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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, the authors 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 [[sup 3]H](R)-3-quinuclidinylbenzilate ([[sup 3]H]QNB) and [[sup 3]H]N-methylscopolamine ([[sup 3]H]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)-[[sup 125]I]IQNB indicate that DIBD crosses the blood brain barrier (BBB). The relationship of the regional percentage decrease in (R,R)-[[sup 125]I]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 modelmore » shows that caution is required when interpreting the in vivo results. The authors 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.« less

Authors:
; ; ; ; ;  [1];  [2]
  1. George Washington Univ. Medical Center, Washington, DC (United States)
  2. George Washington Univ. Medical Center, Washington, DC (United States) Univ. of Chicago Hospital, IL (United States)
Publication Date:
OSTI Identifier:
5444740
DOE Contract Number:  
FG05-88ER60649
Resource Type:
Journal Article
Journal Name:
Life Sciences; (United States)
Additional Journal Information:
Journal Volume: 53:23; Journal ID: ISSN 0024-3205
Country of Publication:
United States
Language:
English
Subject:
38 RADIATION CHEMISTRY, RADIOCHEMISTRY, AND NUCLEAR CHEMISTRY; 62 RADIOLOGY AND NUCLEAR MEDICINE; 63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.; BRAIN; EMISSION COMPUTED TOMOGRAPHY; RADIOPHARMACEUTICALS; CHEMICAL PREPARATION; RECEPTORS; AMINES; DIAZO COMPOUNDS; IODINE 125; NERVOUS SYSTEM DISEASES; BETA DECAY RADIOISOTOPES; BODY; CENTRAL NERVOUS SYSTEM; COMPUTERIZED TOMOGRAPHY; DAYS LIVING RADIOISOTOPES; DIAGNOSTIC TECHNIQUES; DISEASES; DRUGS; ELECTRON CAPTURE RADIOISOTOPES; INTERMEDIATE MASS NUCLEI; INTERNAL CONVERSION RADIOISOTOPES; IODINE ISOTOPES; ISOTOPES; LABELLED COMPOUNDS; MEMBRANE PROTEINS; NERVOUS SYSTEM; NUCLEI; ODD-EVEN NUCLEI; ORGANIC COMPOUNDS; ORGANIC NITROGEN COMPOUNDS; ORGANS; PROTEINS; RADIOISOTOPES; SYNTHESIS; TOMOGRAPHY; 400703* - Radiochemistry & Nuclear Chemistry- Radioisotope Production; 550601 - Medicine- Unsealed Radionuclides in Diagnostics; 560160 - Radionuclide Effects, Kinetics, & Toxicology

Citation Formats

Gitler, M S, Cohen, V I, De La Cruz, R, Boulay, S F, Jin, B, Zeeberg, B R, and Reba, R C. A novel muscarinic receptor ligand which penetrates the blood brain barrier and displays in vivo selectivity for the m2 subtype. United States: N. p., 1993. Web. doi:10.1016/0024-3205(93)90161-U.
Gitler, M S, Cohen, V I, De La Cruz, R, Boulay, S F, Jin, B, Zeeberg, B R, & Reba, R C. A novel muscarinic receptor ligand which penetrates the blood brain barrier and displays in vivo selectivity for the m2 subtype. United States. https://doi.org/10.1016/0024-3205(93)90161-U
Gitler, M S, Cohen, V I, De La Cruz, R, Boulay, S F, Jin, B, Zeeberg, B R, and Reba, R C. 1993. "A novel muscarinic receptor ligand which penetrates the blood brain barrier and displays in vivo selectivity for the m2 subtype". United States. https://doi.org/10.1016/0024-3205(93)90161-U.
@article{osti_5444740,
title = {A novel muscarinic receptor ligand which penetrates the blood brain barrier and displays in vivo selectivity for the m2 subtype},
author = {Gitler, M S and Cohen, V I and De La Cruz, R and Boulay, S F and Jin, B and Zeeberg, B R and Reba, R C},
abstractNote = {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, the authors 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 [[sup 3]H](R)-3-quinuclidinylbenzilate ([[sup 3]H]QNB) and [[sup 3]H]N-methylscopolamine ([[sup 3]H]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)-[[sup 125]I]IQNB indicate that DIBD crosses the blood brain barrier (BBB). The relationship of the regional percentage decrease in (R,R)-[[sup 125]I]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. The authors 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.},
doi = {10.1016/0024-3205(93)90161-U},
url = {https://www.osti.gov/biblio/5444740}, journal = {Life Sciences; (United States)},
issn = {0024-3205},
number = ,
volume = 53:23,
place = {United States},
year = {Fri Jan 01 00:00:00 EST 1993},
month = {Fri Jan 01 00:00:00 EST 1993}
}