Synthesis and characterization of styrylchromone derivatives as β-amyloid imaging agents

An Overview of 2‐Styrylchromones: Natural Occurrence, Synthesis, Reactivity and Biological Properties

“…The classical approach involves a three-step sequence: (i) condensation of appropriate 2′-hydroxyacetophenones with cinnamoyl chlorides, (ii) base-promoted Baker-Venkataraman rearrangement [62,63] of the formed esters 31 into the 5-aryl-3-hydroxy-1-(2-hydroxyaryl)penta-2,4-dien-1-ones 32 (in equilibrium with the corresponding diketone form), and (iii) cyclodehydration to afford the desired 2-SCs 33 (Scheme 8). The cinnamoyl chlorides used in the esterification step may be commercially available or can be prepared in situ by treatment of the corresponding cinnamic acids with phosphoryl chloride in dry pyridine at room temperature or 60-90°C [7,8,18,19,32,45,47,[64][65][66][67][68][69][70][71][72][73][74] or with N,N-dicyclohexylcarbodiimide (DCC) in the presence of a catalytic amount of 4-pyrrolidinepyridine (4-PPy) in dichloromethane at room temperature. [13,75] Transposition of the cinnamoyl group from the 2′-position to position 2 of the acetophenone occurs in the presence of potassium hydroxide with DMSO [13,18,19,7,8,32,[67][68][69]71,73] or pyridine [47,64,70,73,74] as solvent, of sodium hydride in THF at reflux [8,45,65] or under less conventional c...…”

“…[75] The last step was originally achieved in a strongly acidic medium (sulfuric acid in acetic acid at reflux), but this is rarely used nowadays. [64,70,74] It has been replaced by use of milder reagent systems, including the use of a few drops of diluted hydrochloric acid in acetic acid, [73] of p-toluenesulfonic acid (PTSA) in DMSO [13,18,19,7,8,65,67,68,72] or of a catalytic amount of iodine in DMSO. [13,18,8,45,68] Individual attempts with use of concentrated sulfuric acid in ethanol at reflux, [66] grinding with phosphorus pentoxide under solventfree conditions [76] and with potassium carbonate in water under classical heating at reflux or under microwave-assisted conditions [77] have also been reported (Scheme 8).…”

“…The tributyltin intermediates can also undergo iododestannylation, in the pres- ence of hydrogen peroxide as oxidant, in order to prepare 6-radioiodinated 2-SCs. [70,74] A large variety of 2,3-diarylxanthones 103 result as major products from reactions between polysubstituted 3-bromo-2-styrylchromones and styrenes, mediated by palladium catalysts, in one-pot fashion. The proposed mechanism involves Heck coupling between brominated chromones and styrenes to form 2,3-distyrylchromones, in situ electrocyclization, [1,5]-sigmatropic hydrogen migration to give 3,4-dihydroxanthones and finally oxidation to achieve the corresponding 2,3-diarylxanthones 103.…”

“…[16] Several 6-iodinated 2-SCs were synthesized and screened for their application as in vivo imaging probes of -amyloid plaques in Alzheimer's disease. [70,74] In an in vitro binding assay, high affinity towards preformed synthetic A (1-40) aggregates was observed for compounds [ 125 (Figure 7). In addition, in vivo biodistribution of radioactivity after intravenous administration in normal mice revealed high initial brain uptake and fast washout from the brain only for compounds [ 125 I]170 and [ 125 I]171, whereas the slow brain washout observed for [ 125 I]172 made it unsuitable to be used as in vivo -amyloid imaging agent.…”

Synthesis and evaluation of ethyleneoxylated and allyloxylated chalcone derivatives for imaging of amyloid β plaques by SPECT

“…We have previously reported Aβ imaging agents based on flavonoid derivatives, such as flavones 15,16 , chalcones [17][18][19][20] , aurones 21,22 , and styrylchromones 23 studies demonstrated that chalcone derivatives fluoro-pegylated at the p-position of the 1-phenyl ring showed a sufficient brain uptake with a good binding capacity to Aβ plaques 19 . In addition, radioiodinated flavonoids, such as flavone and aurone derivatives, with a methoxy or oligoethyleneoxy group at the p-position of the 3-phenyl ring have the properties of high brain uptake and rapid clearance from the brain without significant decrease in the binding affinity for Aβ 15,22 .…”