Diagnostic Imaging Agents for Alzheimer’s Disease: Copper Radiopharmaceuticals that Target Aβ Plaques

• Published in: Journal of the American Chemical Society Vol. 135; no. 43; pp. 16120 - 16132
• Main Authors: Hickey, James L, Lim, SinChun, Hayne, David J, Paterson, Brett M, White, Jonathan M, Villemagne, Victor L, Roselt, Peter, Binns, David, Cullinane, Carleen, Jeffery, Charmaine M, Price, Roger I, Barnham, Kevin J, Donnelly, Paul S
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 30.10.2013; Amer Chemical Soc
• Subjects: Alzheimer Disease - diagnostic imaging; Amyloid beta-Peptides - chemistry; Animals; Chemistry; Chemistry, Multidisciplinary; Chromatography, High Pressure Liquid; Copper - chemistry; Copper Radioisotopes - chemistry; Crystallography, X-Ray; Dogs; Electrochemistry; Humans; Ligands; Mice; Models, Molecular; Molecular Conformation; Physical Sciences; Plaque, Amyloid - diagnostic imaging; Positron-Emission Tomography; Radiopharmaceuticals - chemistry; Radiopharmaceuticals - pharmacokinetics; Science & Technology; Spectrometry, Mass, Electrospray Ionization; Spectrophotometry, Ultraviolet; Tissue Distribution; IN-VITRO; OXIDATIVE STRESS; PROTEIN; AMYLOID-BETA; BIS(THIOSEMICARBAZONATO) COMPLEXES; STILBENE DERIVATIVES; BLOOD-FLOW; METAL-IONS; PET; ZINC
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja4057807

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, 64Cu. Two of the new CuII 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 64Cu 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.