Evaluation of in vivo binding properties of 3H-NMPB and 3H-QNB in mouse brain.
Apparent muscarinic acetylcholine (mAch) receptor occupancy in mouse cerebral cortex, hippocampus, and striatum by scopolamine, an antagonist, and biperiden, a relatively selective M1 antagonist, was estimated with competitive binding studies using two different radioligands: 3H-N-methyl piperidyl benzilate (3H-NMPB) and 3H-quinuclidinyl benzilate (3H-QNB). Both radioligands labeled mAch receptors in these brain regions, and the relative regional distributions of the specific binding of 3H-NMPB in vivo paralleled the distribution of mAch receptors. 3H-NMPB binding in vivo was much more sensitive to direct competitive inhibition by scopolamine than was 3H-QNB. A similar discrepancy in sensitivity to competitors between 3H-NMPB and 3H-QNB was also observed when biperiden was used as a competitor, indicating that binding to different subtypes of the mAch receptor could not account for the observed differences in sensitivity to competition. An in vivo saturation study suggested that the apparent association rate constant (k on) of 3H-QNB binding might be changed by ligand concentration. The heterogeneity of the free ligand concentration in intact brain was assessed in relation to the ligand concentration dependency of the apparent association rate constant (k on) of 3H-QNB binding. This finding, together with the more favorable accumulation of 3H-NMPB in cerebral cortex, hippocampus, and striatum, leads us to conclude that 3H-NMPB, or its positron emitting counterpart, should be the more favorable radiotracer for the estimation of mAch receptor occupancy by cholinergic drugs in the brain.


BACKGROUND
mAch receptor, QNB, NMPB, in vivo, mouse.
Hosoi
R
R
Department of Medical Physics, School of Allied Health Sciences, Faculty of Medicine, Osaka University, Suita, Japan.
Kobayashi
K
K
Watanabe
Y
Y
Inoue
O
O
D000818:Animals; D001561:Benzilates / Q000378:metabolism*; D001712:Biperiden / Q000494:pharmacology; D001921:Brain / Q000378:metabolism*; D008297:Male; D051379:Mice; D018727:Muscarinic Antagonists / Q000378:metabolism* / Q000494:pharmacology; D010276:Parasympatholytics / Q000378:metabolism*; D010880:Piperidines / Q000378:metabolism*; D011813:Quinuclidinyl Benzilate / Q000378:metabolism*; D011976:Receptors, Muscarinic / Q000378:metabolism
D001561:Benzilates; D018727:Muscarinic Antagonists; D010276:Parasympatholytics; D010880:Piperidines; D011976:Receptors, Muscarinic; D001712:Biperiden; D011813:Quinuclidinyl Benzilate; C020407:enpiperate