title: Synthesis and evaluation of two 18F-labeled 6-iodo-2-(4'-N,N-dimethylamino)phenylimidazo[1,2-a]pyridine derivatives as prospective radioligands for beta-amyloid in Alzheimer's disease.
abstract: This study evaluated (18)F-labeled IMPY [6-iodo-2-(4'-N,N-dimethylamino)phenylimidazo[1,2-a]pyridine] derivatives as agents for imaging beta-amyloid plaque with positron emission tomography (PET). The precursor for radiolabeling and reference compounds was synthesized in up to five steps from commercially accessible starting materials. One of the two N-methyl groups of IMPY was substituted with either a 3-fluoropropyl (FPM-IMPY) or a 2-fluoroethyl (FEM-IMPY) group. FPM-IMPY and FEM-IMPY were found to have moderate affinity for Abeta-aggregates with K(i) = 27 +/- 8 and 40 +/- 5 nM, respectively. A "one-pot" method for (18)F-2-fluoroethylation and (18)F-3-fluoropropylation of the precursor was developed. The overall decay-corrected radiochemical yields were 26-51%. In PET experiments with normal mouse, high uptake of activity was obtained in the brain after iv injection of each probe: 6.4% ID/g for [(18)F]FEM-IMPY at 1.2 min, and 5.7% ID/g for [(18)F]FPM-IMPY at 0.8 min. These values were similar to those of [(123)I/(125)I]IMPY (7.2% ID/g at 2 min). Polar and nonpolar radioactive metabolites were observed in both plasma and brain homogenates after injection of [(18)F]FEM or [(18)F]FPM-IMPY. In contrast to the single-exponential washout of [(123)I/(125)I]IMPY, the washouts of brain activity for the two fluorinated analogues were biphasic, with an initial rapid phase over 20 min and a subsequent much slower phase. Residual brain activity at 2 h, which may represent polar metabolites trapped in the brain, was 4.5% ID/g for [(18)F]FEM-IMPY and 2.1% ID/g for [(18)F]FPM-IMPY. Substantial skull uptake of [(18)F]fluoride was also clearly observed. With a view to slow the metabolism of [(18)F]FEM-IMPY, an analogue was prepared with deuteriums substituted for the four ethyl hydrogens. However, D(4)-[(18)F]FEM-IMPY showed the same brain uptake and clearance as the protio analogue. Metabolism of the [(18)F]FEM-IMPY was appreciably slower in rhesus monkey than in mouse. Autoradiography of postmortem brain sections of human Alzheimer's disease patients with [(18)F]FEM-IMPY showed high displaceable uptake in gray matter and low nonspecific binding in the white matter. This study demonstrates that the IMPY derivatives have favorable in vivo brain pharmacokinetics and a moderate affinity for imaging beta-amyloid plaques; however, further improvements are needed to reduce radioactive metabolites, increase binding affinity, and reduce lipophilicity.
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, 10 Center Drive, Bethesda, Maryland 20892, USA. cail@intra.nimh.nih.gov
authors.forename: Lisheng
authors.initials: L
authors.lastname: Cai
authors.forename: Frederick T
authors.initials: FT
authors.lastname: Chin
authors.forename: Victor W
authors.initials: VW
authors.lastname: Pike
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Toyama
authors.forename: Jeih-San
authors.initials: JS
authors.lastname: Liow
authors.forename: Sami S
authors.initials: SS
authors.lastname: Zoghbi
authors.forename: Kendra
authors.initials: K
authors.lastname: Modell
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Briard
authors.forename: H Umesha
authors.initials: HU
authors.lastname: Shetty
authors.forename: Kathryn
authors.initials: K
authors.lastname: Sinclair
authors.forename: Sean
authors.initials: S
authors.lastname: Donohue
authors.forename: Dnyanesh
authors.initials: D
authors.lastname: Tipre
authors.forename: Mei-Ping
authors.initials: MP
authors.lastname: Kung
authors.forename: Claudio
authors.initials: C
authors.lastname: Dagostin
authors.forename: David A
authors.initials: DA
authors.lastname: Widdowson
authors.forename: Michael
authors.initials: M
authors.lastname: Green
authors.forename: Weiyi
authors.initials: W
authors.lastname: Gao
authors.forename: Mary M
authors.initials: MM
authors.lastname: Herman
authors.forename: Masanori
authors.initials: M
authors.lastname: Ichise
authors.forename: Robert B
authors.initials: RB
authors.lastname: Innis
mesh_terms: D000544:Alzheimer Disease / Q000000981:diagnostic imaging* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D002853:Chromatography, Liquid; D005260:Female; D005462:Fluorine Radioisotopes; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000378:metabolism; D066298:In Vitro Techniques; D007553:Isotope Labeling; D008024:Ligands; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D008875:Middle Aged; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis* / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed
chemical_list: C485228:6-iodo-2-(4'-N-(2-fluoroethyl)methylamino)phenylimidazo(1,2-a)pyridine; C485229:6-iodo-2-(4'-N-(2-fluoropropyl)methylamino)phenylimidazo(1,2-a)pyridine; D016229:Amyloid beta-Peptides; D005462:Fluorine Radioisotopes; D007093:Imidazoles; D008024:Ligands; D010446:Peptide Fragments; D011725:Pyridines; C078592:amyloid beta-protein (1-40)