Diagnostic imaging agents for Alzheimer's disease: copper radiopharmaceuticals that target Aβ plaques.
One of the pathological hallmarks of Alzheimer's disease is the presence of amyloid-β plaques in the brain and the major constituent of these plaques is aggregated amyloid-β peptide. New thiosemicarbazone-pyridylhydrazine based ligands that incorporate functional groups designed to bind amyloid-β plaques have been synthesized. The new ligands form stable four coordinate complexes with a positron-emitting radioactive isotope of copper, (64)Cu. Two of the new Cu(II) complexes include a functionalized styrylpyridine group and these complexes bind to amyloid-β plaques in samples of post-mortem human brain tissue. Strategies to increase brain uptake by functional group manipulation have led to a (64)Cu complex that effectively crosses the blood-brain barrier in wild-type mice. The new complexes described in this manuscript provide insight into strategies to deliver metal complexes to amyloid-β plaques.
School of Chemistry, ‡Bio21 Molecular Science and Biotechnology Institute, §Florey Institute of Neuroscience and Mental Health, □Department of Pharmacology, and ∥Department of Pathology, University of Melbourne, Parkville , Melbourne, Victoria, 3010, Australia.
James L
JL
Hickey
SinChun
S
Lim
David J
DJ
Hayne
Brett M
BM
Paterson
Jonathan M
JM
White
Victor L
VL
Villemagne
Peter
P
Roselt
David
D
Binns
Carleen
C
Cullinane
Charmaine M
CM
Jeffery
Roger I
RI
Price
Kevin J
KJ
Barnham
Paul S
PS
Donnelly
D000544:Alzheimer Disease / Q000000981:diagnostic imaging*; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003300:Copper / Q000737:chemistry*; D003301:Copper Radioisotopes / Q000737:chemistry; D018360:Crystallography, X-Ray; D004285:Dogs; D004563:Electrochemistry; D006801:Humans; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D058225:Plaque, Amyloid / Q000000981:diagnostic imaging*; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000737:chemistry* / Q000493:pharmacokinetics; D021241:Spectrometry, Mass, Electrospray Ionization; D013056:Spectrophotometry, Ultraviolet; D014018:Tissue Distribution
D016229:Amyloid beta-Peptides; D003301:Copper Radioisotopes; D008024:Ligands; D019275:Radiopharmaceuticals; D003300:Copper