Potential Diagnostic Imaging of Alzheimer’s Disease with Copper-64 Complexes That Bind to Amyloid-β Plaques

Abstract

Amyloid-β plaques, consisting of aggregated amyloid-β peptides, are one of the pathological hallmarks of Alzheimer's disease. Copper complexes formed using positron-emitting copper radionuclides that cross the blood−brain barrier and bind to specific molecular targets offer the possibility of noninvasive diagnostic imaging using positron emission tomography. New thiosemicarbazone-pyridylhydrazone based ligands that incorporate pyridyl-benzofuran functional groups designed to bind amyloid-β plaques have been synthesized. The ligands form stable complexes with copper(II) (K d = 10 −18 M) and can be radiolabeled with copper-64 at room temperature. Subtle changes to the periphery of the ligand backbone alter the metabolic stability of the complexes in mouse and human liver microsomes, and influenced the ability of the complexes to cross the blood−brain barrier in mice. A lead complex was selected based on possessing the best metabolic stability and brain uptake in mice. Synthesis of this lead complex with isotopically enriched copper-65 allowed us to show that the complex bound to amyloid-β plaques present in post-mortem human brain tissue using laser ablation-inductively coupled plasma-mass spectrometry. This work provides insight into strategies to target metal complexes to amyloid-β plaques, and how small modifications to ligands can dramatically alter the metabolic stability of metal complexes as well as their ability to cross the blood−brain barrier.

The essential elements of Alzheimer’s disease

“…The bis(thiosemicarbazone) scaffold coordinates Cu 2+ with a range of affinities, depending on its side groups. Members of this chemical class have been considered as potential PET imaging agents that could exchange radiocopper with Aβ as a guide to Aβ deposition (224)(225)(226)(227). Two of these, CuGTSM and CuATSM have been tested in animal models of AD.…”

Copper Coordination Compounds as Biologically Active Agents

“…(Table 3) Cu-ATSM 14 is a biologically active copper coordination compound based on thiosemicarbazides ( Figure 6). This drug labeled with the radioactive isotopes 64 Cu, 62 Cu, and 60 Cu was used as a PET hypoxia imaging agent in head and neck cancer [49]. It demonstrated better results in clinical trials than the 18-fluorodeoxyglucose used in clinical practice [50,51].…”

Copper Complexes of Benzoylacetone Bis-Thiosemicarbazones: Metal and Ligand Based Redox Reactivity

“…The C-C and C-N bond lengths within the six-membered chelate ring are intermediate of double and single bonds. The mean length for a localised C=N (imine) group coordinated to a transition metal is 1.287 Å (n ¼ 40), while a C-C (single) bond within a protonated acac-diimine configuration bearing an sp 3 hybridised apical C-atom is on average 1.480 Å (n ¼ 17). Of those complexes recorded as delocalised across the sixmembered chelate ring (all sp 2 hybridised) the mean values were 1.321 Å (C-N, n ¼ 21) and 1.385 Å (C-C, n ¼ 98), which agree with the bond lengths in this structure.…”

“…Apart from the interesting electronic properties that they impart on the metal, they are also readily functionalised at the terminal N 4 -atom of the thiosemicarbazone. Donnelly and co-workers utilised this property to prepare bifunctional chelators [1][2][3] that have found particular use in medical imaging with radioactive Cu isotopes.…”