Novel Styrylpyridines as Probes for SPECT Imaging of Amyloid Plaques

ArticleinJournal of Medicinal Chemistry 50(9):2157-65 · June 2007with10 Reads
DOI: 10.1021/jm070025+ · Source: PubMed
We report a series of radioiodinated styrylpyridines as single photon emission computed tomography probes for imaging Abeta plaques in the brain of patients with Alzheimer's disease (AD). In vitro binding showed that all of the styrylpyridines displayed very good binding affinities in postmortem AD brain homogenates (Ki = 3.6 to 15.5 nM). No-carrier-added samples of 13a, 13b, 16a, 16b, and 16e (radioiodinated with 125I) were successfully prepared. The in vivo biodistribution in normal mice, at 2 min after injection, showed excellent initial brain penetrations (4.03, 6.22, 5.43, and 8.04% dose/g for [125I]13a, 13b, 16a, and 16b, respectively). Furthermore, in vitro autoradiography of AD brain sections showed that the high binding signal was specifically due to the presence of Abeta plaques. Taken together, these results strongly suggest that these styrylpyridines are useful for imaging Abeta plaques in the living human brain.
    • "On the other hand, there has been a lack of SPECT ligands available for the clinical diagnosis of Alzheimer's disease. In spite of the considerable effort to develop SPECT tracers (Kung et al., 2003; Qu et al., 2007; Ono et al., 2013; Chen et al., 2015), clinically useful amyloid-b imaging agents for SPECT have not been reported in humans. It is well known that the resolution and sensitivity of SPECT are inferior to those of PET. "
    [Show abstract] [Hide abstract] ABSTRACT: Non-invasive imaging of amyloid-β in the brain, a hallmark of Alzheimer's disease, may support earlier and more accurate diagnosis of the disease. In this study, we assessed the novel single photon emission computed tomography tracer (123)I-ABC577 as a potential imaging biomarker for amyloid-β in the brain. The radio-iodinated imidazopyridine derivative (123)I-ABC577 was designed as a candidate for a novel amyloid-β imaging agent. The binding affinity of (123)I-ABC577 for amyloid-β was evaluated by saturation binding assay and in vitro autoradiography using post-mortem Alzheimer's disease brain tissue. Biodistribution experiments using normal rats were performed to evaluate the biokinetics of (123)I-ABC577. Furthermore, to validate (123)I-ABC577 as a biomarker for Alzheimer's disease, we performed a clinical study to compare the brain uptake of (123)I-ABC577 in three patients with Alzheimer's disease and three healthy control subjects. (123)I-ABC577 binding was quantified by use of the standardized uptake value ratio, which was calculated for the cortex using the cerebellum as a reference region. Standardized uptake value ratio images were visually scored as positive or negative. As a result, (123)I-ABC577 showed high binding affinity for amyloid-β and desirable pharmacokinetics in the preclinical studies. In the clinical study, (123)I-ABC577 was an effective marker for discriminating patients with Alzheimer's disease from healthy control subjects based on visual images or the ratio of cortical-to-cerebellar binding. In patients with Alzheimer's disease, (123)I-ABC577 demonstrated clear retention in cortical regions known to accumulate amyloid, such as the frontal cortex, temporal cortex, and posterior cingulate. In contrast, less, more diffuse, and non-specific uptake without localization to these key regions was observed in healthy controls. At 150 min after injection, the cortical standardized uptake value ratio increased by ∼60% in patients with Alzheimer's disease relative to healthy control subjects. Both healthy control subjects and patients with Alzheimer's disease showed minimal (123)I-ABC577 retention in the white matter. These observations indicate that (123)I-ABC577 may be a useful single photon emission computed tomography imaging maker to identify amyloid-β in the human brain. The availability of an amyloid-β tracer for single photon emission computed tomography might increase the accessibility of diagnostic imaging for Alzheimer's disease.
    Full-text · Article · Oct 2015
    • "More recently, a direct comparison study between [ 11 C]PIB and [ 18 F] BAY94-9172 revealed that higher retention in the white matter was observed for [ 18 F]BAY94-9172 [118]. To further decrease the lipohilicity and get faster washout rate of the stilbenes, a series of radiolabeled styrylpyridines (103-110) were screened as A imaging probes119120121122. Two 18 F-labeled probes, [ 18 F]AV19 (109) and [ 18 F] AV45 (florbetapir, 110) with excellent in vivo properties in rodent were selected for human studies122123124125126127. Initial clinical trial of [ 18 F]AV19 suggested that the brain uptake was lower than expected, which may due to a rapid in vivo metabolism caused by N-demethylation [36]. "
    [Show abstract] [Hide abstract] ABSTRACT: The deposition of β-amyloid (Aβ) plaques in the parenchymal and cortical brain is accepted as the main pathological hallmark of Alzheimer's disease (AD). According to the amyloid cascade hypothesis, the Aβ deposition in the brain appears to be a good diagnostic biomarker for AD and may also be a good predictive biomarker of this disease. Molecular imaging of Aβ plaques in the brain with positron emission tomography (PET), single photon emission computed tomography (SPECT) or molecular optical imaging represents a promising approach to the early diagnosis of AD and monitoring the effectiveness of novel therapies for this devastating disease. Our review focuses on the past and recent knowledge in this field with respect to small organic molecules that have been utilized for the development of Aβ imaging probes.
    Full-text · Article · Aug 2013
    • "Many radioiodinated imaging agents derived from Congo Red or thioflavin-T have been developed. Compounds 1 [29], 2 [29], 3 [40], 4 [23], 5 [24], and 6 [25] (Figure 3) are thought to be derived from Congo Red. Although 1, 2, and 3 showed unfavorable pharmacokinetics in vivo such as low uptake into the brain and a slow washout, the radioactivity pharmacokinetics of 5 and 6 was much improved. "
    [Show abstract] [Hide abstract] ABSTRACT: The development of radiotracers for use in vivo to image β-amyloid (Aβ) plaques in cases of Alzheimer's disease (AD) is an important, active area of research. The presence of Aβ aggregates in the brain is generally accepted as a hallmark of AD. Since the only definitive diagnosis of AD is by postmortem staining of affected brain tissue, the development of techniques which enable one to image Aβ plaques in vivo has been strongly desired. Furthermore, the quantitative evaluation of Aβ plaques in the brain could facilitate evaluation of the efficacy of antiamyloid therapies currently under development. This paper reviews the current situation in the development of agents for SPECT-based imaging of Aβ plaques in Alzheimer's brains.
    Full-text · Article · Apr 2011
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