Autoradiographic evidence that (R)-3-quinuclidinyl (S)-4-fluoromethylbenzilate ((R,S)-FMeQNB) displays in vivo selectivity for the muscarinic m2 subtype

• Published in: Nuclear medicine and biology Vol. 23; no. 7; pp. 889 - 896
• Main Authors: Boulay, S.F., Sood, V.K., Rayeq, M.R., Zeeberg, B.R., Eckelman, W.C.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01.10.1996; Elsevier
• Subjects: Animals; Autoradiography; Benzilates - chemical synthesis; Benzilates - pharmacology; Binding, Competitive; Biological and medical sciences; Brain - diagnostic imaging; Brain - metabolism; Cerebral Cortex - metabolism; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Emission tomographic neuroreceptor quantitation; Humans; Iodine Radioisotopes; Kinetics; Male; Medical sciences; Neurology; Pharmacokinetic modeling; Pons - metabolism; Quinuclidines - chemical synthesis; Quinuclidines - pharmacology; Quinuclidinyl Benzilate - metabolism; Radioiodinated (R; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptor, Muscarinic M2; Receptors, Muscarinic - metabolism; S)-4IQNB; S)-FMeQNB; Substrate Specificity; Tomography, Emission-Computed; Radioiodinated (R; Emission tomographic neuroreceptor quantitation; R; S)-4IQNB; Pharmacokinetic modeling; S)-FMeQNB; Radionuclide study; Ligand binding; Nervous system diseases; Rat; Alzheimer disease; Rodentia; Loss rate; Fluorine compound; Selectivity; Experimental study; Cerebral disorder; Autoradiography; In vivo; Vertebrata; Mammalia; Animal; Central nervous system disease; Nervous receptor; Degenerative disease; Muscarinic receptor; Pharmacokinetics; Positron; Emission tomography
• ISSN: 0969-8051; 1872-9614
• DOI: 10.1016/S0969-8051(96)00121-7

Alzheimer's disease (AD) involves selective loss of muscarinic m2, but not m1, subtype neuroreceptors in cortical and hippocampal regions of the human brain. Until recently, emission tomographic study of the loss of m2 receptors in AD has been limited by the absence of available m2-selective radioligands that can penetrate the blood-brain barrier. We now demonstrate the in vivo m2 selectivity of a fluorinated derivative of QNB, (R)-3-quinuclidinyl (S)-4-fluoromethylbenzilate ((R,S)-FMeQNB), by studying autoradiographically the in vivo inhibition of radioiodinated (R)-3-quinuclidinyl (S)-4-iodobenzilate ((R,S)-[ 125I]IQNB) binding by unlabelled (R,S)-FMeQNB. In the absence of (R,S)-FMeQNB, (R,S)-[ 125I]IQNB labels brain regions in proportion to the total muscarinic receptor concentration; in the presence of 75 nmol of (R,S)-FMeQNB, (R,S)-[ 125I]IQNB labelling in those brain regions containing predominantly m2 subtype is reduced to background levels. We conclude that (R,S)-FMeQNB is m2-selective in vivo, and that (R,S)-[ 18F] FMeQNB may be of potential use in positron emission tomographic (PET) study of the loss of m2 receptors in AD.