title: [125/123I]IPH: a radioiodinated analog of epibatidine for in vivo studies of nicotinic acetylcholine receptors.
abstract: Tomographic imaging of central nicotinic acetylcholine receptors (nAChRs) via single photon emission computed tomography (SPECT) has been hampered by the lack of a radioligand with suitable in vivo binding characteristics. Therefore, a novel analog of epibatidine, (+/-)-exo-2-(2-iodo-5-pyridyl)-7-azabicyclo[2.2.1]heptane (IPH), labeled with [(125)I] or [(123)I] was evaluated as an in vivo marker of central nicotinic acetylcholine receptors (nAChRs). [(125)I]IPH showed substantial brain penetration (4.2% of the injected dose at 30 min) and a cerebral biodistribution in mice consistent with the in vivo labeling of nAChRs (% injected dose/gram of thalamus, superior colliculi >> cerebellum). [(125)I]IPH binding sites were shown to be saturable with unlabeled IPH (ED50 approximately 1 microg/kg). The uptake of [(125)I]IPH was blocked significantly by the nicotinic agonists, cytisine, lobeline, and (-)-nicotine, but not by the noncompetitive nAChR antagonist, mecamylamine. Antagonists of muscarinic (scopolamine), serotonin (ketanserin), and opioid (naloxone) receptors had no significant effect on [(125)I]IPH binding. A preliminary SPECT imaging study with [(123)I]IPH in a baboon showed [(123)I]IPH to localize in nAChR-rich areas of brain (thalamus > frontal cortex > cerebellum). [(123)I]IPH binding in baboon brain was also displaced (35-45% displacement) by a challenge dose of cytisine showing that a well-characterized nicotinic agonist effectively competes for [(123)I]IPH binding sites. [(123)I]IPH seems well suited for imaging studies of nAChRs and, to our knowledge, is the first SPECT agent that has allowed for the visualization of nAChRs in primate brain.
authors.affiliation: Department of Radiology, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21287, USA. jlmusachio@petscan.nm.jhu.edu
authors.forename: J L
authors.initials: JL
authors.lastname: Musachio
authors.forename: V L
authors.initials: VL
authors.lastname: Villemagne
authors.forename: U
authors.initials: U
authors.lastname: Scheffel
authors.forename: M
authors.initials: M
authors.lastname: Stathis
authors.forename: P
authors.initials: P
authors.lastname: Finley
authors.forename: A
authors.initials: A
authors.lastname: Horti
authors.forename: E D
authors.initials: ED
authors.lastname: London
authors.forename: R F
authors.initials: RF
authors.lastname: Dannals
mesh_terms: D000818:Animals; D001921:Brain / Q000033:anatomy & histology; D001923:Brain Chemistry; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D007457:Iodine Radioisotopes; D008024:Ligands; D008297:Male; D051379:Mice; D018722:Nicotinic Agonists / Q000493:pharmacokinetics; D010215:Papio; D011725:Pyridines / Q000493:pharmacokinetics; D011978:Receptors, Nicotinic / Q000187:drug effects*; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: C107078:2-(2-iodo-5-pyridyl)-7-azabicyclo(2.2.1)heptane; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007457:Iodine Radioisotopes; D008024:Ligands; D018722:Nicotinic Agonists; D011725:Pyridines; D011978:Receptors, Nicotinic; C082748:epibatidine