title: Synthesis and evaluation of N-methyl and S-methyl 11C-labeled 6-methylthio-2-(4'-N,N-dimethylamino)phenylimidazo[1,2-a]pyridines as radioligands for imaging beta-amyloid plaques in Alzheimer's disease.
abstract: 6-Thiolato-substituted 2-(4'- N,N-dimethylamino)phenylimidazo[1,2- a]pyridines ( RS-IMPYs; 1- 4) were synthesized as candidates for labeling with carbon-11 ( t 1/2 = 20.4 min) and imaging of A beta plaques in living human brain using positron emission tomography (PET). K i values for binding of these ligands to Alzheimer's disease brain homogenates were measured in vitro against tritium-labeled 6 (Pittsburgh compound B). MeS-IMPY ( 3, K i = 7.93 nM) was labeled with carbon-11 at its S- or N-methyl position to give [ (11)C] 7 or [ (11)C] 8, respectively. After injection into rats, [ (11)C] 7 or [ (11)C] 8 gave moderately high brain uptakes of radioactivity followed by rapid washout to low levels. The ratio of radioactivity at maximal uptake to that at 60 min reached 18.7 for [ (11)C] 7. [ (11)C] 7 behaved similarly in mouse and monkey. [ (11)C] 7 also bound selectively to A beta plaques in post mortem human Alzheimer's disease brain. Although rapidly metabolized in rat by N-demethylation, [ (11)C] 7 was stable in rat brain homogenates. The ex vivo brain radiometabolites observed in rats have a peripheral origin. Overall, [ (11)C] 7 merits further evaluation in human subjects.
authors: Molecular Imaging Branch and Clinical Brain Disorders Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, USA. cail@intra.nimh.nih.gov
authors: Lisheng
authors: L
authors: Cai
authors: Jeih-San
authors: JS
authors: Liow
authors: Sami S
authors: SS
authors: Zoghbi
authors: Jessica
authors: J
authors: Cuevas
authors: Cesar
authors: C
authors: Baetas
authors: Jinsoo
authors: J
authors: Hong
authors: H Umesha
authors: HU
authors: Shetty
authors: Nicholas M
authors: NM
authors: Seneca
authors: Amira K
authors: AK
authors: Brown
authors: Robert
authors: R
authors: Gladding
authors: Sebastian S
authors: SS
authors: Temme
authors: Mary M
authors: MM
authors: Herman
authors: Robert B
authors: RB
authors: Innis
authors: Victor W
authors: VW
authors: Pike
mesh_terms: D000544:Alzheimer Disease / Q000000981:diagnostic imaging / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D002250:Carbon Radioisotopes; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D049268:Positron-Emission Tomography; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D014018:Tissue Distribution
chemical_list: D016229:Amyloid beta-Peptides; D002250:Carbon Radioisotopes; D007093:Imidazoles; D011725:Pyridines; D019275:Radiopharmaceuticals