title: In vivo measurement of nicotinic acetylcholine receptors with [18F]norchloro-fluoro-homoepibatidine.
abstract: Functional changes of nicotinic acetylcholine receptors (nAChR) are important during age-related neuronal degeneration. Recent studies demonstrate the applicability of the nAChR ligand 2-[(18)F]F-A-85380 for neuroimaging of patients with dementias. However, its binding kinetics demands a 7-h acquisition time limiting its practicality for clinical PET studies. Thus, the authors developed [(18)F]norchloro-fluoro-homoepibatidine ([(18)F]NCFHEB) for nAChR imaging. The kinetics of the two enantiomers of [(18)F]NCFHEB were compared with 2-[(18)F]F-A85380 in porcine brain to evaluate their potential for human neuroimaging. Twenty-four juvenile female pigs were studied with PET using [(18)F]NCFHEB. Nine animals received an additional i.v. injection (1 mg/kg) of the nAChR agonist A81418 before radiotracer administration followed by infusion (2 mg/kg/7h) thereafter. Several compartment models were applied for quantification. (-)- and (+)-[(18)F]NCFHEB showed a twofold to threefold higher brain uptake than 2-[(18)F]F-A-85380. All three radiotracers displayed spatially heterogeneous binding kinetics in regions with high, moderate, or low specific binding. The equilibrium of specific binding of (-)-[(18)F]NCFHEB was reached earlier than that of (+)-[(18)F]NCFHEB or 2-[(18)F]F-A85380. Continuous administration of the nAChR agonist A81418 inhibited the specific binding of (-)- and (+)-[(18)F]NCFHEB but not of 2-[(18)F]F-A85380. The peripheral metabolism of (+)-[(18)F]NCFHEB proceeded somewhat slower than that of the other radiotracers. Both enantiomers of [(18)F]NCFHEB are appropriate radiotracers for neuroimaging of nAChR in pigs. Their binding profile in vivo appears to be more selective than that of 2-[(18)F]F-A85380. (-)-[(18)F]NCFHEB offers a faster equilibrium of specific binding than 2-[(18)F]F-A85380.
authors: Department of Radiopharmacy, Institute of Interdisciplinary Isotope Research, Permoserstrasse 15, Leipzig, Germany. brust@iif-leipzig.de
authors: Peter
authors: P
authors: Brust
authors: Jörg Thomas
authors: JT
authors: Patt
authors: Winnie
authors: W
authors: Deuther-Conrad
authors: Georg
authors: G
authors: Becker
authors: Marianne
authors: M
authors: Patt
authors: Andreas
authors: A
authors: Schildan
authors: Dietlind
authors: D
authors: Sorger
authors: Kai
authors: K
authors: Kendziorra
authors: Philipp
authors: P
authors: Meyer
authors: Jörg
authors: J
authors: Steinbach
authors: Osama
authors: O
authors: Sabri
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D001931:Brain Mapping; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism*; D005260:Female; D008279:Magnetic Resonance Imaging / Q000379:methods; D018722:Nicotinic Agonists / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013552:Swine; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic