Affiliations: [a] Department of Pharmacology, Tohoku University School of Medicine, Sendai, Japan | [b] Innovation of New Biomedical Engineering Center, Tohoku University, Sendai, Japan | [c] Division of Radiopharmaceutical Chemistry, Cyclotron and Radioisotope Center, Tohoku University, Sendai, Japan | [d] Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan
Correspondence:
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Correspondence to: Nobuyuki Okamura, MD, PhD, Department of Pharmacology, Tohoku University School of Medicine, 2–1 Seiryo-machi, Aoba-ku, Sendai 980–8575, Japan. Tel.: +81 22 717 8058; Fax: +81 22 717 8060; Email: [email protected].
Abstract: Noninvasive detection of amyloid-β (Aβ) deposits in the brain would be beneficial for an early and presymptomatic diagnosis of Alzheimer's disease (AD). We developed THK-265 as a candidate near-infrared fluorescence (NIRF) probe for the in vivo detection of amyloid deposits in the brain. The maximal emission wavelength of THK-265 was greater than 650nm and it showed high quantum yield and molar absorption coefficients. A fluorescence binding assay showed its high binding affinity to Aβ fibrils (Kd = 97 nM). THK-265 clearly stained amyloid plaques in AD neocortical brain sections and showed a moderate log p value (1.8). After intravenous administration of THK-265 in amyloid-β protein precursor (AβPP) transgenic mice, amyloid deposits in the brain were clearly labeled with THK-265. Furthermore, in vivo NIRF imaging demonstrated significantly higher fluorescence intensity in the brains of AβPP transgenic mice than in those of wild-type mice. As THK-265 showed profound hyperchromic effect upon binding to Aβ fibrils, good discrimination between AβPP transgenic and wild-type mice was demonstrated even early after THK-265 administration. Furthermore, the fluorescence intensity of THK-265 correlated with amyloid plaque burden in the brains of AβPP transgenic mice. These findings strongly support the usefulness of THK-265 as an NIRF imaging probe for the noninvasive measurement of brain amyloid load.
