title: Distinct binding of amyloid imaging ligands to unique amyloid-β deposited in the presubiculum of Alzheimer's disease.
abstract: Non-invasive determination of amyloid-β peptide (Aβ) deposition with radioligands serves for the early diagnosis and clarification of pathogenetic mechanisms of Alzheimer's disease (AD). The polymorphic binding site on multimeric Aβ for current radioligands, however, is little understood. In this study, we investigated the binding of several radioligands including (11)C-Pittsburgh Compound B ((11)C-PiB), (3)H-AZD2184, and two recently developed compounds, (125)I-DRM106 and (125)I-DRK092, with unique presubicular Aβ deposits lacking interaction with the commonly used amyloid dyes FSB. (11)C-PiB, (3)H-AZD2184, and (125)I-DRK092 showed overt binding to presubicular Aβ deposits, while (125)I-DRM106 barely bound to these aggregates despite its strong binding in the hippocampal CA1 sector. Unlike neuritic plaques in the CA1, Aβ lesions in the presubiculum were not accompanied by inflammatory gliosis enriched with 18-kDa translocator protein (TSPO). Thus, there are at least two different components in Aβ aggregates providing distinct binding sites for the current amyloid radioligands, and one of these binding components is distinctly present in the presubicular Aβ deposits. Amyloid radioligands lacking affinity for this component, such as (125)I-DRM106, may selectively capture Aβ deposits tightly associated with TSPO neuroinflammation and neurodegeneration as exemplified by CA1 neuritic plaques. Hence, comparative autoradiographic assessments of radioligand binding in CA1 and presubiculum could serve for the development of an amyloid PET imaging agent visualizing neurotoxicity-related Aβ pathologies. Non-invasive determination of amyloid-β peptide (Aβ) serves for the early diagnosis and clarification of pathogenetic mechanisms of Alzheimer's disease (AD). We found that there are at least two different amyloid components in hippocampal CA1 and presubiculum providing distinct binding sites for the current amyloid radioligands. Comparative analysis for radioligand binding in these two regions could serve for developing novel imaging agents selectively visualizing neurotoxicity-related Aβ pathologies.
authors: Molecular Neuroimaging Program, National Institute of Radiological Sciences, Chiba, Japan.
authors: Bin
authors: http://orcid.org/0000-0002-9672-6441
authors: B
authors: Ji
authors: Molecular Neuroimaging Program, National Institute of Radiological Sciences, Chiba, Japan.|Research Department, Fujifilm RI Pharma Co. LTD, Chiba, Japan.
authors: Chun-Jen
authors: CJ
authors: Chen
authors: Research Department, Fujifilm RI Pharma Co. LTD, Chiba, Japan.
authors: Kazunori
authors: K
authors: Bando
authors: Research Department, Fujifilm RI Pharma Co. LTD, Chiba, Japan.
authors: Hiroki
authors: H
authors: Ashino
authors: Research Department, Fujifilm RI Pharma Co. LTD, Chiba, Japan.
authors: Hideaki
authors: H
authors: Shiraishi
authors: Research Department, Fujifilm RI Pharma Co. LTD, Chiba, Japan.
authors: Hiroaki
authors: H
authors: Sano
authors: Research Department, Fujifilm RI Pharma Co. LTD, Chiba, Japan.
authors: Hiroyuki
authors: H
authors: Kasahara
authors: Research Department, Fujifilm RI Pharma Co. LTD, Chiba, Japan.
authors: Takao
authors: T
authors: Minamizawa
authors: Clinical Veterinary Medicine, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Japan.
authors: Kazutaka
authors: K
authors: Yamada
authors: Molecular Neuroimaging Program, National Institute of Radiological Sciences, Chiba, Japan.
authors: Maiko
authors: M
authors: Ono
authors: Molecular Probe Program, National Institute of Radiological Sciences, Chiba, Japan.
authors: Ming-Rong
authors: MR
authors: Zhang
authors: Molecular Neuroimaging Program, National Institute of Radiological Sciences, Chiba, Japan.
authors: Chie
authors: C
authors: Seki
authors: Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm, Sweden.|AstraZeneca Translational Science Center, Karolinska Institute, Stockholm, Sweden.
authors: Lars
authors: L
authors: Farde
authors: Molecular Neuroimaging Program, National Institute of Radiological Sciences, Chiba, Japan.
authors: Tetsuya
authors: T
authors: Suhara
authors: Molecular Neuroimaging Program, National Institute of Radiological Sciences, Chiba, Japan.
authors: Makoto
authors: M
authors: Higuchi
mesh_terms: D000544:Alzheimer Disease / Q000000981:diagnostic imaging / Q000473:pathology*; D000631:Aminopyridines / Q000493:pharmacokinetics; D058227:Amyloidogenic Proteins / Q000378:metabolism*; D000814:Aniline Compounds / Q000493:pharmacokinetics; D001345:Autoradiography; D052160:Benzothiazoles / Q000493:pharmacokinetics; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics; D066298:In Vitro Techniques; D020534:Parahippocampal Gyrus / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D058225:Plaque, Amyloid / Q000000981:diagnostic imaging / Q000473:pathology; D049268:Positron-Emission Tomography; D011725:Pyridines / Q000493:pharmacokinetics; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D018079:Receptors, GABA / Q000378:metabolism; D013844:Thiazoles / Q000493:pharmacokinetics; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: C475519:2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole; C539976:2-(6-(methylamino)pyridin-3-yl)-1,3-benzothiazol-6-ol; C000595794:6-iodo-2-(4-(1H-3-pyrazolyl)phenyl)imidazo(1,2-a)pyridine; D000631:Aminopyridines; D058227:Amyloidogenic Proteins; D000814:Aniline Compounds; D052160:Benzothiazoles; D007093:Imidazoles; D011725:Pyridines; D019275:Radiopharmaceuticals; D018079:Receptors, GABA; C499229:TSPO protein, human; D013844:Thiazoles
keywords: Alzheimer's disease (AD); Amyloid imaging; DRM106; Pittsburgh Compound B; Presubiculum