3-alpha-Chlorimperialine: an M2-selective muscarinic receptor antagonist that penetrates into brain.
Muscarinic M2 receptors have been found to be severely depleted in post-mortem brains of Alzheimer's patients. This loss of receptor may represent a useful diagnostic marker, if it could be quantitatively imaged with single-photon emission computed tomography (SPECT) or positron emission tomography (PET) imaging. In order to develop a radioligand with selectivity for muscarinic M2 receptors, we now report that 3-alpha-chlorimperialine is a potent M2 receptor antagonist with a Ki of 0.32 nM at M2 receptors, a 12-fold selectivity for M2 over M1 receptors, and a 5-fold selectivity for M2 over M4 receptors. Furthermore, 2% of the injected dose of 3-alpha-chlorimperialine per gram tissue penetrates into brain within 30 min, then washes out gradually. Taken together, these studies demonstrate that 3-alpha-chlorimperialine is a potent M2-selective muscarinic antagonist that penetrates into brain and may be a useful substrate for radioiodination and subsequent imaging of brain muscarinic M2 receptors.
Baumgold
J
J
Department of Radiology, George Washington University Medical Center, Washington, DC 20037.
Pryzbyc
R L
RL
Reba
R C
RC
D000818:Animals; D001667:Binding, Competitive; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism*; D016466:CHO Cells; D002595:Cevanes / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D006224:Cricetinae; D008297:Male; D051379:Mice; D018727:Muscarinic Antagonists; D019832:N-Methylscopolamine; D011976:Receptors, Muscarinic / Q000378:metabolism; D012602:Scopolamine Derivatives / Q000378:metabolism; D013237:Stereoisomerism; D014316:Tritium
D002595:Cevanes; D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic; D012602:Scopolamine Derivatives; D014316:Tritium; C086741:3-chlorimperialine; C047331:peiminine; D019832:N-Methylscopolamine