Fluselenamyl: A Novel Benzoselenazole Derivative for PET Detection of Amyloid Plaques (Aβ) in Alzheimer's Disease.
Fluselenamyl (5), a novel planar benzoselenazole shows traits desirable of enabling noninvasive imaging of Aβ pathophysiology in vivo; labeling of both diffuse (an earlier manifestation of neuritic plaques) and fibrillar plaques in Alzheimer's disease (AD) brain sections, and remarkable specificity for mapping Aβ compared with biomarker proteins of other neurodegenerative diseases. Employing AD homogenates, [18F]-9, a PET tracer demonstrates superior (2-10 fold higher) binding affinity than approved FDA tracers, while also indicating binding to high affinity site on Aβ plaques. Pharmacokinetic studies indicate high initial influx of [18F]-9 in normal mice brains accompanied by rapid clearance in the absence of targeted plaques. Following incubation in human serum, [18F]-9 indicates presence of parental compound up to 3h thus indicating its stability. Furthermore, in vitro autoradiography studies of [18F]-9 with AD brain tissue sections and ex vivo autoradiography studies in transgenic mouse brain sections show cortical Aβ binding, and a fair correlation with Aβ immunostaining. Finally, multiphoton- and microPET/CT imaging indicate its ability to penetrate brain and label parenchymal plaques in transgenic mice. Following further validation of its performance in other AD rodent models and nonhuman primates, Fluselenamyl could offer a platform technology for monitoring earliest stages of Aβ pathophysiology in vivo.
ICCE Institute, Molecular Imaging Center, Washington University School of Medicine, MO 63110, USA.|Mallinckrodt Institute of Radiology, Washington University School of Medicine, MO 63110, USA.
G S M
GS
Sundaram
Department of Neurology, Washington University School of Medicine, MO 63110, USA.|Hope Center for Neurological Disorders, Washington University School of Medicine, MO 63110, USA.
Dhruva D
DD
Dhavale
ICCE Institute, Molecular Imaging Center, Washington University School of Medicine, MO 63110, USA.|Mallinckrodt Institute of Radiology, Washington University School of Medicine, MO 63110, USA.
Julie L
JL
Prior
Department of Neurology, Washington University School of Medicine, MO 63110, USA.|Hope Center for Neurological Disorders, Washington University School of Medicine, MO 63110, USA.
Ping
P
Yan
Department of Neurology, Washington University School of Medicine, MO 63110, USA.|Hope Center for Neurological Disorders, Washington University School of Medicine, MO 63110, USA.|Knight Alzheimer's Disease Research Center, Washington University School of Medicine, MO 63110, USA.
John
J
Cirrito
Departments of Chemistry &Biochemistry, University of Missouri, St. Louis, MO 63121, USA.
Nigam P
NP
Rath
Mallinckrodt Institute of Radiology, Washington University School of Medicine, MO 63110, USA.
Richard
R
Laforest
Knight Alzheimer's Disease Research Center, Washington University School of Medicine, MO 63110, USA.|Department of Pathology &Immunology, Washington University School of Medicine, MO 63110, USA.
Nigel J
NJ
Cairns
Mallinckrodt Institute of Radiology, Washington University School of Medicine, MO 63110, USA.|Department of Neurology, Washington University School of Medicine, MO 63110, USA.|Hope Center for Neurological Disorders, Washington University School of Medicine, MO 63110, USA.|Department of Biomedical Engineering, School of Engineering &Applied Science, Washington University, St. Louis, 63105, USA.
Jin-Moo
JM
Lee
Department of Neurology, Washington University School of Medicine, MO 63110, USA.|Hope Center for Neurological Disorders, Washington University School of Medicine, MO 63110, USA.
Paul T
PT
Kotzbauer
ICCE Institute, Molecular Imaging Center, Washington University School of Medicine, MO 63110, USA.|Mallinckrodt Institute of Radiology, Washington University School of Medicine, MO 63110, USA.|Department of Neurology, Washington University School of Medicine, MO 63110, USA.|Department of Biomedical Engineering, School of Engineering &Applied Science, Washington University, St. Louis, 63105, USA.
Vijay
V
Sharma
D000544:Alzheimer Disease / Q000175:diagnosis* / Q000000981:diagnostic imaging / Q000503:physiopathology*; D000818:Animals; D001345:Autoradiography / Q000379:methods; D001665:Binding Sites / Q000502:physiology; D015415:Biomarkers / Q000134:cerebrospinal fluid; D001921:Brain / Q000000981:diagnostic imaging*; D051379:Mice; D008822:Mice, Transgenic; D016566:Organoselenium Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D058225:Plaque, Amyloid / Q000000981:diagnostic imaging*; D000072078:Positron Emission Tomography Computed Tomography / Q000379:methods*; D011485:Protein Binding / Q000502:physiology
D015415:Biomarkers; D016566:Organoselenium Compounds