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

• Published in: Journal of medicinal chemistry Vol. 38; no. 20; pp. 3908 - 3917
• Main Authors: McPherson, Daniel W, Lambert, Carla R, Jahn, Kristi, Sood, Virendar, McRee, Robert C, Zeeberg, Barry, Reba, Richard C, Knapp, Furn F
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 29.09.1995; Amer Chemical Soc
• Subjects: Animals; Biological and medical sciences; Chemistry; Chemistry, Medicinal; CHO Cells; Cholinergic system; Cricetinae; Exact sciences and technology; Female; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Iodine Radioisotopes; Life Sciences & Biomedicine; Ligands; Medical sciences; Muscarinic Antagonists - metabolism; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Organic chemistry; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Preparations and properties; Quinuclidines - metabolism; Rats; Receptors, Muscarinic - analysis; Receptors, Muscarinic - metabolism; Science & Technology; Stereoisomerism; Structure-Activity Relationship; Tissue Distribution; Tomography, Emission-Computed, Single-Photon; ACETYLCHOLINE-RECEPTORS; ALZHEIMERS-DISEASE; HUMAN-BRAIN; RAT-BRAIN; 3-QUINUCLIDINYL BENZILATE; POTENTIAL RADIOPHARMACEUTICALS; CHOLINERGIC RECEPTOR; BINDING; EMISSION COMPUTED-TOMOGRAPHY; OPTICAL ISOMERS; Stereoisomer; Intravenous administration; Hydroxyester; Rat; Angular nitrogen heterocycle; Ligand; Tissue; Cholinergic receptor; Tertiary alcohol; Bicyclic compound; Chemical synthesis; Radiolabelling; Aliphatic compound; Rodentia; Iodine Isotopes; In vitro; Biological activity; CHO cell line; In vivo; Vertebrata; Biological fixation; Mammalia; Optical resolution; Animal; Distribution; Affinity; Benzenic compound; Muscarinic receptor; Pharmacokinetics; Ethylenic compound
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00020a004

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 ml molecular subtype (K-D, 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 M(1) (m1, m4) mAChR areas of the rain. In addition, (Z)-(-)-(-)-IQNP also demonstrated significant uptake in tissues containing the M(2) (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.