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
Dw. Mcpherson et al., 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, Journal of medicinal chemistry, 38(20), 1995, pp. 3908-3917
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.