ABSTRACT
Florbetapir F-18 is a molecular imaging agent combining high affinity for ß-amyloid, pharmacokinetic properties that allow positron emission tomography (PET) imaging within a convenient time after dose administration, and the wide availability of the radionuclide fluorine-18. Florbetapir F-18 is prepared by nucleophilic radiofluorination in approximately 60 minutes with a decay-corrected yield of 20%-40% and with a specific activity typically exceeding 100 Ci/mmol. The florbetapir F-18 dissociation constant (K(d)) for binding to ß-amyloid in brain tissue from Alzheimer's disease (AD) patients was 3.7 ± 0.3 nmol/L, and the maximum binding capacity (B(max)) was 8800 ± 1600 fmol/mg protein. Autoradiography studies have shown that florbetapir F-18 selectively binds to ß-amyloid aggregates in AD patient brain tissue, and the binding intensity is correlated with the density of ß-amyloid quantified by standard neuropathologic techniques. Studies in animals revealed no safety concerns and rapid and transient normal brain uptake (6.8% injected dose/g at 2 minutes and 1.9% injected dose/g at 60 minutes in the mouse). Florbetapir F-18 has been well-tolerated in studies of more than 2000 human subjects. Biodistribution studies in humans revealed predominantly hepatobiliary excretion. The whole body effective dose was 7 mSv from a dose of 370 MBq. The pharmacokinetic of florbetapir F-18 make it possible to obtain a PET image with a brief (10 minutes) acquisition time within a convenient time window of 30-90 minutes after dose administration. Clinical studies have demonstrated a clear correlation between in vivo PET imaging with florbetapir F-18 and postmortem histopathologic quantitation of ß-amyloid in the brain.
Subject(s)
Alzheimer Disease/diagnostic imaging , Amyloid beta-Peptides/metabolism , Aniline Compounds/pharmacokinetics , Cerebral Cortex/diagnostic imaging , Ethylene Glycols/pharmacokinetics , Positron-Emission Tomography/methods , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Aniline Compounds/chemistry , Animals , Cerebral Cortex/metabolism , Cerebral Cortex/pathology , Dogs , Ethylene Glycols/chemistry , Humans , Mice , Molecular Imaging , Radiopharmaceuticals/chemistry , Radiopharmaceuticals/pharmacokinetics , Rats , Tissue DistributionABSTRACT
UNLABELLED: beta-amyloid plaques (Abeta plaques) in the brain, containing predominantly fibrillary Abeta peptide aggregates, represent a defining pathologic feature of Alzheimer disease (AD). Imaging agents targeting the Abeta plaques in the living human brain are potentially valuable as biomarkers of pathogenesis processes in AD. (E)-4-(2-(6-(2-(2-(2-(18)F-fluoroethoxy)ethoxy)ethoxy)pyridin-3-yl)vinyl)-N-methyl benzenamine ((18)F-AV-45) is such as an agent currently in phase III clinical studies for PET of Abeta plaques in the brain. METHODS: In vitro binding of (18)F-AV-45 to Abeta plaques in the postmortem AD brain tissue was evaluated by in vitro binding assay and autoradiography. In vivo biodistribution of (18)F-AV-45 in mice and ex vivo autoradiography of AD transgenic mice (APPswe/PSEN1) with Abeta aggregates in the brain were performed. Small-animal PET of a monkey brain after an intravenous injection of (18)F-AV-45 was evaluated. RESULTS: (18)F-AV-45 displayed a high binding affinity and specificity to Abeta plaques (K(d), 3.72 +/- 0.30 nM). In vitro autoradiography of postmortem human brain sections showed substantial plaque labeling in AD brains and not in the control brains. Initial high brain uptake and rapid washout from the brain of healthy mice and monkey were observed. Metabolites produced in the blood of healthy mice after an intravenous injection were identified. (18)F-AV-45 displayed excellent binding affinity to Abeta plaques in the AD brain by ex vivo autoradiography in transgenic AD model mice. The results lend support that (18)F-AV-45 may be a useful PET agent for detecting Abeta plaques in the living human brain.
Subject(s)
Amyloid beta-Peptides/metabolism , Aniline Compounds/metabolism , Benzene/metabolism , Brain/diagnostic imaging , Brain/pathology , Ethylene Glycols/metabolism , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Aniline Compounds/pharmacokinetics , Animals , Autoradiography , Benzene/pharmacokinetics , Brain/metabolism , Ethylene Glycols/pharmacokinetics , Female , Haplorhini , Humans , Injections, Intravenous , Male , Mice , Mice, Transgenic , Positron-Emission Tomography , Tissue DistributionABSTRACT
We report a series of radioiodinated styrylpyridines as single photon emission computed tomography probes for imaging Abeta plaques in the brain of patients with Alzheimer's disease (AD). In vitro binding showed that all of the styrylpyridines displayed very good binding affinities in postmortem AD brain homogenates (Ki = 3.6 to 15.5 nM). No-carrier-added samples of 13a, 13b, 16a, 16b, and 16e (radioiodinated with 125I) were successfully prepared. The in vivo biodistribution in normal mice, at 2 min after injection, showed excellent initial brain penetrations (4.03, 6.22, 5.43, and 8.04% dose/g for [125I]13a, 13b, 16a, and 16b, respectively). Furthermore, in vitro autoradiography of AD brain sections showed that the high binding signal was specifically due to the presence of Abeta plaques. Taken together, these results strongly suggest that these styrylpyridines are useful for imaging Abeta plaques in the living human brain.
Subject(s)
Alzheimer Disease/diagnostic imaging , Brain/diagnostic imaging , Plaque, Amyloid/metabolism , Pyridines/chemical synthesis , Radiopharmaceuticals/chemical synthesis , Styrenes/chemical synthesis , Amyloid beta-Peptides/metabolism , Animals , Autoradiography , Binding, Competitive , Brain/metabolism , Cell Line , Humans , Iodine Radioisotopes , Male , Mice , Mice, Inbred ICR , Pyridines/chemistry , Pyridines/pharmacokinetics , Radioligand Assay , Radiopharmaceuticals/chemistry , Radiopharmaceuticals/pharmacokinetics , Structure-Activity Relationship , Styrenes/chemistry , Styrenes/pharmacokinetics , Tissue Distribution , Tomography, Emission-Computed, Single-PhotonABSTRACT
[reaction: see text] 2,5-disubstituted and 2,4,5-trisubstituted oxazol-5-yl carbonyl compounds were prepared in good yields by a mild SiO2-mediated cycloisomerization of propargyl amides.
Subject(s)
Amides/chemistry , Oxazoles/chemical synthesis , Catalysis , Combinatorial Chemistry Techniques , Cyclization , Silicon Dioxide/chemistry , StereoisomerismABSTRACT
[reaction: see text] The synthesis of stable, C-linked analogues of glycopeptides is being investigated with two complementary synthetic strategies, co-translational and post-translational glycopeptide synthesis. The key feature of the present approach lies in an effective olefin cross-metathesis reaction that allows formation of both glycoamino acids and glycopeptides.
