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

Lachlan E. McInnes, Asif Noor, Kai Kysenius, Carleen Cullinane, Peter Roselt, Catriona A. McLean, Francis C.K. Chiu, Andrew K. Powell, Peter J. Crouch, Jonathan M. White, Paul S. Donnelly

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)3382-3395
Number of pages14
JournalInorganic Chemistry
Volume58
Issue number5
DOIs
Publication statusPublished - 4 Mar 2019

Cite this

McInnes, Lachlan E. ; Noor, Asif ; Kysenius, Kai ; Cullinane, Carleen ; Roselt, Peter ; McLean, Catriona A. ; Chiu, Francis C.K. ; Powell, Andrew K. ; Crouch, Peter J. ; White, Jonathan M. ; Donnelly, Paul S. / Potential Diagnostic Imaging of Alzheimer's Disease with Copper-64 Complexes That Bind to Amyloid-β Plaques. In: Inorganic Chemistry. 2019 ; Vol. 58, No. 5. pp. 3382-3395.
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title = "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.",
author = "McInnes, {Lachlan E.} and Asif Noor and Kai Kysenius and Carleen Cullinane and Peter Roselt and McLean, {Catriona A.} and Chiu, {Francis C.K.} and Powell, {Andrew K.} and Crouch, {Peter J.} and White, {Jonathan M.} and Donnelly, {Paul S.}",
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McInnes, LE, Noor, A, Kysenius, K, Cullinane, C, Roselt, P, McLean, CA, Chiu, FCK, Powell, AK, Crouch, PJ, White, JM & Donnelly, PS 2019, 'Potential Diagnostic Imaging of Alzheimer's Disease with Copper-64 Complexes That Bind to Amyloid-β Plaques', Inorganic Chemistry, vol. 58, no. 5, pp. 3382-3395. https://doi.org/10.1021/acs.inorgchem.8b03466

Potential Diagnostic Imaging of Alzheimer's Disease with Copper-64 Complexes That Bind to Amyloid-β Plaques. / McInnes, Lachlan E.; Noor, Asif; Kysenius, Kai; Cullinane, Carleen; Roselt, Peter; McLean, Catriona A.; Chiu, Francis C.K.; Powell, Andrew K.; Crouch, Peter J.; White, Jonathan M.; Donnelly, Paul S.

In: Inorganic Chemistry, Vol. 58, No. 5, 04.03.2019, p. 3382-3395.

Research output: Contribution to journalArticleResearchpeer-review

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AU - McInnes, Lachlan E.

AU - Noor, Asif

AU - Kysenius, Kai

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AU - Donnelly, Paul S.

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