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

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-[F]fluoroethyl)(methyl)amino]-2-naphthyl)ethylidene)malono nitrile ([F]FDDNP) has been studied in humans, showing more binding in the brains of patients with AD than in those of healthy people (14). However, [F]FDDNP showed low signal/noise ratios for PET imaging because it is highly lipophilic. -methyl-[C]-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 C ([C]6-OH-BTA-1 or [C]PIB). [C]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 ( = 2–5) for PET imaging of Aβ plaques in the brain. Two of them, [F]BAY94-9172 ([F]AV-1) (18) and ([F]AV-45, also known as [F]Florbetapir) (19), have been evaluated in clinical trials. [F]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 and 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-(2,4)-5-(6-hydroxy-4-oxo-2-thioxo-1,2,3,4-tetrahydroxy-5 pyrimidinyl)-2,4-pentadienylidene-2-thioxodihydro-4,6(1,5)-pyrimidinedione (THK-265) as a NIR fluorescence imaging probe for imaging of Aβ in an animal model of AD.