IN-VIVO COMPETITION STUDIES OF Z-(-,-)-[I-125]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 lo ss 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 dis section and autoradiographic studies of the in vivo inhibition of radi oiodinated Z-1-azabicyclo [2.2.2]oct-3-yl hydroxy-alpha-(1-iodo-1-prop en-3-yl)-alpha-phenyl- acetate (Z-(-,-)-[I-125]IQNP) binding by unlabe led BrQNT in rat brain. In the absence of BrQNT, Z-(-,-)[I-125]IQNP la bels brain regions containing muscarinic receptors, with an enhanced s electivity for the m2 subtype. In the presence of 60-180 nmol of co-in jected racemic BrQNT, Z-(-,-)-[I-125]IQNP labeling in those brain regi ons containing predominantly m2 subtype is reduced to background level s, while levels of radioactivity in areas not enriched in the m2 subty pe do not significantly decrease. We conclude that BrQNT is m2-selecti ve in vivo, and that [Br-76]BrQNT, or a radiofluorinated analog, may b e 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) stud ies.