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

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.

doi:10.1021/ja4057807

Cited by 97 publications

(122 citation statements)

References 77 publications

(156 reference statements)

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“…[24] It is noteworthy that exploration of the “metal hypothesis of AD” with PET is actively pursued by several laboratories, with recent accounts of carbon-11 and fluorine-18 labeled analogs of L2-b ( N 1 , N 1 -dimethyl- N 4 -(pyridin-2-ylmethyl)benzene-1,4-diamine)s[25] and copper-64-labeled bis(thiosemicarbazonato)Cu II complexes. [26,27]…”

Section: Introductionmentioning

confidence: 99%

PET Neuroimaging Studies of [¹⁸F]CABS13 in a Double Transgenic Mouse Model of Alzheimer’s Disease and Nonhuman Primates

Liang

Holland

Stephenson

et al. 2015

ACS Chem. Neurosci.

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Fluorine-18 labeled 2-fluoro-8-hydroxyquinoline ([18F]CABS13) is a promising positron emission tomography (PET) radiopharmaceutical based on a metal chelator developed to probe the “metal hypothesis of Alzheimer’s disease”. Herein, a practical radiosynthesis of [18F]CABS13 was achieved by radiofluorination followed by deprotection of an O-benzyloxymethyl group. Automated production and formulation of [18F]CABS13 resulted in 19 ± 5% uncorrected radiochemical yield, relative to starting [18F]fluoride, with ≥95% chemical and radiochemical purities, and high specific activity (>2.5 Ci/μmol) within 80 minutes. Temporal PET neuroimaging studies were carried out in female transgenic B6C3- Tg(APPswe,PSEN1dE9)85Dbo/J (APP/PS1) and age-matched wild-type (WT) B6C3F1/J control mice at 3, 7 and 10 months of age. [18F]CABS13 showed an overall higher uptake and retention of radioactivity in the central nervous system of APP/PS1 mice versus WT mice with increasing age. However, PET/magnetic resonance imaging in normal non-human primates revealed that the tracer had low uptake in the brain and rapid formation of a hydrophilic radiometabolite. Identification of more metabolically stable 18F-hydroxyquinolines that can be readily accessed by the radiochemical strategy presented herein is underway.

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Section: Introductionmentioning

confidence: 99%

PET Neuroimaging Studies of [¹⁸F]CABS13 in a Double Transgenic Mouse Model of Alzheimer’s Disease and Nonhuman Primates

Liang

Holland

Stephenson

et al. 2015

ACS Chem. Neurosci.

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“…218 It is widely accepted that amyloid peptides are formed by the cleavage of amyloid precursor protein (APP) by various secretase enzymes. 252 It was also found that these processes can be suppressed by the wellknown copper chelator D-penicillamine.…”

Section: Thermodynamic Kinetic and Structural Studies On The Metal Cmentioning

confidence: 99%

Metal complexes of amino acids and peptides

Farkas¹,

Sóvágó²

2014

Amino Acids, Peptides and Proteins

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“…More recently a novel metal imaging PET approach has been developed, using radioactive coordination bis(thiosemicarbazonato)copper complex of 64 Cu. This targets copper homeostasis and has been designed to bind selectively to amyloid plaques (Hickey et al, 2013). Copper radiolabels are essential for increasing our understanding on of the mechanisms of copper dyshomeostasis in AD.…”

Section: General Overview Of Elemental Imaging Techniques For Biologimentioning

confidence: 99%

Metal and complementary molecular bioimaging in Alzheimer's disease

Braidy

Poljak

Marjo

et al. 2014

Front. Aging Neurosci.

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Alzheimer's disease (AD) is the leading cause of dementia in the elderly, affecting over 27 million people worldwide. AD represents a complex neurological disorder which is best understood as the consequence of a number of interconnected genetic and lifestyle variables, which culminate in multiple changes to brain structure and function. These can be observed on a gross anatomical level in brain atrophy, microscopically in extracellular amyloid plaque and neurofibrillary tangle formation, and at a functional level as alterations of metabolic activity. At a molecular level, metal dyshomeostasis is frequently observed in AD due to anomalous binding of metals such as Iron (Fe), Copper (Cu), and Zinc (Zn), or impaired regulation of redox-active metals which can induce the formation of cytotoxic reactive oxygen species and neuronal damage. Metal chelators have been administered therapeutically in transgenic mice models for AD and in clinical human AD studies, with positive outcomes. As a result, neuroimaging of metals in a variety of intact brain cells and tissues is emerging as an important tool for increasing our understanding of the role of metal dysregulation in AD. Several imaging techniques have been used to study the cerebral metallo-architecture in biological specimens to obtain spatially resolved data on chemical elements present in a sample. Hyperspectral techniques, such as particle-induced X-ray emission (PIXE), energy dispersive X-ray spectroscopy (EDS), X-ray fluorescence microscopy (XFM), synchrotron X-ray fluorescence (SXRF), secondary ion mass spectrometry (SIMS), and laser ablation inductively coupled mass spectrometry (LA-ICPMS) can reveal relative intensities and even semi-quantitative concentrations of a large set of elements with differing spatial resolution and detection sensitivities. Other mass spectrometric and spectroscopy imaging techniques such as laser ablation electrospray ionization mass spectrometry (LA ESI-MS), MALDI imaging mass spectrometry (MALDI-IMS), and Fourier transform infrared spectroscopy (FTIR) can be used to correlate changes in elemental distribution with the underlying pathology in AD brain specimens. Taken together, these techniques provide new techniques to probe the pathobiology of AD and pave the way for identifying new therapeutic targets. The current review aims to discuss the advantages and challenges of using these emerging elemental and molecular imaging techniques, and highlight clinical achievements in AD research using bioimaging techniques.

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

Cited by 97 publications

References 77 publications

PET Neuroimaging Studies of [¹⁸F]CABS13 in a Double Transgenic Mouse Model of Alzheimer’s Disease and Nonhuman Primates

PET Neuroimaging Studies of [¹⁸F]CABS13 in a Double Transgenic Mouse Model of Alzheimer’s Disease and Nonhuman Primates

Metal complexes of amino acids and peptides

Metal and complementary molecular bioimaging in Alzheimer's disease

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

Cited by 97 publications

References 77 publications

PET Neuroimaging Studies of [18F]CABS13 in a Double Transgenic Mouse Model of Alzheimer’s Disease and Nonhuman Primates

PET Neuroimaging Studies of [18F]CABS13 in a Double Transgenic Mouse Model of Alzheimer’s Disease and Nonhuman Primates

Metal complexes of amino acids and peptides

Metal and complementary molecular bioimaging in Alzheimer's disease

Contact Info

Product

Resources

About

PET Neuroimaging Studies of [¹⁸F]CABS13 in a Double Transgenic Mouse Model of Alzheimer’s Disease and Nonhuman Primates

PET Neuroimaging Studies of [¹⁸F]CABS13 in a Double Transgenic Mouse Model of Alzheimer’s Disease and Nonhuman Primates