Resolution and in vitro and initial in vivo evaluation of isomers of iodine-125-labeled 1-azabicyclo[2.2.2]oct-3-yl alpha-hydroxy-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 alpha-hydroxy-alpha-(1-iodo-1-propen-3-yl)- alpha-phenylacetate (IQNP, 1), is a highly selective ligand for the muscarinic acetylcholinergic receptor (mAChR). There are eight stereoisomers in the racemic mixture. The optical isomers of alpha-hydroxy-alpha-phenyl-alpha-(1-propyn-3-yl)acetic acid were resolved as the alpha-methylbenzylamine salts, and the optical isomers of 3-quinuclidinol were resolved as the tartrate salts. The E and Z isomers were prepared by varying the reaction conditions for the stannylation of the triple bond followed by purification utilizing flash column chromatography. In vitro binding assay of the four stereoisomers containing the (R)-(-)-3-quinuclidinyl ester demonstrated that each isomer of 1 bound to mAChR with high affinity. In addition, (E)-(-)-(-)-IQNP demonstrated the highest receptor subtype specificity between the m1 molecular subtype (KD, nM, 0.383 +/- 0.102) and the m2 molecular subtype (29.6 +/- 9.70). In vivo biodistribution studies demonstrated that iodine-125-labeled (E)-(-)-(+)-1 cleared rapidly from the brain and heart. In contrast, iodine-125-labeled (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 with retention in M1 (m1, m4) mAChR areas of the rain. In addition, (Z)-(-)-(-)-IQNP also demonstrated significant uptake in tissues containing the M2 (m2) mAChR subtype. These results demonstrate that the iodine-123-labeled analogues of the (E)-(-)-(-)- and (Z)-(-)-(-)-IQNP isomers are attractive candidates for single-photon emission-computed tomographic imaging of cerebral and cardiac mAChR receptor densities.
McPherson
D W
DW
Health Sciences Research Division, Oak Ridge National Laboratory (ORNL), Tennessee 37831-6229, USA.
Lambert
C R
CR
Jahn
K
K
Sood
V
V
McRee
R C
RC
Zeeberg
B
B
Reba
R C
RC
Knapp
F F
FF
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D005260:Female; D007457:Iodine Radioisotopes; D008024:Ligands; D018727:Muscarinic Antagonists / Q000378:metabolism*; D011812:Quinuclidines / Q000378:metabolism*; D051381:Rats; D011976:Receptors, Muscarinic / Q000032:analysis / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon
D007457:Iodine Radioisotopes; D008024:Ligands; D018727:Muscarinic Antagonists; D011812:Quinuclidines; D011976:Receptors, Muscarinic; C080526:1-azabicyclo(2.2.2)oct-3-yl 2-hydroxy-2-(1-iodo-1-propen-3-yl)-2-phenylacetate