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Tytuł:
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Stereoselective synthesis and biodistribution of potent [11C]-labeled antagonists for positron emission tomography imaging of muscarinic receptors in the airways.
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Autorzy:
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Visser TJ; Positron Emission Tomography (PET) Center, Groningen University Hospital, The Netherlands.
van Waarde A
Jansen TJ
Visser GM
van der Mark TW
Kraan J
Ensing K
Vaalburg W
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Źródło:
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Journal of medicinal chemistry [J Med Chem] 1997 Jan 03; Vol. 40 (1), pp. 117-24.
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Typ publikacji:
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Journal Article; Research Support, Non-U.S. Gov't
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Język:
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English
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Imprint Name(s):
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Publication: Washington Dc : American Chemical Society
Original Publication: [Easton, Pa.] : American Chemical Society, [c1963-
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MeSH Terms:
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Receptors, Muscarinic/*chemistry
Respiratory System/*metabolism
Animals ; Kinetics ; Male ; Rats ; Rats, Wistar ; Receptor, Muscarinic M1 ; Receptor, Muscarinic M2 ; Receptor, Muscarinic M3 ; Receptors, Muscarinic/metabolism ; Stereoisomerism ; Tissue Distribution ; Tomography, Emission-Computed
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Substance Nomenclature:
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0 (Receptor, Muscarinic M1)
0 (Receptor, Muscarinic M2)
0 (Receptor, Muscarinic M3)
0 (Receptors, Muscarinic)
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Entry Date(s):
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Date Created: 19970103 Date Completed: 19970304 Latest Revision: 20061115
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Update Code:
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20240104
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DOI:
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10.1021/jm960374w
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PMID:
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9016336
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Quantitation of muscarinic receptors in the lungs in vivo with positron emission tomography (PET) is of clinical interest. For that purpose we decided to develop [11C]-labeled ligands with a high affinity (KD < 0.1 nM). Three quaternary muscarinic antagonists, racemic N-methylpiperidin-4-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate methiodide 1a (pKB = 10.39), its (R)-isomer 1b (pKB = 11.08), and (R,R)-quinuclidin-3-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate methiodide 2 (pKB = 11.28), were labeled by reacting [11C]CH3I with their tertiary amine precursors. The enantiomerically pure tertiary amine precursors were prepared by stereoselective synthesis starting from (R)-(-)-mandelic acid. In vitro binding assay of 1b and 2 demonstrated that both ligands bind with very high affinity to the muscarinic receptor subtypes M1, M2, and M3. They are more potent than the muscarinic antagonist (R)-N-methylquinuclidinyl benzilate ((R)-MQNB). Distribution studies with 1a, 1b, and 2 in control and atropine-treated male Wistar rats demonstrated significant specific binding (90-99% of total issue uptake) in tissues containing cholinoceptors (heart, intestine, lung, pancreas, spleen, stomach, submandibular gland). Because the tissue/plasma concentration ratios of 1b are most favorable, this ligand was used for further evaluation. Analysis of plasma samples showed a very rapid clearance (t1/2 = 0.3 min) of the radioligand 1b and a relatively slow appearance of a hydrophilic metabolite. At 15 min postinjection of 1b, analysis of heart, lungs, and liver showed that respectively 99%, 88%, and 8% of the tissue radioactivity corresponded with the parent compound. Ligand 1b appears to be an excellent candidate for PET studies of mAChR receptors in heart and lungs.