Synthesis and evaluation of indolinyl- and indolylphenylacetylenes as PET imaging agents for beta-amyloid plaques.
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)-1H-indole 14, targeting beta-amyloid (Abeta) 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 1.5nM 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 2min after injection) with moderate to low washout rates from the brain (1.71% ID/g at 2h and 2.10% ID/g at 3h, respectively). Autoradiography and homogenate binding studies demonstrated the high specific binding of [(18)F]14 to the Abeta 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 Abeta plaque imaging agent.
Qu
Wenchao
W
Department of Radiology, University of Pennsylvania, 3700 Market Street, Room 305, Philadelphia, PA 19104, USA.
Choi
Seok-Rye
SR
Hou
Catherine
C
Zhuang
Zhiping
Z
Oya
Shunichi
S
Zhang
Wei
W
Kung
Mei-Ping
MP
Manchandra
Rajesh
R
Skovronsky
Daniel M
DM
Kung
Hank F
HF
D000114:Acetylene / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D000544:Alzheimer Disease / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D003287:Contrast Media / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry; D051379:Mice; D058225:Plaque, Amyloid / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D049268:Positron-Emission Tomography
D016229:Amyloid beta-Peptides; D003287:Contrast Media; D007211:Indoles; C044736:phenylacetylene; D000114:Acetylene