A novel muscarinic receptor ligand which penetrates the blood brain barrier and displays in vivo selectivity for the m2 subtype

Journal Article · Fri Jan 01 00:00:00 EST 1993 · Life Sciences; (United States)

DOI:https://doi.org/10.1016/0024-3205(93)90161-U· OSTI ID:5444740

Gitler, M S; Cohen, V I; De La Cruz, R; Boulay, S F; Jin, B; Zeeberg, B R ^[1]; Reba, R C ^[2]

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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)

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.

• DOE Contract Number: FG05-88ER60649
• OSTI ID: 5444740
• Journal Information: Life Sciences; (United States), Vol. 53:23; ISSN 0024-3205
• Country of Publication: United States
• Language: English

Related Subjects

38 RADIATION CHEMISTRY, RADIOCHEMISTRY, AND NUCLEAR CHEMISTRY
62 RADIOLOGY AND NUCLEAR MEDICINE
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BRAIN
EMISSION COMPUTED TOMOGRAPHY
RADIOPHARMACEUTICALS
CHEMICAL PREPARATION
RECEPTORS
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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
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TOMOGRAPHY
400703* - Radiochemistry & Nuclear Chemistry- Radioisotope Production
550601 - Medicine- Unsealed Radionuclides in Diagnostics
560160 - Radionuclide Effects
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