Novel styrylpyridines as probes for SPECT imaging of amyloid plaques.
ABSTRACT 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.
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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.Current Medicinal Chemistry 08/2013; · 3.72 Impact Factor
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ABSTRACT: Graphical abstract We report ethyleneoxylated and allyloxylated chalcone derivatives as new SPECT imaging probes for β-amyloid plaques.Bioorganic & medicinal chemistry 05/2014; · 2.82 Impact Factor
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ABSTRACT: As a continuation of our research efforts towards the development of tryptophan based radiotracers for tumor imaging with positron emission tomography (PET), three new fluoroethoxy tryptophan analogues were synthesized and evaluated in vivo. These new tracers (namely 4-(2-[18F]fluoroethoxy)-DL-tryptophan ([18F]4-FEHTP), 6-(2-[18F]fluoroethoxy)-DL-tryptophan ([18F]6-FEHTP) and 7-(2-[18F]fluoroethoxy)-DL-tryptophan ([18F]7-FEHTP) carry the fluoroethoxy side chain either at positions 4-, 6- or 7- of the indole core. Reference compounds and precursors were synthesized by multistep approaches. Radiosynthesis was accomplished by no-carrier-added nucleophilic 18F-fluorination following either an indirect approach (O-alkylation of the corresponding hydroxytryptophan with [18F]fluoroethyltosylate) or a direct approach using a protected mesyl precursor. Radiochemical yields (decay corrected) for both methods were in the range of 10 - 18% . Small animal PET imaging with xenograft bearing mice revealed highest tumor/background ratio for [18F]6-FEHTP which, in a direct comparison, outperformed the other two tryptophan tracers and also the well established tyrosine analogue O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET). Investigation of the transport mechanism of [18F]6-FEHTP in small cell lung cancer cells (NCI-H69) revealed that it is most probably taken up exclusively via the large neutral amino acid transporter(s) (LAT).Molecular Pharmaceutics 07/2014; · 4.79 Impact Factor