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Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.

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Molecular Imaging and Contrast Agent Database (MICAD) [Internet].

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5-(2E,4E)-5-(6-hydroxy-4-oxo-2-thioxo-1,2,3,4-tetrahydroxy-5 pyrimidinyl)-2,4-pentadienylidene-2-thioxodihydro-4,6(1H,5H)-pyrimidinedione

THK-265
, PhD
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD
Corresponding author.

Created: ; Last Update: October 25, 2012.

Chemical name:5-(2E,4E)-5-(6-hydroxy-4-oxo-2-thioxo-1,2,3,4-tetrahydroxy-5 pyrimidinyl)-2,4-pentadienylidene-2-thioxodihydro-4,6(1H,5H)-pyrimidinedioneimage 144203551 in the ncbi pubchem database
Abbreviated name:THK-265
Synonym:
Agent category:Compound
Target:Amyloid-beta (Aβ) peptide
Target category:Acceptor
Method of detection:Optical, near-infrared (NIR) fluorescence imaging
Source of signal:THK-265
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
Click on the above structure for additional information in PubChem.

Background

[PubMed]

Alzheimer's disease (AD) is a form of dementia with gradual memory loss and a progressive decline in mental functions over time (1, 2). It is characterized pathologically by neuronal loss, extracellular senile plaques (aggregates of amyloid-beta (Aβ) peptides consisting of 40–42 amino acids formed as the proteolytic cleavage of Aβ protein precursor (AβPP)), and intracellular neurofibrillary tangles (filaments of microtubule-binding hyper-phosphorylated protein tau) in the brain, especially in the hippocampus and associative regions of the cortex (3, 4). Aβ peptides and tau protein are implicated as the main causes of neuronal degeneration and cell death (5, 6). Early diagnosis of AD is important for treatment consideration and disease management (7). Various Aβ imaging agents have been developed for magnetic resonance imaging (MRI), single-photon emission computed tomography (SPECT), and positron emission tomography (PET) (8-13). The binding of different derivatives of Congo red, thioflavin, stilbene, and aminonaphthalene has been studied in human postmortem brain tissue and in transgenic mice. 2-(1-(6-[(2-[18F]fluoroethyl)(methyl)amino]-2-naphthyl)ethylidene)malono nitrile ([18F]FDDNP) has been studied in humans, showing more binding in the brains of patients with AD than in those of healthy people (14). However, [18F]FDDNP showed low signal/noise ratios for PET imaging because it is highly lipophilic. N-methyl-[11C]-2-(4'-methylaminophenyl)-6-hydroxybenzothiasole, a Aβ binding compound based on a series of neutral thioflavin-T derivatives (15), was radiolabeled with the positron-emitting radionuclide 11C ([11C]6-OH-BTA-1 or [11C]PIB). [11C]6-OH-BTA-1 was found to be a promising imaging agent for senile plaques in the brain (16). Zhang et al. (17) reported the development of a series of fluorinated polyethylene glycol (PEG) units (n = 2–5) for PET imaging of Aβ plaques in the brain. Two of them, [18F]BAY94-9172 ([18F]AV-1) (18) and ([18F]AV-45, also known as [18F]Florbetapir) (19), have been evaluated in clinical trials. [18F]Florbetapir is approved for estimation of brain amyloid plaque content in patients with cognitive decline by the United States Food and Drug Administration (US FDA).

Optical imaging is increasingly being used to monitor biological functions of specific targets in vitro and in vivo to provide real-time imaging (20-22). Small near-infrared (NIR) fluorescence probes (emission wavelength, 650–900 nm) exhibit a reduction of the natural background fluorescence interference of biomolecules, providing a high contrast between target and background tissues in small animals. A number of optical probes for the detection of Aβ plaques are available, such as Congo red, thioflavin, CRANAD-2, and AOI987 (23, 24). Okamura et al. (25) evaluated 5-(2E,4E)-5-(6-hydroxy-4-oxo-2-thioxo-1,2,3,4-tetrahydroxy-5 pyrimidinyl)-2,4-pentadienylidene-2-thioxodihydro-4,6(1H,5H)-pyrimidinedione (THK-265) as a NIR fluorescence imaging probe for in vivo imaging of Aβ in an animal model of AD.

Synthesis

[PubMed]

THK-265 is commercially available (Organica, Wolfen, Germany) (25). THK-265 displayed the following fluorescent properties in methanol: one single absorption maximum at 627 nm, one single emission maximum at 644 nm, a high absorption coefficient of 96,198 M–1cm–1, and a high quantum yield of 38.5%. Similar maximum excitation and emission wavelengths were observed in human serum and potassium phosphate buffer (pH, 7.4). THK-265 exhibited a log P value of 1.8 ± 0.8 (moderate lipophilicity).

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Differential fluorescence spectroscopy performed by Okamura et al. (25) showed that the magnitude of the fluorescence increase was dependent on the concentration of THK-265 (3–1,000 nM) in the presence of aggregated Aβ peptides (5 µM). The Kd value for THK-265 was estimated to be 97 ± 5 nM, which was lower than that of AOI987 (200 nM). THK-265 staining of amyloid plaques was observed in postmortem brain tissues of the brain (the surface region of frontal cortex) of one AD male patient (age 69 years). THK-265 staining pattern colocalized with Aβ immunostaining. THK-265 also stained neurofibrillary tangles.

Animal Studies

Rodents

[PubMed]

The blood–brain barrier (BBB) penetration of THK-265 was assessed ex vivo using 7-week-old wild-type (Wt) male mice (n = 3–4/group) after intravenous injection of 1 mg/kg THK-265 (25). Brain accumulation levels of THK-265 were 0.04% injected dose per gram (ID/g) at 2 min and 0.0065% ID/g at 30 min as measured with high-performance liquid chromatography. Ex vivo NIR fluorescence imaging showed that THK-265 entered the brain rapidly (6.2 × 107 p/s/cm2/sr) at 2 min and was then gradually eliminated from the brain, with 2.4 × 107 p/s/cm2/sr and 2.1 × 107 p/s/cm2/sr at 60 min and 120 min, respectively. No acute toxicity of THK-265 at 10 mg/kg in normal mice was observed up to 7 days after injection.


In vivo NIR fluorescence imaging of Aβ using THK-265 (1 mg/kg) was performed in 19-month-old (19M) and 32-month-old (32M) AβPP transgenic (Tg) and age-matched Wt female mice (n = 3/group) at 0, 3, 30, 64, and 118 min after injection (25). THK-265 entered rapidly into the brains and was consistently higher in Tg mice than in Wt mice. Fluorescence intensity levels at 3 min after injection were 3.8, 2.6, 1.8, and 1.7 × 108 p/s/cm2/sr for 32M Tg, 19M Tg, 32M Wt, and 19M Wt mice, respectively. Additional studies were performed in 27M Tg and 27M Wt mice with THK-265, AOI987, and ICG. Both THK-265 and AOI987 showed higher fluorescence signals in Tg mice than in Wt mice, whereas ICG showed similar fluorescence signals in both types of mice. The brain/neck ratios at 113 min after injection were 1.2, 1.2, 1.2, 1.6, 1.3, and 2.2 for ICG/Wt, ICG/Tg, AOI987/Wt, AOI987/Tg, THK-265/Wt, and THK-265/Tg, respectively. THK-265 displayed similar brain/neck ratios with AOI987 and ICG in the Wt mice but significantly higher ratios than AOI987 and ICG in the Tg mice (P < 0.05). There was a significant correlation (r = 0.943, P < 0.017) of THK-265 brain/neck ratios with the number of amyloid plaques in Tg mice.

Schmidt et al. (26) performed in vivo NIR fluorescence imaging of Aβ using THK-265 (1 mg/kg) using younger Tg and Wt mice (75, 100, and 200 d) (n = 5/group) at 10, 20, 30, 60, and 90 min after injection. There was an increase of signal in the Tg mice correlating with age, whereas little change in signal was observed in Wt mice versus baseline background. Quantitative analysis of fluorescence signals in the brain at 30 min after injection showed that Tg (75 d), Tg (100 d), and Tg (200 d) mice exhibited 20%, 80%, and 140% increase in signal compared with the age-matched Wt mice. Histological analysis showed that there was co-localization of THK-265 staining with amyloid plaques and an increasing number of amyloid plaques with stronger fluorescence signal.

Other Non-Primate Mammals

[PubMed]

No publication is currently available.

Non-Human Primates

[PubMed]

No publication is currently available.

Human Studies

[PubMed]

No publication is currently available.

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