A NOVEL MUSCARINIC RECEPTOR-LIGAND WHICH PENETRATES THE BLOOD-BRAIN-BARRIER AND DISPLAYS IN-VIVO SELECTIVITY FOR THE M2 SUBTYPE

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.