3-ALPHA-CHLORIMPERIALINE - AN M(2)-SELECTIVE MUSCARINIC RECEPTOR ANTAGONIST THAT PENETRATES INTO BRAIN

Muscarinic M(2) 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 M(2) receptors, we now report that 3-alpha-chlorimperialine is a potent M(2) receptor antagonist with a K-i of 0.32 nM at M(2) receptors, a 12-fold selectivity for M(2) over M(1) receptors, and a 5-fold selectivity for M(2) over M(4) 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 M(2)-selective muscarinic antagonist that penetrates into brain and may be a useful substrate for radioiodination and subsequent imaging of brain muscarinic M(2) receptors.