Copper(II) Binding to PBT2 Differs from That of Other 8-Hydroxyquinoline Chelators: Implications for the Treatment of Neurodegenerative Protein Misfolding Diseases

Abstract

PBT2 (5,7-dichloro-2-[(dimethylamino)­methyl]-8-hydroxyquinoline) is a small Cu­(II)-binding drug that has been investigated in the treatment of neurodegenerative diseases, namely, Alzheimer’s disease (AD). PBT2 is thought to be highly effective at crossing the blood–brain barrier and has been proposed to exert anti-Alzheimer’s effects through the modulation of metal ion concentrations in the brain, specifically the sequestration of Cu­(II) from amyloid plaques. However, despite promising initial results in animal models and in clinical trials where PBT2 was shown to improve cognitive function, larger-scale clinical trials did not find PBT2 to have a significant effect on the amyloid plaque burden compared with controls. We propose that the results of these clinical trials likely point to a more complex mechanism of action for PBT2 other than simple Cu­(II) sequestration. To this end, herein we have investigated the solution chemistry of Cu­(II) coordination by PBT2 primarily using X-ray absorption spectroscopy (XAS), high-energy-resolution fluorescence-detected XAS, and electron paramagnetic resonance. We propose that a novel bis-PBT2 Cu­(II) complex with asymmetric coordination may coexist in solution with a symmetric four-coordinate Cu­(II)-bis-PBT2 complex distorted from coplanarity. Additionally, PBT2 is a more flexible ligand than other 8HQs because it can act as both a bidentate and a tridentate ligand as well as coordinate Cu­(II) in both 1:1 and 2:1 PBT2/Cu­(II) complexes.

Alzheimer’s Drug PBT2 Interacts with the Amyloid β 1–42 Peptide Differently than Other 8-Hydroxyquinoline Chelating Drugs

“…We previously found the EXAFS of a solution of excess PBT2:Cu­(II) to be best fitted to a distorted 4-coordinate Cu­(II)- bis -PBT2 coordination environment with two pyridine nitrogen ligands and two phenol oxygen ligands . Additionally, we previously found the EXAFS of a solution of equimolar Aβ(1–42) and Cu­(II) at pH 7.4 to be best fitted to an average Cu­(II) coordination environment consisting of two histidine nitrogens and two additional oxygen or nitrogen ligands .…”

“…In conventional K-edge XAS, the short lifetime of the 1s core hole causes spectral broadening and consequent loss of detail and chemical sensitivity. As described previously, − Cu K-edge HERFD-XAS uses the Cu Kα 1 fluorescence line and observes a small subset of the 2p 3/2 → 1s transitions that produce the Cu Kα 1 fluorescence, eliminating most of the lifetime broadening from the 1s core hole and improving the spectral resolution.…”

Iron Metabolism in Aging and Age-Related Diseases

“…In other words, it has low selectivity for metal ions [ 152 ]. An advanced compound, PBT2, mainly binds to excess copper and zinc and possibly iron in the brain, thereby reducing the number of amyloid plaques and relocating these metal ions to the depleted cell and neuron compartments [ 145 ].…”

8-Hydroxyquinolines: A Promising Pharmacophore Potentially Developed as Disease-Modifying Agents for Neurodegenerative Diseases: A Review

“…92 The PBT2 can form (bi-or tri-dentate) complex with Cu 2+ and demonstrated good brain penetration and good ability to sequestrate Cu 2+ from Aβ plaque. 90,140 This more structural flexibility is related to an ability of the compound to form tri-dentate complex with Cu 2+ ion which could contribute to its superior ionophoric activity beyond that of the CQ. 87 More promising anti-AD effect of the PBT2 also may be due to its potential to form bi-/tri-dentate complex with many possible Cu 2+ -binding ligand such as phenolic oxygen, tertiary amine nitrogen, and pyridine nitrogen.…”

“…87 More promising anti-AD effect of the PBT2 also may be due to its potential to form bi-/tri-dentate complex with many possible Cu 2+ -binding ligand such as phenolic oxygen, tertiary amine nitrogen, and pyridine nitrogen. 87,140 In vivo study showed that oral administration of PBT2 decreased Aβ aggregation and oligomerization in AD mice models. 87 Clinical trial phase IIa demonstrated beneficial effect on AD patients.…”