylcholine receptors in baboon brain.
abstract: The radioligand 2-[(18)F]fluoro-A-85380 has been developed for imaging alpha(4)beta(2) nAChRs with PET. However, it has slow kinetics and a large fraction of bound activity is nondisplaceable. In an attempt to address these problems, two epibatidine-based alpha(4)beta(2) nicotinic antagonists, coded FPhEP and F(2)PhEP, were evaluated in vivo in baboons. They were radiolabeled with fluorine-18 from the corresponding N-Boc-protected bromo-derivatives and the no-carrier-added K[(18)F]F-Kryptofix(222) complex. Radiochemically pure [(18)F]FPhEP or [(18)F]F(2)PhEP was obtained in 80 min in amounts of 1.11-2.22 GBq (111-185 GBq/micromol). After injection of 215 MBq of [(18)F]FPhEP or [(18)F]F(2)PhEP, dynamic PET data were acquired. Thalamic radioactivity peaked at 20 min (4.9% +/- 0.2% ID/100 mL tissue) for [(18)F]FPhEP. For [(18)F]F(2)PhEP, the peak was at 45 min (3.3% +/- 0.1% ID/100 mL tissue). Regional distribution of both radiotracers was in accordance with the known distribution of nAChRs. In presaturation experiments, nicotine, cytosine, or FPhEP reduced brain radioactivity of [(18)F]FPhEP. In a displacement experiment with nicotine only a small amount of [(18)F]F(2)PhEP was dislodged. In spite of a moderate to high in vitro affinity, both ligands do not fulfill the widely adopted criteria for a PET radioligand.
authors.affiliation: CEA, Institut d'Imagerie Biomédicale, Service Hospitalier Frédéric Joliot, 4 Place du Général Leclerc, F-91406 Orsay, France. heric.valette@cea.fr
authors.forename: Héric
authors.initials: H
authors.lastname: Valette
authors.forename: Frédéric
authors.initials: F
authors.lastname: Dollé
authors.forename: Wadad
authors.initials: W
authors.lastname: Saba
authors.forename: Gaelle
authors.initials: G
authors.lastname: Roger
authors.forename: Françoise
authors.initials: F
authors.lastname: Hinnen
authors.forename: Christine
authors.initials: C
authors.lastname: Coulon
authors.forename: Michele
authors.initials: M
authors.lastname: Ottaviani
authors.forename: André
authors.initials: A
authors.lastname: Syrota
authors.forename: Michel
authors.initials: M
authors.lastname: Bottlaender
mesh_terms: D000818:Animals; D001384:Azetidines / Q000493:pharmacokinetics; D001667:Binding, Competitive / Q000187:drug effects*; D001921:Brain / Q000000981:diagnostic imaging* / Q000187:drug effects* / Q000378:metabolism; D001923:Brain Chemistry; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005462:Fluorine Radioisotopes / Q000097:blood / Q000493:pharmacokinetics; D007090:Image Interpretation, Computer-Assisted; D008279:Magnetic Resonance Imaging; D010215:Papio / Q000033:anatomy & histology; D011725:Pyridines / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013997:Time Factors; D014055:Tomography, Emission-Computed
chemical_list: C104288:A 85380; D001384:Azetidines; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005462:Fluorine Radioisotopes; D011725:Pyridines; D011978:Receptors, Nicotinic; C082748:epibatidine