doi:10.1016/j.bmcl.2005.11.055 
Copyright © 2005 Elsevier Ltd All rights reserved.
Design, synthesis, and structure–activity relationship of novel thiophene derivatives for β-amyloid plaque imaging
Rajesh Chandraa, Mei-Ping Kunga and Hank F. Kunga, b, 
, 
aDepartment of Radiology, University of Pennsylvania, Room 305, 3700 Market Street, Philadelphia, PA 19104, USA
bDepartment of Pharmacology, University of Pennsylvania, Room 305, 3700 Market Street, Philadelphia, PA 19104, USA
Received 11 October 2005;
revised 14 November 2005;
accepted 14 November 2005.
Available online 1 December 2005.
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Abstract
Novel 2,5-diphenylthiophene derivatives were synthesized and structure activity relationship with regard to Aβ plaque binding was studied. Binding affinities of these compounds were found to range from 3.9 to >1000 nM, depending on the substitution patterns on the phenyl ring. The fluoroethyl-substituted thiophene derivatives showed excellent binding affinities. These compounds may be useful for the development of novel PET tracers for the imaging of β-amyloid plaques in the brain of patients with Alzheimer’s disease.
Graphical abstract
Synthesis and SAR of novel 2,5-diphenylthiophene derivatives as Aβ plaque imaging agents are reported. The inhibition constant (Ki) of potent compounds ranges from 3.9 to 10 nM.
Keywords: In vitro binding; PET imaging; Alzheimer’s disease
Scheme 1. Reagents and conditions: (i) 2 M Na2CO3/Pd(PPh3)4, DMF, 100 °C, 24 h; (ii) BBr3 (2 equiv)/CH2Cl2, 50 °C, 6 h; (iii) BBr3 (1 equiv)/CH2Cl2, 50 °C, 6 h; (iv) SnCl2/ethanol, 85 °C, 12 h.
Scheme 2. Reagents and conditions: (i) POCl3/DMF, 60 °C, 3 h; (ii) a—Na2S/DMF, rt, 2 h; b—4-nitrobenzylbromide, 50 °C, 3 h; c—NaOMe; 10 min; (iii) SnCl2/ethanol, 85 °C, 12 h; (iv) BBr3 (1 equiv)/CH2Cl2, 50 °C, 6 h; (v) (CH2O)n, AcOH, NaCNBH3, 18 h; (vi) K2CO3/DMF, 90 °C, 1 h then BrCH2CH2F, 90 °C, 12 h; (vii) a—(Boc)2O, THF, reflux, 18 h; b—NaH, DMF, 50 °C, 30 min then MeI, 50 °C, 3 h; c—BBr3/CH2Cl2, microwave, 140 °C, 5 min; (viii) BBr3 (1 equiv)/CH2Cl2, −78 °C to rt, 18 h.
Table 1.
Inhibition constants (Ki, nM) of compounds (3a–q) on ligand binding to AD brain homogenatesa
a Values are means ± SEM of three independent experiments, each in duplicate. Binding assays were carried out in 12 × 75 mm borosilicate glass tubes. For the competition binding, the reaction mixture contained 50 μL tissue homogenates (20–50 μg), 50 μL of [
125I]IMPY (diluted in PBS, 0.02–0.04 nM) and 50 μL of inhibitors (10
−5 to 10
−10 M diluted serially in PBS containing 0.1% bovine serum albumin) in a final volume of 1 mL. Non-specific binding was defined in the presence of 600 nM IMPY in the same assay tubes. The mixture was incubated at 37 °C for 2 h, and the bound and the free radioactivity were separated by vacuum filtration through Whatman GF/B filters using a Brandel M-24R cell harvester followed by 2 × 3 mL washes of PBS at room temperature. Filters containing the bound I-125 ligand were counted in a gamma counter (Packard 5000) with 70% counting efficiency. Protein determinations were performed with Lowy’s method using bovine serum albumin as a standard. The results of inhibition experiments were subjected to non-linear regression analysis using EBDA by which
Ki values were calculated.
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