Abstract
A new series of derivatives of 3-(1,4-diazabicyclo[3.2.2]nonan-4-yl)dibenzo[b,d]thiophene 5,5-dioxide with high binding affinities and selectivity for α7-nicotinic acetylcholine receptors (α7-nAChRs) (Ki = 0.4-20 nM) has been synthesized for positron emission tomography (PET) imaging of α7-nAChRs. Two radiolabeled members of the series [(18)F]7a (Ki = 0.4 nM) and [(18)F]7c (Ki = 1.3 nM) were synthesized. [(18)F]7a and [(18)F]7c readily entered the mouse brain and specifically labeled α7-nAChRs. The α7-nAChR selective ligand 1 (SSR180711) blocked the binding of [(18)F]7a in the mouse brain in a dose-dependent manner. The mouse blocking studies with non-α7-nAChR central nervous system drugs demonstrated that [(18)F]7a is highly α7-nAChR selective. In agreement with its binding affinity the binding potential of [(18)F]7a (BPND = 5.3-8.0) in control mice is superior to previous α7-nAChR PET radioligands. Thus, [(18)F]7a displays excellent imaging properties in mice and has been chosen for further evaluation as a potential PET radioligand for imaging of α7-nAChR in non-human primates.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Azabicyclo Compounds / chemical synthesis*
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Azabicyclo Compounds / chemistry
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Azabicyclo Compounds / pharmacokinetics
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Brain / diagnostic imaging
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Brain / metabolism
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Central Nervous System Agents / pharmacology
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Cyclic S-Oxides / chemical synthesis*
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Cyclic S-Oxides / chemistry
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Cyclic S-Oxides / pharmacokinetics
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Cystine / pharmacology
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Fluorine Radioisotopes
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HEK293 Cells
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Humans
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Male
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Mice
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Nicotine / pharmacology
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Nicotinic Agonists / pharmacology
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Positron-Emission Tomography
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Radiopharmaceuticals / chemical synthesis*
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Radiopharmaceuticals / chemistry
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Radiopharmaceuticals / pharmacokinetics
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Rats
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Receptors, Serotonin, 5-HT3 / metabolism
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Structure-Activity Relationship
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Thiophenes / chemical synthesis*
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Thiophenes / chemistry
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Thiophenes / pharmacokinetics
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Tissue Distribution
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alpha7 Nicotinic Acetylcholine Receptor / metabolism*
Substances
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3-(1,4-diazabicyclo(3.2.2)nonan-4-yl)-6-fluorodibenzo(b,d)thiophene 5,5-dioxide
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Azabicyclo Compounds
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Central Nervous System Agents
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Cyclic S-Oxides
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Fluorine Radioisotopes
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Nicotinic Agonists
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Radiopharmaceuticals
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Receptors, Serotonin, 5-HT3
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Thiophenes
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alpha7 Nicotinic Acetylcholine Receptor
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Cystine
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Nicotine