Synthesis and evaluation of indolinyl- and indolylphenylacetylenes as PET imaging agents for β-amyloid plaques

Abstract Two new phenylacetylene derivatives, 5-((4-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)phenyl)ethynyl)indoline 8 and 5-((4-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)phenyl)ethynyl)-1 H -indole 14 , targeting β-amyloid (Aβ) plaques have been prepared. In vitro binding carried out in tissue homogenates prepared from postmortem AD brains with [ 125 I]IMPY (6-iodo-2-(4′-dimethylamino-)phenyl-imidazo[1,2- a ]pyridine) as the radioligand indicated good binding affinities ( K i  = 4.0 and 1.5 nM for 8 and 14 , respectively). Brain penetration of the corresponding radiofluorinated ligands, evaluated in the normal mice, showed good initial brain penetration (4.50 and 2.43% ID/g (injected dose/gram) for [ 18 F] 8 and [ 18 F] 14 at 2 min after injection) with moderate to low washout rates from the brain (1.71% ID/g at 2 h and 2.10% ID/g at 3 h, respectively). Autoradiography and homogenate binding studies demonstrated the high specific binding of [ 18 F] 14 to the Aβ plaques; however, [ 18 F] 8 showed low specific binding. These preliminary results identified that indolylphenylacetylene, 14 , may be a good lead for further structural modification to develop a useful Aβ plaque imaging agent.