title: Comparative distribution of binding of the muscarinic receptor ligands pirenzepine, AF-DX 384, (R,R)-I-QNB and (R,S)-I-QNB to human brain.
abstract: Quinuclidinyl benzilate (QNB) and its derivatives are being developed to investigate muscarinic receptor changes in vivo in Alzheimer's disease and dementia with Lewy bodies. This is the first study of [125I]-(R,R)-I-QNB and [125I]-(R,S)-I-QNB binding in vitro in human brain. We have compared the in vitro binding of the muscarinic ligands [3H]pirenzepine and [3H]AF-DX 384, which have selectivity for the M1 and M2/M4 receptor subtypes, respectively, to the binding of [125I]-(R,R)-I-QNB and [125I]-(R,S)-I-QNB. This will provide a guide to the interpretation of in vivo SPET images generated with [123I]-(R,R)-I-QNB and [123I]-(R,S)-I-QNB. Binding was investigated in striatum, globus pallidus, thalamus and cerebellum, and cingulate, insula, temporal and occipital cortical areas, which show different proportions of muscarinic receptor subtypes, in post-mortem brain from normal individuals. M1 receptors are of high density in cortex and striatum and are relatively low in the thalamus and cerebellum, while M4 receptors are mainly expressed in the striatum, and M2 receptors are most evident in the cerebellum and thalamus. [125I]-(R,R)-I-QNB and [125I]-(R,S)-I-QNB density distribution patterns were consistent with binding to both M1 and M4 receptors, with [125I]-(R,R)-I-QNB additionally binding to a non-cholinergic site not displaceable by atropine. This distribution can be exploited by in vivo imaging, developing ligands for both SPET and PET, to reveal muscarinic receptor changes in Alzheimer's disease and dementia with Lewy bodies during the disease process and following cholinergic therapy.
authors.affiliation: Newcastle General Hospital, MRC/University of Newcastle Centre Development in Clinical Brain Ageing, MRC Building, Westgate Road, NE4 6BE, Newcastle-upon-Tyne, UK. m.a.piggott@ncl.ac.uk
authors.forename: Margaret
authors.initials: M
authors.lastname: Piggott
authors.forename: Jonathan
authors.initials: J
authors.lastname: Owens
authors.forename: John
authors.initials: J
authors.lastname: O'Brien
authors.forename: Sean
authors.initials: S
authors.lastname: Paling
authors.forename: David
authors.initials: D
authors.lastname: Wyper
authors.forename: John
authors.initials: J
authors.lastname: Fenwick
authors.forename: Mary
authors.initials: M
authors.lastname: Johnson
authors.forename: Robert
authors.initials: R
authors.lastname: Perry
authors.forename: Elaine
authors.initials: E
authors.lastname: Perry
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001665:Binding Sites / Q000502:physiology; D001921:Brain / Q000378:metabolism*; D005260:Female; D006801:Humans; D008024:Ligands; D008297:Male; D010890:Pirenzepine / Q000031:analogs & derivatives* / Q000378:metabolism*; D011813:Quinuclidinyl Benzilate / Q000378:metabolism*; D011976:Receptors, Muscarinic / Q000378:metabolism*; D013237:Stereoisomerism
chemical_list: D008024:Ligands; D011976:Receptors, Muscarinic; C065959:AFDX 384; D010890:Pirenzepine; D011813:Quinuclidinyl Benzilate