Autoradiographic evidence that quinuclidinyl 4-(bromophenyl)-2-thienylglycolate (QBPTG) displays in vivo selectivity for the muscarinic 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 an analogue of QNB, 4-(bromophenyl)-2-thienylglycolate (QBPTG), by studying autoradiographically the in vivo inhibition of radioiodinated (R)-3-quinuclidinyl (S)-4-iodobenzilate ((R,S)-[125I]IQNB) binding by unlabeled QBPTG in rat brain. In the absence of QBPTG, (R,S)-[125I]IQNB labels brain regions in proportion to the total muscarinic receptor concentration; in the presence of 37.5 nmol of racemic QBPTG, (R,S)-[125I]IQNB labeling in those brain regions containing predominantly the m2 subtype is reduced to background levels. We conclude that QBPTG is m2-selective in vivo and that [76Br]QBPTG, or a radiofluorinated analogue, may be of potential use in positron emission tomographic study of the loss of m2 receptors in AD. In addition, a radioiodinated analogue may be of potential use in single photon emission tomographic studies.
Boulay
S F
SF
George Washington University Medical Center, Section of Radiopharmaceutical Chemistry, Washington, DC 20037, USA.
Sood
V K
VK
Rayeq
M R
MR
McRee
R C
RC
Cohen
E I
EI
Cohen
V I
VI
Zeeberg
B R
BR
Reba
R C
RC
D000544:Alzheimer Disease / Q000473:pathology; D000818:Animals; D001345:Autoradiography / Q000295:instrumentation*; D001921:Brain / Q000473:pathology; D006801:Humans; D007091:Image Processing, Computer-Assisted / Q000295:instrumentation*; 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