neuro-primary-mental-health-2017-keynote

8 / 8

Page 46
J Neurol Neurorehabil Res 2017 | Volume 2 Issue 3
allied
academies
17th International Conference on 4 th International Conference on
NEUROLOGY AND NEUROSCIENCE & MENTAL HEALTH AND PRIMARY CARE
October 16-18, 2017 | Toronto, Canada
Vijay Sharma
Washington University School of Medicine, USA
Interplay between Intuition and Design of PET Tracers to Counteract Challenges
for Imaging Alzheimer’s Diseas
Alzheimer’s disease (AD) is a devastating neurodegenerative
disorder characterized by progressive decline in cognitive
functions. For therapeutic interventions (antibodies;
anti-amyloid disease modifying drugs and small organic
molecules; BACE 1 Inhibitors) to be effective, drugs need to be
administered at earliest stages prior to clinical manifestation
of the disease. For stratification of patients likely to be
benefitted from a given mode of treatment, it is imperative to
diagnose AD at prodromal stages for offering significant help to
effected individuals. To accomplish this objective, Florbetapir,
Flutemetamol, and Florbetaben have gained FDA approval for
Aβ imaging. Although promising for visualizing compact plaques
in vivo, these agents also show high nonspecific white matter
retention, cross reactivity with other β-sheet structures (myelin
binding protein), and are unable to detect oligomers and
diffuse Aβ plaques. To achieve an accurate quantification of Aβ
pathophysiology non-invasively, a highly specific (at a molecular
level) yet sensitive 18F-PET agent, potentially capable of binding
to both fibrillar and diffuse plaques, to enable ultrasensitive
detection capability (at prodromal stages of the disease)
would be desired. To accomplish this objective, our lab has
rationally designed a novel heterocyclic fluorescent molecule
(named Fluselenamyl) belonging to an entirely new class of
molecules that shows concentration dependent and saturable
binding, with Kd values of 1.4±0.35nM and 2.9 ±1.35nM, to
AD homogenates and preformed Aβ1-42 fibrils, respectively.
The agent detects both fibrillar plaques and displays cerebral
amyloid angiopathy (CAA) ex vivo in the hippocampus regions
of brain sections in APPsw+/-/PS1 mice, while also exhibiting
high sensitivity for detecting diffuse plaques, compact plaques,
and vascular deposits (CAA) in human tissues. Further, the PET
tracer 18F-Fluselenamyl demonstrates an extremely high
first pass extraction in brains (8.86 ± 0.32 %ID/g %ID/g; 2
min post tail-vein injection) of FVB mice, and followed by a
washout (25% faster than 18F-Avid 45) in absence of targeted
plaques. ComparedwithFDAapproved tracers undergoing facile
metabolism in vivo, 18F-Fluselenamyl remains non-metabolized
in human serumup to 3h. Additionally, multiphotonmicroscopy
in live APPsw+/-/PS1 (15 months old) mice demonstrates
that Fluselenamyl traverses the blood brain barrier (BBB)
instantaneously to label plaques in brain parenchyma and blood
vessels (CAA). Furthermore, microPET/CT imaging shows higher
brain uptake of the radiotracer (30 min post-tail-vein injection),
and its retention in the cortex of transgenicmice comparedwith
their age-matched Bl6 counterparts, consistent with the binding
of the tracer to Aβ plaques, which also correlates with ex vivo
autoradiography and immunohistochemistry. While dosimetry
studies in mice (n=40), using MIRD methodology indicate an
effective dose equivalent of 18F-Fluselenamyl to an allowable
maximum injection of 20 mCi in humans, the radiotracer also
penetrates primate brain (5%ID/g), and clears to background
levels in the absence of targeted plaques. Finally and
importantly, Fluselenamyl provides a highly specific molecular
signature for AD (displays no cross-reactivity with biomarkers of
other neurodegenerative diseases); while also detecting diffuse
and compact plaques in an 11C-PIB PET imaging negative, but an
Aβ+ AD case. Some of these aspects would be compared with
the existing state-of- the art in Neuro2017.
Speaker Biography
Following post-doctoral training with Prof. Jim Wuest in University of Montreal, Que-
bec, Canada, Dr. Sharma joined in August 1994 Mallinckrodt Institute of Radiology,
Washington University School of Medicine, St. Louis. He is currently a tenured pro-
fessor within departments of Radiology, Neurology, and Biomedical Engineering. Dr.
Sharma is also a founding member of the ICCE institute, member of Siteman cancer
center, and director of the radiopharmaceutical sciences in Molecular Imaging Cen-
ter, AMGEN faculty mentor, and program director of MIR summer research program.
He is a NIH funded principal investigator for over 20 years in biomedical research. Dr.
Sharma serves on review panel of over 40 plus biomedical journals in interdisciplinary
sciences, editorial boards, grant review panels for National Institutes of Aging (NIA),
Mental Health (NIMH), Allergies and Infectious Diseases (NIAID), Centers for Excellence
& Commercialization of Research (CECR, NSERC, Canada), and Killam Faculty Fellow-
ship Awards (NSERC, Canada), national foundations, and AXA Research Fund, Paris,
France. At School of Medicine, Dr. Sharma directs a research program focused upon
design and development of PET tracers for biomedical imaging in neurodegenerative
diseases, interrogating roles of adenosine binding cassette (ABC)-family of transport-
ers in chemotherapeutic resistance including blood brain barrier, cancer biology, and
cardiovascular diseases.
e: