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 receptors subtypes, respectively, to the biniding of [125I]-(R,R)-I-QNB and [125I]-(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-morten brain from normal individuals. M1 receptors are of high density in cortex and striatum and are relatively low in the thalmus 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 consistant with binding to both M1 and M4 receptors, with [125I]-(R,R)-I-QNB additionally binding to a non-cholinergic site not displacable 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.
Piggott M, Owens J, O'Brien J, Paling S, Wyper D, Fenwick J, Johnson M, Perry R, Perry E. 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. Journal of Chemical Neuroanatomy 24 (2002) 211-223.
Dr. Sean Paling, NGH Unit, Newcastle upon Tyne. Tel: +44 (0)191-233-6161.
Regional Medical Physics Department, Newcastle General Hospital, Newcastle upon Tyne, NE4 6BE, UK.
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