In vivo competition studies of Z-(-,-)-[125I]IQNP against 3-quinuclidinyl 2-(5-bromothienyl)-2-thienylglycolate (BrQNT) demonstrating in vivo m2 muscarinic subtype selectivity for BrQNT.
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 an analog of (R)-QNB, 3-quinuclidinyl 2-(5-bromothienyl)-2-thienylglycolate (BrQNT), by dissection and autoradiographic studies of the in vivo inhibition of radioiodinated Z-1-azabicyclo[2.2.2]oct-3-yl alpha-hydroxy-alpha-(1-iodo-1-propen-3-yl)-alpha-phenyl-acetate (Z-(-,-)-[125I]IQNP) binding by unlabeled BrQNT in rat brain. In the absence of BrQNT, Z-(-,-)-[125I]IQNP labels brain regions containing muscarinic receptors, with an enhanced selectivity for the m2 subtype. In the presence of 60-180 nmol of co-injected racemic BrQNT, Z-(-,-)-[125I]IQNP labeling in those brain regions containing predominantly m2 subtype is reduced to background levels, while levels of radioactivity in areas not enriched in the m2 subtype do not significantly decrease. We conclude that BrQNT is m2-selective in vivo, and that [76Br]BrQNT, or a radiofluorinated analog, may be of potential use in positron emission tomographic (PET) study of the loss of m2 receptors in AD. In addition, a radioiodinated analog may be of potential use in single photon emission tomographic (SPECT) studies.
Cohen
V I
VI
George Washington University Medical Center, Section of Radiopharmaceutical Chemistry, Washington, DC 20037, USA.
Zeeberg
B R
BR
Boulay
S F
SF
Sood
V K
VK
Rayeq
M R
MR
Danesh
R A
RA
McPherson
D W
DW
Reba
R C
RC
D000544:Alzheimer Disease / Q000175:diagnosis / Q000473:pathology; D000818:Animals; D001345:Autoradiography; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism*; D001967:Bromine Radioisotopes; D016616:Cryoultramicrotomy; D006016:Glycolates / Q000378:metabolism*; D008297:Male; D011812:Quinuclidines / Q000378:metabolism*; D011869:Radioligand Assay / Q000379:methods*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic / Q000378:metabolism*; D012680:Sensitivity and Specificity; D014055:Tomography, Emission-Computed; D015899:Tomography, Emission-Computed, Single-Photon
C110326:5-BrQNT; D001967:Bromine Radioisotopes; D006016:Glycolates; D011812:Quinuclidines; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic; C080526:1-azabicyclo(2.2.2)oct-3-yl 2-hydroxy-2-(1-iodo-1-propen-3-yl)-2-phenylacetate