Evaluation of novel PET ligands (+)N-[11C]methyl-3-piperidyl benzilate ([11C](+)3-MPB) and its stereoisomer [11C](-)3-MPB for muscarinic cholinergic receptors in the conscious monkey brain: a PET study in comparison with.

Abstract

The novel muscarinic cholinergic ligands (+)N-[11C]methyl-3-piperidyl benzilate ([11C](+)3-MPB) and its stereoisomer [11C](-)3-MPB were evaluated in comparison with [11C]4-MPB in the brains of conscious monkeys (Macaca mulatta) using high-resolution positron emission tomography (PET). The regional distribution patterns of [11C](+)3-MPB and [11C]4-MPB at 60-91 min postinjection were almost identical: highest in the striatum and occipital cortex; intermediate in the temporal and frontal cortices, cingulate gyrus, hippocampus, and thalamus; lower in the pons; and lowest in the cerebellum. The uptake of [11C](+)3-MPB in all regions was higher and the dynamic range of regional uptake differences of [11C](+)3-MPB was better than those of [11C]4-MPB. The levels of [11C](-)3-MPB were much lower in all regions of the brain than [11C](+)3-MPB and [11C]4-MPB. Administration of scopolamine, a muscarinic cholinergic antagonist, at a dose of 50 microg/kg reduced the radioactivity of [11C](+)3-MPB and [11C]4-MPB in all regions except the cerebellum. Time-activity curves of [11C](+)3-MPB peaked in all regions, while those of [11C]4-MPB showed gradual increases with time in all regions except the thalamus, pons, and cerebellum. Two graphical analyses (Logan plot and Patlak plot) with plasma radioactivity as an input function into the brain were applied to evaluate receptor binding in vivo. [11C](+)3-MPB showed linear regression curves on Logan plot analysis and nonlinear curves on Patlak plot in all regions, suggesting that [11C](+)3-MPB bound reversibly to the muscarinic receptors. The in vivo binding parameters as well as uptake at 60-91 min postinjection of [11C](+)3-MPB were consistent with muscarinic receptor density in the brain as reported in vitro.