Review
Diagnostic imaging of Alzheimer's disease with copper and technetium complexes

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Abstract

The most common form of dementia is Alzheimer's disease, a progressive neurodegenerative disease that leads to synaptic failure and neuronal death. This review discusses the development of copper and technetium coordination complexes designed as radiopharmaceuticals to assist in the diagnosis of Alzheimer's disease using positron emission tomography or single photon emission computed tomography. Technetium complexes used to image regional brain perfusion are discussed as well as copper and technetium complexes specifically designed to bind to amyloid-β plaques that are associated with the onset of symptoms of the disease.

Highlights

► Copper and technetium complexes designed to assist in diagnosis of Alzheimer's disease. ► Technetium complexes used to image regional brain perfusion. ► Copper and technetium complexes designed to bind to amyloid-β plaques. ► Copper complexes used to measure changes in copper metabolism.

Section snippets

Alzheimer's disease

The most common form of dementia is Alzheimer's disease (AD), a progressive neurodegenerative disease that leads to synaptic failure and neuronal death. These symptoms can initially manifest as mild forgetfulness but progress to complete loss of cognition and ultimately death [1], [2]. The condition is more prevalent in older people and an ageing population means its prevalence is set to increase. Characteristic pathological hallmarks in the brains of those suffering with the disease include

Single photon emission computed tomography and positron emission tomography

The techniques of single photon emission computed tomography (SPECT) and positron emission tomography (PET) offer the opportunity of non-invasive imaging to enhance diagnosis and monitor therapeutic intervention. They involve the use of radiolabelled compounds (tracers) that are injected into a patient and an external detector detects the emitted radiation. SPECT relies on tracers that emit γ-radiation whereas PET relies on a tracer that emits a positron that annihilates, releasing two gamma

Diagnosis of Alzheimer's disease using positron emission tomography

A challenge in diagnostic imaging of AD is to achieve earlier diagnosis and differential diagnosis from other types of neurodegeneration. Early diagnosis is seen as a critical precursor to effective treatment and preventative strategies. Whilst new therapeutic strategies for the treatment of AD are under development, there is an urgent need for tools to monitor the progress of treatment [2], [12]. Other causes of loss of brain function can complicate a definitive diagnosis of AD. Older people

Copper radioisotopes for diagnostic imaging

In principle, the rapid and simple incorporation of a radioactive metal ion into a specific targeting ligand is an attractive alternative to covalent modification with 11C or 18F. The system must be carefully designed, and factors such as complexation kinetics, thermodynamic stability and biodistribution need to be considered. Copper-64 is a positron emitter with a half-life of 12.7 h and ideal properties for PET imaging [27], [28], [29]. The long half-life of copper-64 allows PET imaging to be

Bis(thiosemicarbazone) ligands for copper radiopharmaceuticals

The bis(thiosemicarbazone) family of ligands derived from 1,2-diones have been investigated for several decades and early studies into their pharmacological activity focussed on their potential as anti-tumour agents where the compounds were administered as “free” ligands [34]. Subsequent studies demonstrated the importance of copper ions to their biological activity [35], [36], [37]. Upon binding copper(II) the ligands doubly deprotonate and act as dianionic N2S2 quadridentate ligands to

Copper radiopharmaceuticals for diagnostic imaging of Alzheimer's disease

A considerable challenge in developing metal-based complexes to act as radioactive tracers to be used for neuroimaging applications is to design metal complexes that are capable of crossing the blood–brain barrier (BBB), a series of endothelial cells with tight junctions that serve to prevent the passage of chemicals from the blood into the brain tissue. It is generally accepted that only certain small molecules (generally MW < 600 Da) within a designated window of lipophilicity are capable of

Technetium-99m brain imaging radiopharmaceuticals

Although the increase in the application of 18F-FDG imaging to assist in the diagnosis of a variety of indications has led to an increase in the number of hospitals equipped with PET infrastructure, SPECT remains the major nuclear medicine technique due, at least in part, to the greater number of hospitals that possess the requisite equipment. The most commonly used radioisotope for SPECT is 99mTc, and importantly unlike 18F that requires a cyclotron for production of tracers, 99mTc is readily

Technetium radiopharmaceuticals for diagnostic imaging of Alzheimer's disease

Attempts to provide technetium complexes suitable for diagnostic imaging of Aβ plaque burden have generally involved a bifunctional chelate approach, where ligands suitable for technetium are tethered to known plaque binding functional groups such as benzothiazoles and congo-red inspired derivatives. The organic dyes, congo red and chrysamine G both bind to Aβ plaques (as well as other amyloid proteins) An attempt to adapt these dyes to coordinate radioactive technetium was achieved by

Plaque targeting functionalised N2S2 ligands for the [TcVO]3+ core

A related approach is to tether a chrysamine G derivative to a monoamide-monoamine dithiol ligand (H3L4), that is capable of acting as trianionic N2S2 tetradentate ligand to a [TcVO]3+ core to give five coordinate square pyramidal neutral complexes (Fig. 12). During the synthesis of the ligand the thiol groups are protected with S-trityl functional groups, a commonly adopted strategy for the use of dithiol containing ligands to prevent oxidation to disulphides. The S-trityl protecting groups

Plaque targeting technetium-99m complexes using the fac-[TcI(CO)3]+ core

A change from using the [TcVO]3+ core and quadridentate N2S2 ligands is the use of the low valent fac-[TcI(CO)3]+ core. Seminal developments in synthetic methods that allow the preparation of technetium compounds of the type fac-[TcI(CO)3(H2O)3]+ under conditions amenable to radiopharmaceutical applications have stimulated the focus on this approach and reinvigorated research into targeted technetium radiopharmaceuticals [120], [121]. The “carbonyl core” approach exploits the stability of the

Summary and outlook

AD is an age-related progressive neurodegenerative disease and an ageing population has led some to warn of an impending dementia epidemic. The actual contributions of Aβ plaques, oligomers and neurofibrillary tangles to cognitive decline continue to be debated and there is much about the disease that is not understood. The advent of non-invasive imaging technology where specifically designed radiopharmaceuticals localise in selected molecular targets, such as Aβ plaques, does offer the

Acknowledgements

Ms. SinChun Lim, Dr. Michelle T. Fodero-Tavoletti, Dr. Victor L. Villemagne and A.Prof. Kevin J. Barnham (all from the University of Melbourne) are thanked for their vital contributions to our ongoing collaborative research in this area. Financial support from the Australian Research Council and the National Health and Medical Research Council (Australia) is greatly appreciated.

References (131)

  • M.T. Fodero-Tavoletti et al.

    Int. J. Biochem. Cell Biol.

    (2011)
  • W.E. Klunk et al.

    Life Sci.

    (2001)
  • C.A. Mathis et al.

    Nucl. Med. Biol.

    (2007)
  • M. Ono et al.

    Nucl. Med. Biol.

    (2003)
  • X. Chen

    J. Mol. Struct. (Theochem.)

    (2006)
  • W. Zhang et al.

    Nucl. Med. Biol.

    (2007)
  • C.C. Rowe et al.

    Lancet Neurol.

    (2008)
  • P.J. Blower et al.

    Nucl. Med. Biol.

    (1996)
  • S.V. Smith

    J. Inorg. Biochem.

    (2004)
  • V.S. Le et al.

    Appl. Radiat. Isot.

    (2009)
  • D. Petering

    Biochem. Pharmacol.

    (1974)
  • M.A. Green et al.

    Nucl. Med. Biol.

    (2007)
  • A.L. Vāvere et al.

    Nucl. Med. Biol.

    (2008)
  • Y. Arano et al.

    Int. J. Nucl. Med. Biol.

    (1986)
  • W.M. Pardridge

    Drug Discov. Today

    (2007)
  • M. Ikawa et al.

    Nucl. Med. Biol.

    (2011)
  • M.A. Lovell et al.

    J. Neurol. Sci.

    (1998)
  • A.R. White et al.

    Brain Res.

    (1999)
  • C.J. Maynard et al.

    J. Inorg. Biochem.

    (2006)
  • K.J. Barnham et al.

    J. Biol. Chem.

    (2003)
  • P.S. Donnelly et al.

    Curr. Opin. Chem. Biol.

    (2007)
  • P.A. Adlard et al.

    Neuron

    (2008)
  • P.S. Donnelly et al.

    J. Biol. Chem.

    (2008)
  • P. Richards et al.

    Int. J. Appl. Radiat. Isot.

    (1982)
  • G.S. Thomas et al.

    J. Nucl. Cardiol.

    (2010)
  • S.R. Banerjee et al.

    Nucl. Med. Biol.

    (2005)
  • F. Tisato et al.

    Coord. Chem. Rev.

    (1994)
  • G. Bandoli et al.

    Coord. Chem. Rev.

    (2001)
  • G. Bandoli et al.

    Coord. Chem. Rev.

    (2006)
  • Y. Fujibayashi et al.

    Nucl. Med. Biol.

    (1998)
  • A. Gardner et al.

    Nucl. Med. Biol.

    (2004)
  • V.L. Villemagne et al.

    J. Clin. Neurosci.

    (2005)
  • D.O. Slosman et al.

    Brain Res. Rev.

    (2001)
  • S. Lever et al.

    Inorg. Chim. Acta

    (1990)
  • H.F. Kung et al.

    Nucl. Med. Biol.

    (2007)
  • C.L. Masters et al.

    J. Neurochem.

    (2006)
  • M. Citron

    Nat. Rev. Drug Discov.

    (2010)
  • C.L. Masters et al.

    Proc. Natl. Acad. Sci. U.S.A.

    (1985)
  • J.A. Hardy et al.

    Science (N.Y.)

    (1992)
  • J.A. Hardy et al.

    Science (N.Y.)

    (2002)
  • D.J. Selkoe

    Nat. Med.

    (2011)
  • E. Karran et al.

    Nat. Rev. Drug Discov.

    (2011)
  • J. Marx

    Science (N.Y.)

    (2007)
  • L.M. Ittner et al.

    Nat. Rev. Neurosci.

    (2011)
  • P. Buchhave et al.

    Arch. Gen. Psychiatry

    (2012)
  • C.C. Rowe et al.

    J. Nucl. Med.

    (2011)
  • M.T. Fodero-Tavoletti et al.

    J. Neurosci.

    (2007)
  • C.A. Mathis et al.

    J. Med. Chem.

    (2003)
  • D.E. Huddleston et al.

    Nat. Clin. Prac. Neurol.

    (2005)
  • W. Zhang et al.

    J. Med. Chem.

    (2005)
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