Background

[PubMed]

Alzheimer's disease (AD) is a form of dementia with a 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-β peptides consisting of 40–42 amino acids), 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). β-Amyloid fibrils and tau neurofibrillary tangles 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 β-amyloid imaging agents have been developed for magnetic resonance imaging, single-photon emission computed tomography, and positron emission tomography (PET) (8-13). The binding properties of different derivatives of Congo red, thioflavin, stibene, and aminonaphthalene have been studied in post-mortem human brain tissue and in transgenic mice. Of these analogs, 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). [¹⁸F]FDDNP has been found to bind to both β-amyloid fibrils and tau neurofibrillary tangles. 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 β-amyloid binding compound based on a series of neutral thioflavin-T derivatives, 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 β-amyloid fibrils in the brain (10). Okamura et al. (15) identified a series of quinolone derivatives that bind tau neurofibrillary tangles with higher affinity than β-amyloid fibrils. One of these derivatives, 2-(4-aminophenyl)-6-(2-([¹⁸F]fluoroethoxy))quinolone ([¹⁸F]THK523), has been evaluated for imaging of tau pathology in the brain (16).

Synthesis

[PubMed]

[¹⁸F]THK523 was readily synthesized by standard ¹⁸F-fluorination of the tosylate precursor ([¹⁸F]KF/Kryptofix2.2.2, 10 min at 110°C) (16). [¹⁸F]THK523 was purified with high-performance liquid chromatography. Overall yield was 24%, with a specific activity of 100 GBq/µmol (2.7 Ci/µmol) at the end of synthesis and a radiochemical purity of >95%. Total synthesis time was not reported. The LogP_oct (lipophilicity) value was measured to be 2.91 ± 0.13 (n = 3).

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Fodero-Tavoletti et al. (16) performed saturation binding studies of [¹⁸F]THK523 with β-amyloid(1-40) fibrils and human recombinant K18Δ280K-tau fibrils in the presence of excess THK523. [¹⁸F]THK523 exhibited two binding sites on K18Δ280K-tau fibrils, with K_d1 and K_d2 values of 1.67 nM and 21.74 nM, respectively. On the other hand, only one [¹⁸F]THK523 binding site was identified on β-amyloid(1-40) fibrils with a K_d value of 20.7 nM. [¹⁸F]THK523 was bound to tau neurofibrillary tangles but not to β-amyloid plaques in the hippocampus of post-mortem AD brain slices as visualized with in vitro autoradiography and immunostaining studies.

Animal Studies

Human Studies

[PubMed]

No publication is currently available.

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