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Predicate | Object |
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
1
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pubmed:dateCreated |
1997-3-4
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pubmed:abstractText |
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.
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pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Receptor, Muscarinic M1,
http://linkedlifedata.com/resource/pubmed/chemical/Receptor, Muscarinic M2,
http://linkedlifedata.com/resource/pubmed/chemical/Receptor, Muscarinic M3,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Muscarinic
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pubmed:status |
MEDLINE
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pubmed:month |
Jan
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pubmed:issn |
0022-2623
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pubmed:author | |
pubmed:issnType |
Print
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pubmed:day |
3
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pubmed:volume |
40
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
117-24
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pubmed:dateRevised |
2006-11-15
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pubmed:meshHeading |
pubmed-meshheading:9016336-Animals,
pubmed-meshheading:9016336-Kinetics,
pubmed-meshheading:9016336-Male,
pubmed-meshheading:9016336-Rats,
pubmed-meshheading:9016336-Rats, Wistar,
pubmed-meshheading:9016336-Receptor, Muscarinic M1,
pubmed-meshheading:9016336-Receptor, Muscarinic M2,
pubmed-meshheading:9016336-Receptor, Muscarinic M3,
pubmed-meshheading:9016336-Receptors, Muscarinic,
pubmed-meshheading:9016336-Respiratory System,
pubmed-meshheading:9016336-Stereoisomerism,
pubmed-meshheading:9016336-Tissue Distribution,
pubmed-meshheading:9016336-Tomography, Emission-Computed
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pubmed:year |
1997
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pubmed:articleTitle |
Stereoselective synthesis and biodistribution of potent [11C]-labeled antagonists for positron emission tomography imaging of muscarinic receptors in the airways.
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pubmed:affiliation |
Positron Emission Tomography (PET) Center, Groningen University Hospital, The Netherlands.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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