Nuclear Medicine Program progress report for quarter ending September 30, 1994

In this report we describe the synthesis of the Z (cis) isomers of R-l-azabicyclo [2.2.2] oct-3-yl R-and S-{alpha}-hydroxy-{alpha}-(liodo-l-propen-3-yl) - {alpha}-phenylacetate. We also report the results of the in vitro binding assays of the E and Z isomers of the (R, R)- and (R, S)-isomers of IQNP. The Z isomers of IQNP were prepared by there action of (R, R)- or (R, S)-l-azabicyclo [2.2.2] oct-3-yl - {alpha} - hydroxy - {alpha} - phenyl - {alpha} - (l-propyn-3-yl) acetate with tributyltin hydride in HMPA followed by subsequent reaction of the cis tributylstannyl substrate with iodine. In an attempt to increase the yield of the Z isomers, the preparation of the Z isomers of the R-or S-ethyl {alpha}-hydroxy-{alpha}-phenyl-{alpha}-(l-propyn-3-yl)acetate was also investigated under a variety of reaction conditions. Results of the in vitro binding assays demonstrated that although all the isomers showed high affinity for the muscarinic receptor, the E-(R, R)-IQNP isomer had a 100 times greater higher affinity for m{sub 1} and m{sub 3} receptor subtypes as compared to m{sub 2} subtype. We are currently evaluating the in vivo biodistribution properties and pharmocokinetic and autoradiographic analyses of these promising new ligands in detail for potential use of the iodine-123-labeled agents to study muscarinicmore » receptors by Single Photon Emission Computed Tomography (SPECT).« less