Norchloro-fluoro-homoepibatidine (NCFHEB) — A promising radioligand for neuroimaging nicotinic acetylcholine receptors with PET

• Published in: European neuropsychopharmacology 2008-03, Vol.18 (3), p.222-229
• Main Authors: Deuther-Conrad, W, Patt, J.T, Lockman, P.R, Allen, D.D, Patt, M, Schildan, A, Ganapathy, V, Steinbach, J, Sabri, O, Brust, P
• Format: Article
• Language: English
• Subjects: Animals; Azetidines; Benzamides - chemistry; Benzamides - pharmacokinetics; Biological Transport, Active; Blood-brain barrier; Blood-Brain Barrier - drug effects; Bridged Bicyclo Compounds, Heterocyclic - chemistry; Bridged Bicyclo Compounds, Heterocyclic - pharmacokinetics; Choline - metabolism; Epibatidine; Female; Indicators and Reagents; Internal Medicine; Isotope Labeling; Male; Mice; Perfusion; Positron emission tomography; Psychiatry; Radiopharmaceuticals - chemistry; Radiopharmaceuticals - pharmacokinetics; Receptors, Nicotinic - metabolism; Stereoisomerism; Stereoselectivity; Subtype specificity; Tissue Distribution
• ISSN: 0924-977X; 1873-7862
• DOI: 10.1016/j.euroneuro.2007.07.002

Abstract Cholinergic neurotransmission depends on the integrity of nicotinic acetylcholine receptors (nAChRs), and impairment of both is characteristic for various neurodegenerative diseases. Visualization of specific receptor subtypes by positron emission tomography (PET) has potential to assist with diagnosis of such neurodegenerative diseases and with design of suitable therapeutic approaches. The goal of our study was to evaluate in vivo the potential of18 F-labelled (+)- and (−)-norchloro-fluoro-homoepibatidine ([18 F]NCFHEB) in comparison to 2-[18 F]F-A-85380 as PET tracers. In the brains of NMRI mice, highest levels of radioactivity were detected at 20 min post-injection of (+)-[18 F]NCFHEB, (−)-[18 F]NCFHEB, and 2-F-[18 F]-A-85380 (7.45, 5.60, and 3.2% ID/g tissue, respectively). No marked pharmacological adverse effects were observed at 25 μg NCFHEB/kg. Uptake studies in RBE4 cells and in situ perfusion studies suggest an interaction of epibatidine and NCFHEB with the carrier-mediated choline transport at the blood-brain barrier. The data indicate that (+)- and (−)-[18 F]NCFHEB have potential for further development as PET tracers.