title: Iodine-123 labelled Z-(R,R)-IQNP: a potential radioligand for visualization of M(1 )and M(2) muscarinic acetylcholine receptors in Alzheimer's disease.
abstract: Z-(R)-1-Azabicyclo[2.2.2]oct-3-yl (R)-alpha-hydroxy-alpha-(1-iodo-1-propen-3-yl)-alpha-phenylacetate (Z-IQNP) has high affinity to the M(1 )and M(2) muscarinic acetylcholine receptor (mAChR) subtypes according to previous in vitro and in vivo studies in rats. In the present study iodine-123 labelled Z-IQNP was prepared for in vivo single-photon emission tomography (SPET) studies in cynomolgus monkeys. SPET studies with Z-[(123)I]IQNP demonstrated high accumulation in monkey brain (>5% of injected dose at 70 min p.i.) and marked accumulation in brain regions such as the thalamus, the neocortex, the striatum and the cerebellum. Pretreatment with the non-selective mAChR antagonist scopolamine (0.2 mg/kg) inhibited Z-[(123)I]IQNP binding in all these regions. The percentage of unchanged Z-[(123)I]IQNP measured in plasma was less than 10% at 10 min after injection, which may be due to rapid hydrolysis, as has been demonstrated previously with the E-isomer of IQNP. Z-[(123)I]IQNP showed higher uptake in M(2)-rich regions, compared with previously obtained results with E-[(123)I]IQNP. In conclusion, the radioactivity distribution from Z-[(123)I]IQNP in monkey brain indicates that Z-[(123)I]IQNP binds to the M(1)- and M(2)-rich areas and provides a high signal for specific binding, and is thus a potential ligand for mAChR imaging with SPET.
authors.affiliation: Department of Clinical Neuroscience, Psychiatry and Nuclear Medicine Sections, Karolinska Institutet, Karolinska Hospital, Stockholm, Sweden.
authors.forename: K A
authors.initials: KA
authors.lastname: Bergström
authors.forename: C
authors.initials: C
authors.lastname: Halldin
authors.forename: A
authors.initials: A
authors.lastname: Savonen
authors.forename: Y
authors.initials: Y
authors.lastname: Okubo
authors.forename: J
authors.initials: J
authors.lastname: Hiltunen
authors.forename: K
authors.initials: K
authors.lastname: Nobuhara
authors.forename: C G
authors.initials: CG
authors.lastname: Swahn
authors.forename: P
authors.initials: P
authors.lastname: Karlsson
authors.forename: D
authors.initials: D
authors.lastname: McPherson
authors.forename: F F
authors.initials: FF
authors.lastname: Knapp
authors.forename: S
authors.initials: S
authors.lastname: Larsson
authors.forename: P O
authors.initials: PO
authors.lastname: Schnell
authors.forename: L
authors.initials: L
authors.lastname: Farde
mesh_terms: D000544:Alzheimer Disease / Q000000981:diagnostic imaging*; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging*; D007457:Iodine Radioisotopes; D008024:Ligands; D008252:Macaca fascicularis; D008297:Male; D018727:Muscarinic Antagonists; D011812:Quinuclidines; D011976:Receptors, Muscarinic / Q000032:analysis*; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: 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