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.

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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.
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    • "To compare the binding affinity of [125I]IPBF to amylin aggregates with the other Aβ imaging probes reported previously, we conducted in vitro inhibition experiments using [125I]IPBF as the competing ligand. Several Aβ imaging probes with satisfactory binding properties for fibrils, including pyridylbenzofuran derivatives (IPBF15 and FPYBF-116), an arylquinoxaline derivative (PQ-6)17, 6-iodo-2-(4-N,N-dimethylamino)-phenylimidazo[1,2-a]pyridine (IMPY)18, and (E)-4-(2-(6-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)pyridin-3-yl)vinyl)-N-methylaniline (AV-45, Florbetapir)19, were chosen as the test compounds (Figure 3). The results are shown in Table 1. "
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    ABSTRACT: Islet amyloid deposition composed of amylin aggregates is regarded as one of the hallmarks of type 2 diabetes mellitus (T2DM). For the diagnosis of T2DM, several nuclear medical imaging probes have been developed. However, there have been no reports regarding the development of imaging probes targeting amylin. In this report, we investigated the feasibility of amylin imaging using [(125)I]IPBF as one of the model compounds of β-amyloid (Aβ) imaging probes. In in vitro experiments, [(125)I]IPBF exhibited high binding affinity for amylin aggregates (Kd = 8.31 nM). Moreover, autoradiographic images showed that [(125)I]IPBF specifically bound to islet amyloid composed of amylin. These results suggest the potential application of Aβ imaging probes to amylin imaging. In addition, [(125)I]IPBF is one of the promising lead compounds for amylin imaging, and further structural optimization based on [(125)I]IPBF may lead to useful tracers for the in vivo imaging of islet amyloids in the pancreas.
    Scientific Reports 08/2014; 4:6155. DOI:10.1038/srep06155 · 5.58 Impact Factor
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    • "II.1 underwent an AV-45 PET scan in a research study approved by the local Ethics Committee. AV-45 images were acquired for 20 minutes, 50 minutes after injection [34] [35] [36]. Twenty-five predemential amnestic AD patients [37] (for details about recruitment criteria , see Saint-Aubert et al. [38]) (mean age: 72.5 ± 4.9, level of education: 11.4 ± 2.7) and 17 healthy elderly controls (mean age: 69.7 ± 4.3, level of education: 12.8 ± 3.4) were recruited and underwent the same AV-45 PET examination, and also 3D-T1 MRI and FDG-PET scans. "
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    ABSTRACT: We report the case of a 65-year-old woman, clinically diagnosed with the logopenic variant of primary progressive aphasia (PPA), and carrier of C9ORF72 expansion, despite cerebrospinal fluid biomarkers suggesting Alzheimer's disease (AD). She underwent structural MRI, metabolic PET, and amyloid PET imaging using florbetapir. Comparison with healthy controls revealed widespread hypometabolism, left sided cortical atrophy, and an increased cortical amyloid load. No difference in amyloid binding was found between the patient and predemential AD patients. This case provides evidence of amyloidopathy in a carrier of C9ORF72 expansion exhibiting a clinical profile of the logopenic variant of PPA.
    Journal of Alzheimer's disease: JAD 06/2014; 42(2). DOI:10.3233/JAD-140222 · 4.15 Impact Factor
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