Ms. Gitler et al., A NOVEL MUSCARINIC RECEPTOR-LIGAND WHICH PENETRATES THE BLOOD-BRAIN-BARRIER AND DISPLAYS IN-VIVO SELECTIVITY FOR THE M2 SUBTYPE, Life sciences, 53(23), 1993, pp. 1743-1751
Alzheimer's disease (AD) involves selective loss of muscarinic m2, but
not ml, subtype neuroreceptors in the posterior parietal cortex of th
e 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-s
elective radioligand which can penetrate the blood-brain barrier. In o
ur efforts to prepare such a radioligand, we have used competition stu
dies against currently existing muscarinic receptor radioligands to in
fer the in vitro and in vivo properties of a novel muscarinic receptor
ligand, o)butyl]-1-phenyl]acetyl]-10,11-dihydro-5H-dibenzo [b,e][1,4]
diazepin-11-one (DIBD). In vitro competition studies against [H-3](R)-
3-quinuclidinylbenzilate ([H-3]QNB) and [H-3]N-methylscopolamine ([H-3
]NMS), using membranes derived from transfected cells expressing only
ml, m2, m3, or m4 receptor subtypes, indicate that DIBD is selective f
or m2/m4 over ml/m3. In vivo competition studies against (R,R)-[I-125]
IQNB indicate that DIBD crosses the blood brain barrier (BBB). The rel
ationship of the regional percentage decrease in (R,R)-[I-125]IQNB ver
sus the percentage of each of the receptor subtypes indicates that DIB
D competes more effectively in those brain regions which are known to
be enriched in the m2, relative to the ml, m3, and m4, receptor subtyp
e; however, analysis of the data using a mathematical model shows that
caution is required when interpreting the in vivo results. We conclud
e that a suitably radiolabeled derivative of DIBD may be of potential
use in emission tomographic study of changes in m2 receptors in the ce
ntral nervous system.