Targeting prion amyloid deposits in vivo.
The diagnosis of prion diseases in humans is challenging due to a lack of specific and sensitive non-invasive tests. Many forms of human prion disease including variant Creutzfeldt-Jakob disease (vCJD), Gerstmann-Sträussler-Scheinker (GSS) syndrome, and 10% of sporadic CJD cases are associated with amyloid deposition. Several positron emission tomography (PET) ligands have recently been developed to directly image beta-amyloid associated with Alzheimer disease. One of them, methoxy-X04, is a fluorescent derivative of Congo red with high binding affinity toward amyloid fibrils and good blood-brain barrier permeability. Using methoxy-X04, we investigated whether amyloid-targeting ligands can be also employed for direct imaging of amyloid deposits associated with some prion diseases. Such a method could potentially become a novel diagnostic approach for these conditions. Studies were performed on MB mice infected with the 87V mouse-adapted scrapie strain. Labeling of PrP amyloid plaques in brains of presymptomatic and symptomatic mice was demonstrated using in vivo transcranial two-photon microscopy after systemic administration of methoxy-X04. During real-time imaging, PrP amyloid deposits could be clearly distinguished 15 min after intravenous administration of methoxy-X04. The ligand showed rapid clearance from brain areas that did not contain amyloid deposits. PrP amyloid deposits could also be detected by direct application of methoxy-X04 on cerebellar sections from GSS patients. These results suggest that methoxy-X04 or similar derivatives could be used as PET imaging agents to improve the diagnosis of human prion diseases associated with amyloid deposition.
Sadowski
Marcin
M
Department of Neurology, New York University School of Medicine, New York, New York 10016, USA.
Pankiewicz
Joanna
J
Scholtzova
Henrieta
H
Tsai
Julia
J
Li
Yongsheng
Y
Carp
Richard I
RI
Meeker
Harry C
HC
Gambetti
Pierluigi
P
Debnath
Manik
M
Mathis
Chester A
CA
Shao
Li
L
Gan
Wen-Biao
WB
Klunk
William E
WE
Wisniewski
Thomas
T
D000475:Alkenes / Q000378:metabolism / Q000493:pharmacokinetics; D016229:Amyloid beta-Peptides / Q000032:analysis*; D000818:Animals; D001555:Benzene Derivatives / Q000378:metabolism / Q000493:pharmacokinetics; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology; D051379:Mice; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology*; D011237:Predictive Value of Tests; D017096:Prion Diseases / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology*; D015203:Reproducibility of Results; D012608:Scrapie / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D013267:Stilbenes; D014055:Tomography, Emission-Computed / Q000379:methods*
C465418:1,4-bis(4'-hydroxystyryl)-2-methoxybenzene; D000475:Alkenes; D016229:Amyloid beta-Peptides; D001555:Benzene Derivatives; D013267:Stilbenes