Autoradiographic evidence that 3-quinuclidinyl-4-fluorobenzilate (FQNB) displays in vivo selectivity for the m2 subtype.
Alzheimer's disease (AD) involves selective loss of muscarinic m2, but not m1, subtype neuroreceptors in cortical and hippocampal regions of the human brain. Emission tomographic study of the loss of m2 receptors in AD is limited by the fact that there is currently no available m2-selective radioligand which can penetrate the blood-brain barrier. We now demonstrate the in vivo m2 selectivity of a fluorine derivative of QNB (FQNB), by studying autoradiographically the in vivo inhibition of radioiodinated (R)-3-quinuclidinyl (S)-4-iodobenzilate ((R,S)-[125I]IQNB) binding by unlabeled FQNB. In the absence of FQNB, (R,S)-[125I]IQNB labels brain regions in proportion to the total muscarinic receptor concentration; in the presence of 30.0 nmol of racemic FQNB, (R,S)-[125I]IQNB labeling in those brain regions containing predominantly the m2 subtype is reduced to background levels. We conclude that FQNB is m2-selective in vivo and that [18F]FQNB or a closely related analogue may be of potential use in positron emission tomographic study of the loss of m2 receptors in AD.
Boulay
S F
SF
Section of Radiopharmaceutical Chemistry, Walter G. Ross Hall, George Washington University Medical Center, Washington, DC 20037, USA.
Sood
V K
VK
Rayeq
M R
MR
Cohen
V I
VI
Zeeberg
B R
BR
Reba
R C
RC
D000544:Alzheimer Disease / Q000175:diagnosis* / Q000473:pathology; D000818:Animals; D001345:Autoradiography; D001667:Binding, Competitive; D001921:Brain / Q000473:pathology*; D001931:Brain Mapping; D002540:Cerebral Cortex / Q000473:pathology; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008297:Male; D018727:Muscarinic Antagonists / Q000493:pharmacokinetics*; D011813:Quinuclidinyl Benzilate / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic / Q000378:metabolism*
D018727:Muscarinic Antagonists; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic; D011813:Quinuclidinyl Benzilate; C040062:3-quinuclidinyl-4-iodobenzilate