title: PET study of the M1-agonists [11C]xanomeline and [11C]butylthio-TZTP in monkey and man.
abstract: Xanomeline, a substituted TZTP, is a new M1 selective muscarinic agonist in clinical trials for Alzheimer's disease. The brain uptake of [11C]xanomeline and the analog [11C]butylthio-TZTP was examined by positron emission tomography (PET). Radioactivity accumulated most markedly in the neocortex and the striatum. Pharmacological characterization in vitro and in cynomolgus monkeys in vivo by PET indicated specific [11C]butylthio-TZTP binding to muscarinic receptors and to sigma-1 recognition sites. More than 5% of the radioactivity was in the human brain 5 min after i.v. injection of [11C]xamomeline or [11C]butylthio-TZTP. This high brain uptake may be clinically advantageous in the sense that substituted TZTP may induce central muscarinic agonist effects at a dose level for which there is a low risk of peripheral side-effects.
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Farde
authors.forename: T
authors.initials: T
authors.lastname: Suhara
authors.forename: C
authors.initials: C
authors.lastname: Halldin
authors.forename: H
authors.initials: H
authors.lastname: Nybäck
authors.forename: Y
authors.initials: Y
authors.lastname: Nakashima
authors.forename: C G
authors.initials: CG
authors.lastname: Swahn
authors.forename: P
authors.initials: P
authors.lastname: Karlsson
authors.forename: N
authors.initials: N
authors.lastname: Ginovart
authors.forename: F P
authors.initials: FP
authors.lastname: Bymaster
authors.forename: H E
authors.initials: HE
authors.lastname: Shannon
authors.forename: C
authors.initials: C
authors.lastname: Foged
authors.forename: P D
authors.initials: PD
authors.lastname: Suzdak
authors.forename: P
authors.initials: P
authors.lastname: Sauerberg
mesh_terms: D000328:Adult; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D018721:Muscarinic Agonists / Q000493:pharmacokinetics*; D011725:Pyridines / Q000493:pharmacokinetics*; D011976:Receptors, Muscarinic / Q000378:metabolism; D017480:Receptors, sigma / Q000378:metabolism; D013045:Species Specificity; D013830:Thiadiazoles / Q000493:pharmacokinetics*; D014055:Tomography, Emission-Computed; D014057:Tomography, X-Ray Computed
chemical_list: D018721:Muscarinic Agonists; D011725:Pyridines; D011976:Receptors, Muscarinic; D017480:Receptors, sigma; D013830:Thiadiazoles; C103291:3-(3-butylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine; C075257:xanomeline