RESOLUTION AND IN-VITRO AND INITIAL IN-VIVO EVALUATION OF ISOMERS OF IODINE-125-LABELED 1-AZABICYCLO[2.2.2]OCT-3-YL Y-ALPHA-(1-IODO-1-PROPEN-3-YL)-ALPHA-PHENYLACETATE - A HIGH-AFFINITY LIGAND FOR THE MUSCARINIC RECEPTOR

1-Azabicyclo[2.2.2]oct-3-yl y-alpha-(1-iodo-1-propen-3-yl)-alpha-pheny lacetate (IQNP, 1), is a highly selective ligand for the muscarinic ac etylcholinergic receptor (mAChR). There are eight stereoisomers in the racemic mixture. The optical isomers of a-hydroxy-alpha-phenyl-alpha- (1-propyn-3-yl)acetic acid were resolved as the alpha-methylbenzylamin e salts, and the optical isomers of 3-quinuclidinol were resolved as t he tartrate salts. The E and Z isomers were prepared by varying the re action conditions for the stannylation of the triple bond followed by purification utilizing flash column chromatography. In vitro binding a ssay of the four stereoisomers containing the (R)-(-)-3-quinuclidinyl ester demonstrated that each isomer of 1 bound to mAChR with high affi nity. In addition, (E)-(-)-(-)-IQNP demonstrated the highest receptor subtype specificity between the ml molecular subtype (K-D, nM, 0.383 /- 0.102) and the m2 molecular subtype (29.6 +/- 9.70). In vivo biodis tribution studies demonstrated that iodine-125-labeled (E)-(-)-(+)-1 c leared rapidly from the brain and heart. In contrast, iodine-125-label ed (E)-(-)-(-)-, (Z)-(-)-(-)-, and (Z)-(-)-(+)-1 have high uptake and retention in mAChR rich areas of the brain. It was also observed that( E)-(-)-(-)-IQNP demonstrated an apparent subtype selectivity in vivo w ith retention in M(1) (m1, m4) mAChR areas of the rain. In addition, ( Z)-(-)-(-)-IQNP also demonstrated significant uptake in tissues contai ning the M(2) (m2) mAChR subtype. These results demonstrate that the i odine-123-labeled analogues of the (E)-(-)-(-)- and (Z)-(-)-(-)-IQNP i somers are attractive candidates for single-photon emission-computed t omographic imaging of cerebral and cardiac mAChR receptor densities.