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IC‐P‐215: COMPARISON OF 18F‐THK5117 AND 11C‐PIB PET IMAGES IN PATIENTS WITH ALZHEIMER'S DISEASE
Author(s) -
Okamura Nobuyuki,
Harada Ryuichi,
Furumoto Shozo,
Furukawa Katsutoshi,
Ishiki Aiko,
Tomita Naoki,
Tashiro Manabu,
Iwata Ren,
Yanai Kazuhiko,
Arai Hiroyuki,
Kudo Yukitsuka
Publication year - 2014
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2014.05.223
Subject(s) - precuneus , posterior cingulate , nuclear medicine , hippocampus , senile plaques , alzheimer's disease , positron emission tomography , temporal cortex , cortex (anatomy) , pathology , medicine , neuroscience , psychology , disease , cognition
Background: Diagnostic imaging agents targeting amyloid-b (Ab) in Alzheimer’s disease (AD) are already in clinical use. Such tau probes are needed to monitor AD progression, the efficacy of tau-targeting therapies, and to identify Ab negative tauopathies. Antibody-derived ligands are likely to provide excellent specificity for detecting tau lesions, and in particular smaller single chain variable antibody fragments (scFv’s) are attractive for in vivo imaging of tau aggregates. Methods: Libraries of scFv’s were generated from tau antibody hybridomas using phage display technology. Numerous phospho-tau (P-Ser396,404) selective scFv’s were identified by ELISA and characterized further by immunoprecipitation, histology and Biacore. Subsequently, the diagnostic imaging utility for tauopathies was assessed for one of the scFv’s and compared to its parent antibody using In Vivo Imaging System (IVIS) for proof of concept prior to PET studies. Results: The scFv’s showed strong selectivity for phospho-tau vs. non-phospho-tau epitope in ELISA, pulled down tau proteins from AD brains, and bound to pathological tau in AD and Pick’s disease brain sections. The potential diagnostic imaging utility of one of these, with the best phospho-tau selectivity on Biacore (1x10 -8 M vs. 4x10 -3 M for non-phospho-tau), was characterized further by IVIS. Intracarotid or intravenous scFv injection led to a strong IVIS brain signal in transgenic tauopathy mice, that correlated nicely with scFv signal from brain tissue (r1⁄40.97, p<0.0001, n1⁄49), and brain tau pathology (r1⁄40.94, p<0.0001, n1⁄413). Importantly, limited signal was detected in wild-type mice. Similar findings were observed with the parent antibody (r1⁄40.86, p1⁄40.1, n1⁄45 vs. r1⁄40.75, p<0.062, n1⁄411), although its IVIS signal appeared to be less but these differences need to be confirmed by comparing both probes in the same mice. Analyses of brain tissue collected 4-6 h after injection showed a partial to complete co-localization with stained intraneuronal tau aggregates in tg tauopathy mice but not in wt mice for both scFv and its parent antibody. Furthermore, both colocalized with markers of endosomes-autophagosomes-lysosomes, which are known to contain tau aggregates, suggesting that this interaction takes place in these degradation pathways. Conclusions: Tau scFv’s are promising as novel diagnostic markers for AD and related tauopathies, and have therapeutic potential as well.