Choi SR, Golding G, Zhuang Z, et al. Preclinical properties of 18F-AV-45: a PET agent for Abeta plaques in the brain

Avid Radiopharmaceutical Inc., Philadelphia, Pennsylvania, USA.
Journal of Nuclear Medicine (Impact Factor: 6.16). 11/2009; 50(11):1887-94. DOI: 10.2967/jnumed.109.065284
Source: PubMed


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.

    • "Table-1 summarizes some of these agents and their relative binding affinities with respect to PIB. The four fluorinated agents florbetaben, florbetapir, flutemeatmol and NAV4694 had relative binding of 0.4, 0.3, 1.1 and 0.4 respectively with respect to PIB, suggesting that only flutemetamol has a slightly higher affinity than PIB (0.74 nM versus 0.80 nM,Choi et al., 2009). The affinity of TAZA was found to be approx. "
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    ABSTRACT: Objective: Alzheimer's disease (AD) is a neurodegenerative disease characterized by Aβ plaques in the brain. The aim of this study was to evaluate the effectiveness of a novel radiotracer, 4-[(11) C]methylamino-4'-N,N-dimethylaminoazobenzene ([(11) C]TAZA), for binding to Aβ plaques in postmortem human brain (AD and normal control (NC)). Methods: Radiosyntheses of [(11) C]TAZA, related [(11) C]Dalene ((11) C-methylamino-4'-dimethylaminostyrylbenzene) and reference [(11) C]PIB were carried out by using [(11) C]methyltriflate prepared from [(11) C]CO2 and purified using HPLC. In vitro binding affinities were carried out in human AD brain homogenate with Aβ plaques labeled with [(3) H]PIB. In vitro autoradiography studies with the three radiotracers were performed on of hippocampus of AD and NC brains. PET/CT studies were carried out in normal rats to study brain and whole body distribution. Results: The 3 radiotracers were produced in high radiochemical yields (>40%) and had specific activities >37 GBq/μmol. TAZA had an affinity, Ki= 0.84 nM and was to be 5 times more potent than PIB. [(11) C]TAZA bound specifically to Aβ plaques present in AD brains with grey matter to white matter ratios >20. [(11) C]TAZA was displaced by PIB (>90%), suggesting similar binding site for [(11) C]TAZA and [(11) C]PIB. [(11) C]TAZA exhibited slow kinetics of uptake in the rat brain and whole body images showed uptake in interscapular brown adipose tissue (IBAT). Binding in brain and IBAT were affected by pre-injection of atomoxetine, a norepinephrine transporter blocker. Conclusion: [(11) C]TAZA exhibited high binding to Aβ plaques in human AD hippocampus. Rat brain kinetics were slow and peripheral binding to IBAT needs to be further evaluated. This article is protected by copyright. All rights reserved.
    No preview · Article · Jan 2016 · Synapse
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    • "Therefore, amyloid-b imaging agents for PET or single photon emission computed tomography (SPECT) that can detect amyloid-b plaques in vivo may not only assist with the early and accurate diagnosis of Alzheimer's disease but may also play an important role in the development of anti-amyloid-b therapies by identifying subjects with amyloid-b plaques in the brain and monitoring their treatment response. Over the past few years, three such amyloid-b imaging agents for PET [ 18 F-florbetapir (Choi et al., 2009; Clark et al., 2011), 18 F-flutemetamol (Nelissen et al., 2009; Vandenberghe et al., 2010), and 18 F-florbetaben (Rowe et al., 2008; Barthel et al., 2011)] have been approved by the United States Food and Drug Administration and the European Medicines Agency as radioactive diagnostic agents to estimate amyloid-b neuritic plaque density in adults being evaluated for Alzheimer's disease and dementia . On the other hand, there has been a lack of SPECT ligands available for the clinical diagnosis of Alzheimer's disease. "
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    ABSTRACT: Non-invasive imaging of amyloid-β in the brain, a hallmark of Alzheimer's disease, may support earlier and more accurate diagnosis of the disease. In this study, we assessed the novel single photon emission computed tomography tracer (123)I-ABC577 as a potential imaging biomarker for amyloid-β in the brain. The radio-iodinated imidazopyridine derivative (123)I-ABC577 was designed as a candidate for a novel amyloid-β imaging agent. The binding affinity of (123)I-ABC577 for amyloid-β was evaluated by saturation binding assay and in vitro autoradiography using post-mortem Alzheimer's disease brain tissue. Biodistribution experiments using normal rats were performed to evaluate the biokinetics of (123)I-ABC577. Furthermore, to validate (123)I-ABC577 as a biomarker for Alzheimer's disease, we performed a clinical study to compare the brain uptake of (123)I-ABC577 in three patients with Alzheimer's disease and three healthy control subjects. (123)I-ABC577 binding was quantified by use of the standardized uptake value ratio, which was calculated for the cortex using the cerebellum as a reference region. Standardized uptake value ratio images were visually scored as positive or negative. As a result, (123)I-ABC577 showed high binding affinity for amyloid-β and desirable pharmacokinetics in the preclinical studies. In the clinical study, (123)I-ABC577 was an effective marker for discriminating patients with Alzheimer's disease from healthy control subjects based on visual images or the ratio of cortical-to-cerebellar binding. In patients with Alzheimer's disease, (123)I-ABC577 demonstrated clear retention in cortical regions known to accumulate amyloid, such as the frontal cortex, temporal cortex, and posterior cingulate. In contrast, less, more diffuse, and non-specific uptake without localization to these key regions was observed in healthy controls. At 150 min after injection, the cortical standardized uptake value ratio increased by ∼60% in patients with Alzheimer's disease relative to healthy control subjects. Both healthy control subjects and patients with Alzheimer's disease showed minimal (123)I-ABC577 retention in the white matter. These observations indicate that (123)I-ABC577 may be a useful single photon emission computed tomography imaging maker to identify amyloid-β in the human brain. The availability of an amyloid-β tracer for single photon emission computed tomography might increase the accessibility of diagnostic imaging for Alzheimer's disease.
    Full-text · Article · Oct 2015 · Brain
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    • "Several other amyloid tracers were developed: 2- (1-6-[(2-[F]Fluoroethyl)(methyl)amino]-2-naphthyl ethylidene)malononitrile ([ 18 F]FDDNP) [48], [ 11 C]AZD2184 [49], [ 11 C]SB-13 [50], [ 18 F]BAY94- 9172 [51], and [ 18 F]AmyvidTM [52]. Contrary, it was shown in APP transgenic mice that A plaques were only marginally captured by PET imaging [53] [54]. "
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    ABSTRACT: Current therapies for Alzheimer's disease (AD) offer partial symptomatic relief and do not modify disease progression. There is substantial evidence indicating a disease onset years before clinical diagnosis, at which point no effective therapy has been found. In this study, we investigated the efficacy of a new multi-target drug, M30, at relatively early stages of the AD-like amyloid pathology in a robust rat transgenic model. McGill-R-Thy1-APP transgenic rats develop the full AD-like amyloid pathology in a progressive fashion, and have a minimal genetic burden. McGill rats were given 5 mg/kg M30 or vehicle per os, every 2 days for 4 months, starting at a stage where the transgenic animals suffer detectable cognitive impairments. At the completion of the treatment, cognitive functions were assessed with Novel Object Location and Novel Object Recognition tests. The brains were then analyzed to assess amyloid-β (Aβ) burden and the levels of key inflammatory markers. Longterm treatment with M30 was associated with both the prevention and the reversal of transgene-related cognitive decline. The effects on cognition were accompanied by a shift of the Aβ-immunoreactive material toward an amyloid plaque aggregated molecular form, diminished molecular signs of CNS inflammation and a change in microglia morphology toward a surveying phenotype. This study is the first to demonstrate the therapeutic potential of M30 in a rat model of the AD amyloid pathology. It provides a rationale for further investigations with M30 and with potential multi-target approaches to delay, prevent or reverse the progression the AD pathology at early disease-stages.
    Full-text · Article · Jul 2015 · Journal of Alzheimer's disease: JAD
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