title: Radiosynthesis of the candidate beta-amyloid radioligand [(11)C]AZD2184: Positron emission tomography examination and metabolite analysis in cynomolgus monkeys.
abstract: Beta-amyloid accumulation is associated with the pathogenesis of Alzheimer's disease (AD). AZD2184, a new radioligand for high-contrast positron emission tomography (PET) imaging of Abeta-deposits, has recently been developed and characterized in vitro and in rodents ex vivo. The objective of this study was to label AZD2184 with carbon-11, to perform in vivo characterization of [(11)C]AZD2184 ([(11)C]5) in the cynomolgus monkey brain as well as whole-body dosimetry, and to examine the metabolism of the labeled radioligand. [(11)C]5 was prepared by a two-step radiosynthesis starting with the reaction of 5-(6-(tert-butyldimethylsilyloxy)benzo[d]thiazol-2-yl)pyridin-2-amine with [(11)C]methyl iodide followed by deprotection using water. Four brain PET measurements in two cynomolgus monkeys and one whole-body PET measurement were performed with [(11)C]5. There was a high and rapid brain uptake (2.2-3.4% of injected dose at 2 min). The distribution of brain radioactivity was fairly uniform, with early to late-brain concentration ratios (peak vs. 60 min) higher for [(11)C]5 than ratios previously reported for [(11)C]PIB (8.2 and 4.6, respectively). Based on the whole-body data, it was estimated that an effective dose in an adult male would be 6.2 muSv/MBq and thus would be safe from a radiation point of view for multiple scans within the same year. [(11)C]5 shows binding characteristics, suggesting low levels of white-matter retention, and may thus provide improved contrast when compared with currently used PET radioligands for visualization of Abeta-deposits. On the basis of the labeling chemistry and the results of the biological evaluation, we conclude that [(11)C]5 should be useful for routine clinical studies.
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden. j.d.andersson@ki.se
authors.forename: Jan D
authors.initials: JD
authors.lastname: Andersson
authors.forename: Katarina
authors.initials: K
authors.lastname: Varnäs
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Cselényi
authors.forename: Balázs
authors.initials: B
authors.lastname: Gulyás
authors.forename: David
authors.initials: D
authors.lastname: Wensbo
authors.forename: Sjoerd J
authors.initials: SJ
authors.lastname: Finnema
authors.forename: Britt-Marie
authors.initials: BM
authors.lastname: Swahn
authors.forename: Samuel
authors.initials: S
authors.lastname: Svensson
authors.forename: Svante
authors.initials: S
authors.lastname: Nyberg
authors.forename: Lars
authors.initials: L
authors.lastname: Farde
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
mesh_terms: D000631:Aminopyridines / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D052160:Benzothiazoles / Q000737:chemistry / Q000378:metabolism*; D001921:Brain / Q000033:anatomy & histology / Q000000981:diagnostic imaging* / Q000378:metabolism*; D002250:Carbon Radioisotopes / Q000737:chemistry / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D021621:Imaging, Three-Dimensional / Q000379:methods; D008252:Macaca fascicularis / Q000033:anatomy & histology / Q000378:metabolism*; D013058:Mass Spectrometry; D049268:Positron-Emission Tomography; D011854:Radiochemistry / Q000379:methods; D051598:Whole Body Imaging / Q000379:methods
chemical_list: C539976:2-(6-(methylamino)pyridin-3-yl)-1,3-benzothiazol-6-ol; D000631:Aminopyridines; D052160:Benzothiazoles; D002250:Carbon Radioisotopes