title: In vitro characterization of 6-[18F]fluoro-A-85380, a high-affinity ligand for alpha4beta2* nicotinic acetylcholine receptors.
abstract: Nicotinic acetylcholine receptors are involved in tobacco dependence and several other neuropathologies (e.g., Alzheimer's disease, Parkinson's disease), as well as in attention, learning, and memory. Performing in vivo imaging of these receptors in humans holds great promise for understanding their role in these conditions. Recently, three radiohalogenated analogs of 3-(2(S)-azetidinylmethoxy)pyridine (A- 85380) were used successfully for the in vivo visualization of alpha4beta2* nicotinic receptors in the human brain with PET/SPECT. Herein, we present the results of the in vitro characterization of one of these radioligands, 6-[18F]fluoro-3-(2(S)-azetidinylmethoxy)-pyridine (6-[18F]fluoro-A-85380), which is a fluoro-analog of the potent nonopioid analgesic ABT-594. In human postmortem cortical tissue, 6-[18F]fluoro-A-85380 reversibly binds with high affinity to a single population of sites (Kd = 59 pM at 37 degrees C, Bmax = 0.7 pmol/g tissue). The binding is fully reversible and is characterized at 37 degrees C by T(1/2assoc) = 2.2 min (at a ligand concentration of 39 pM) and by T(1/2dissoc) = 3.6 min. 6-Fluoro-A-85380 exhibits clear selectivity for alpha4beta2* over the other major mammalian nicotinic receptor subtypes: alpha7, alpha3beta4, and muscle-type. These results suggest that 6-[18F]fluoro-A-85380 is a promising radioligand for in vivo imaging of brain alpha4beta2* nicotinic receptors.
authors.affiliation: Neuroimaging Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, DHHS, Baltimore, Maryland 21224, USA.
authors.forename: Daniela
authors.initials: D
authors.lastname: Gündisch
authors.forename: Andrei O
authors.initials: AO
authors.lastname: Koren
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Horti
authors.forename: Olga A
authors.initials: OA
authors.lastname: Pavlova
authors.forename: Alane S
authors.initials: AS
authors.lastname: Kimes
authors.forename: Alexey G
authors.initials: AG
authors.lastname: Mukhin
authors.forename: Edythe D
authors.initials: ED
authors.lastname: London
mesh_terms: D000818:Animals; D001384:Azetidines / Q000737:chemistry / Q000493:pharmacokinetics*; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000166:cytology / Q000000981:diagnostic imaging / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004557:Electric Organ / Q000378:metabolism; D004843:Epistasis, Genetic; D005462:Fluorine Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D066298:In Vitro Techniques; D007456:Iodine Isotopes / Q000493:pharmacokinetics; D008024:Ligands; D011180:Postmortem Changes; D011869:Radioligand Assay / Q000379:methods; D011877:Radionuclide Imaging; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013696:Temperature; D013997:Time Factors; D014018:Tissue Distribution; D014101:Torpedo
chemical_list: D001384:Azetidines; D005462:Fluorine Radioisotopes; D007456:Iodine Isotopes; D008024:Ligands; D011978:Receptors, Nicotinic; C104288:A 85380