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

Bioorganic & Medicinal Chemistry Letters
Wenchao QuHank F Kung

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)-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.

References

Nov 4, 2006·Science·Michel Goedert, Maria Grazia Spillantini
Mar 15, 2008·Brain : a Journal of Neurology·Milos D IkonomovicSteven T DeKosky

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Citations

Sep 8, 2010·Chemical Society Reviews·Calden N CarrollDarren W Johnson
Aug 1, 2009·Future Medicinal Chemistry·Boyenoh Gaye, Adeboye Adejare
Apr 16, 2009·Contrast Media & Molecular Imaging
Oct 13, 2014·European Journal of Medicinal Chemistry·Yanping Yang, Mengchao Cui
Apr 12, 2012·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Yang YangBo-Li Liu
Nov 11, 2017·Alzheimer's & Dementia : Translational Research & Clinical Interventions·Ying-Hwey NaiHiroshi Watabe

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