title: A novel muscarinic receptor ligand which penetrates the blood brain barrier and displays in vivo selectivity for the m2 subtype.
abstract: Alzheimer's disease (AD) involves selective loss of muscarinic m2, but not m1, subtype neuroreceptors in the posterior parietal cortex 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. In our efforts to prepare such a radioligand, we have used competition studies against currently existing muscarinic receptor radioligands to infer the in vitro and in vivo properties of a novel muscarinic receptor ligand, 5-[[4-[4-(diisobutylamino)butyl]-1-phenyl]acetyl]-10,11-dihydro-5H - -dibenzo [b,e][1,4]diazepin-11-one (DIBD). In vitro competition studies against [3H](R)-3-quinuclidinylbenzilate ([3H]QNB) and [3H]N-methylscopolamine ([3H]NMS), using membranes derived from transfected cells expressing only m1, m2, m3, or m4 receptor subtypes, indicate that DIBD is selective for m2/m4 over m1/m3. In vivo competition studies against (R,R)-[125I]IQNB indicate that DIBD crosses the blood brain barrier (BBB). The relationship of the regional percentage decrease in (R,R)-[125I]IQNB versus the percentage of each of the receptor subtypes indicates that DIBD competes more effectively in those brain regions which are known to be enriched in the m2, relative to the m1, m3, and m4, receptor subtype; however, analysis of the data using a mathematical model shows that caution is required when interpreting the in vivo results. We conclude that a suitably radiolabeled derivative of DIBD may be of potential use in emission tomographic study of changes in m2 receptors in the central nervous system.
authors.affiliation: Department of Radiology, George Washington University Medical Center, Washington D.C. 20037.
authors.forename: M S
authors.initials: MS
authors.lastname: Gitler
authors.forename: V I
authors.initials: VI
authors.lastname: Cohen
authors.forename: R
authors.initials: R
authors.lastname: De la Cruz
authors.forename: S F
authors.initials: SF
authors.lastname: Boulay
authors.forename: B
authors.initials: B
authors.lastname: Jin
authors.forename: B R
authors.initials: BR
authors.lastname: Zeeberg
authors.forename: R C
authors.initials: RC
authors.lastname: Reba
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001812:Blood-Brain Barrier; D003984:Dibenzazepines / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D011813:Quinuclidinyl Benzilate / Q000031:analogs & derivatives / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000145:classification / Q000187:drug effects*
chemical_list: D003984:Dibenzazepines; D011976:Receptors, Muscarinic; C084487:5-((4-(4-(diisobutylamino)butyl)-1-phenyl)acetyl)-10,11-dihydro-5H-dibenzo(b,e)(1,4)diazepin-11-one; D011813:Quinuclidinyl Benzilate; C040062:3-quinuclidinyl-4-iodobenzilate