molecular nuclear imaging 성균관의대 핵의학교실 이 경한 current status
TRANSCRIPT
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MOLECULAR
NUCLEAR IMAGING
성균관의대 핵의학교실 이 경한
Current Status
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AREAS OF DISCUSSION
What is Molecular Imaging ?
Why Molecular Nuclear Imaging ?
Current Status of Molecular Imaging
Prospects of Future Techniques
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WHAT IS
MOLECULAR IMAGING ?
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"You can’t make an omelet without breaking eggs." — V. I. Lenin
:The omelet is the molecular imaging approach to diagnosis, and the eggs are the old ways of thinking about anatomically based imaging
Molecular Imaging: The Diagnostic Imaging Revolution
— SM. Larson, MSKC Center
A paradigm shift away from traditional anatomically based imaging toward methods for imaging biochemical changes within cells
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These discoveries have led to an increased understanding of the fundamental mechanisms of disease and to the development of genetically based therapies
BACKGROUND
Tremendous advances in molecular biology have revealed: - sequence, structure, and function of genes and proteins - physicochemical properties of ligands and receptors - crucial details cell signaling pathways
Research in biologic sciences combined with exploration in imaging sciences could allow us to image the molecular basis of disease or image responses to therapy on a molecular level
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Molecular imaging springs from the joining of two powerful forces - On the one hand, there has been an explosion of knowledge regarding molecular biology - On the other hand, there have been marvelous advances in imaging technology, based on improved electronics and new tracers for key molecules in cell biology
Molecular imaging methods mentioned that are applicable to clinical medicine include gamma camera imaging, SPECT, PET, MRI, MRS, optical imaging, and ultrasound
Over 20,000 articles in Medline lay claim to "molecular imaging" as a component of their approach
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Noninvasive imaging of the key molecules and molecular-based events that are fundamental to the biology of human disease
An emerging field of study that deals with imaging of ds on a cellular or genetic level
New abilities of diagnostic imaging methods to detect and characterize cell biology in ds states
A growing research discipline aimed at developing and testing novel tools, reagents, and methods to image specific molecular pathways invivo, particularly those that are key targets in ds processes
DEFINITION
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WHY
MOLECULAR IMAGING
in NUCLEAR MEDICINE ?
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“Advances in molecular biology begun now will dramatically impact medicine practiced tomorrow.”
“Because nuclear medicine is inherently molecular, we are poised for a pivotal role in future medical advances.”
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SNM, 2001
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Pinwica Worms
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ICMICs (P50s)
Massachusetts General Hospital Ralph Weissleder, PI
Memorial Sloan Kettering Cancer Center Ron Blasberg, PI
University of California – Los Angeles Harvey Herschman, PI
Biomedical Imaging Program (BIP)
NCI has recognized the great untapped potential of imaging technology and identified it as an area of extraordinary opportunity
NCI has awarded three grants to support "In vivo Cellular and Molecular Imaging Centers“ that will facilitate interaction among scientists from a variety of fields to conduct multidisciplinary research on molecular imaging
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Pre-ICMICs (P20s)
Duke University Ed Coleman, PI
Case Western Reserve University James Willson, PI
Indiana University Gary Hutchins, PI
Johns Hopkins University Zaver Bhujwalla, PI
Stanford King Li, PI
University of California - Irvine Orhan Nalcioglu, PI
University of California - San Diego Robert Mattrey, PI
University of Iowa Michael Graham, PI
University of Michigan Brian Ross, PI
University of Missouri Wynn Volkert, PI
University of Pennsylvania Jerry Glickson, PI
University of Southern California Peter Conti, PI
University of Texas Southwestern Ralph Mason, PI
University of Wisconsin - Madison Tom Grist, PI
Vanderbilt University David Piston, PI
Washington University David Piwnica-Worms, PI
The NCI has also funded 16 Pre-ICMIC planning grants which provide time and funds for investigators and institutions to prepare themselves, organizationally and scientifically, to establish an ICMIC
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CURRENT STATUS
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GENE EXPRESSION IMAGING
Weissleder R.Radiology, 2001:219
Weissleder, MGH
The influence of the Human Gene Project on diagnostic imaging will be widespread
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Vectors
GENE THERAPY
Delivery
Swisher, MD Anderson
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Current Methods for Detecting Gene Expression
Northen Blot
Southern Blot
Western Blot for proteins
Immunostaining for proteins
Staining for b-galactosidase
Luminometric measurements for luciferase
Flurosecent imaging for GFP
GFP gene
--Gal gene
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HSV Thymidine Kinase Imaging
Gambhir, UCLA
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Carcinoembryonic antigen gene: radioiodine COL-1 imaging
Dopamine type 2 receptor gene: 11C-raclopride, 18F-FESPimaging
Sodium/Iodine Symporter gene: radioiodine imaging
Other specific cell surface receptor gene: Radioligand imaging
Receptor or Transporter Mediated Gene Imaging
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0
5000
10000
15000
20000
25000
Control TrkA
NG
F B
indi
ng (
cpm
)
p<0.001
0
5000
10000
15000
20000
25000
30000
35000
40000
TC on TC off
TA-88 cells
P<0.02
Gene Transfer and NGF Receptor Imaging
KH Lee, 2001
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Weissleder, 1999
MRI Methods for Gene Imaging
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Weissleder, 1999
Optical Methods for Gene Imaging
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Luciferase for Real-Time Indicator of Gene Activation
HIV LTR promoter was activated with DMSO and topical application of substrate of half of the back of a LTR-luc Tg mouse
Contag, Standford, 1997
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Source: fluorescence, absorption, reflectance, bioluminescenc
e
Imaging - Diffuse optical tomography - Reflectance diffuse tomography - Phase-array detection - Confocal imaging - Multiphoton imaging - Intravital microscopy
Near-infrared fluorescence imaging: proteases (cathepsin D/H
)
Fluorescent technique: GFP
Bioluminescence technique: Luciferase
OPTICAL IMAGING
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Current Methods for In vivo Gene Imaging
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ANGIOGENESIS IMAGING
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v
[18F]Galacto-RGD PET of Melanoma Bearing Mice
Haubner R, Cancer Res 2001
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Apoptosis: a physiologic form of programmed cell death
Signaling – amplification of signals – activation of caspases – DNA fragmentation
Defective apoptosis : cancer, autoimmune ds, viral infection
Hyperactive apoptosis: AIDS, neurodegenerative ds, ischemia, stroke, myelodysplastic synd.
APOPTOSIS IMAGING
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In Vivo Detection of Phosphatidylserine Expression During Programmed Cell Death
Blankenberg FG, PNAS USA 1998
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Cytoxan Control
Blankenberg FG, PNAS USA 1998
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Hofstra L, JAMA. 2001
Detection of Apoptosis in Cardiac Tumor
Tc-99m labeled Annexin-V, a high affinity molecule for phosphatidyl-serine which is expressed on cell surface in the terminal stages of apoptosis
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Labeled caspase-3 peptide substrates (asp-glut-val-asp sequence)
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Development of transgenic/knockout mice to model human ds Need for phenotyping imaging of small animals
Imaging of Genetically Manipulated Animals
Micro-MR imaging
- In vivo resolution 50 m in 3 hr (vs. 800 m for humans)
Micro-CT
- In vivo resolution of 50 m in 20 min - Ex vivo resolution of 4 um
Micro-PET imaging
- UCLA: resolution of 2 mm - MGH: resolution of 1 mm
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Autoradiography Small Animal PET
SNM, 2001
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Ankyrin B (-/-)
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Obese transgene
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FUTURE PROSPECTS
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Development of radiotracers for reporter gene imaging
Development of mutant surface receptors for reporter imaging
Development of new vectors for reporter gene imaging
Imaging protein interactions of signal transduction pathways
Imaging of cell surface receptor regulation
Imaging of specific cell transporters
Imaging of gene expression with antisense oligonucleotides
Endogenous Gene Expression Imaging
Transgene Expression Imaging
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Imaging tumor vasculature to assess angiogenesis
Imaging tumor oncogenes or proto-oncogenes
Imaging tumor suppressor genes
Imaging tumor apoptosis
Tumor Biology Imaging
Imaging drug resistance
Imaging to assess chemotherapeutic response
Imaging to monitor gene therapy response
Imaging molecular therapy response
Tumor Therapy Resonse Monitoring
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Imaging cell surface expressed growth factor receptors
Development of novel peptido-mimetics for imaging
Cell Growth Factor Receptor Imaging
Integration of multi-modality equipment and techniques
Utilization of microPET in living animals
New Instrumentation
Cell Trafficking Imaging
In vivo tracking of progenitor or immune cells
In vivo tracking of viral delivery for gene therapy
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IMAGING ENDOGENOUS GENE EXPRESSION
Construction of dual gene vectors for imaging
M. Doubrovin, PNAS, 2001
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M. Doubrovin, PNAS, 2001
Test virus in right shoulder, negative control in left shoulder,and positive control in the left thigh
Imaging Transcriptional Regulation of p53-Dependent Genes with PET
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99mTc-MIBI assessment of MDR1 overexpression in musculoskeletal sarcomas compared with therapy response
IMAGING DRUG RESISTANCE
Burak Z, Eur J Nucl Med. 2001
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1. Develop new radioprobes that are SN to detect early abnormalities
2. Develop techniques that predict clinical course and tx response
3. Foster interaction and collaboration among imaging scientists and basi
c biologists, chemists, and physicists to advance imaging research
4. Create infrastructures to advance research in developing, assessing, an
d validating new imaging techniques and assessment methodologies
GOAL OF FUTURE EFFORTS
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Weissleder, MGH
Molecular targets for therapeutic drugs will increase form a current 500 to an excess of 10,000 in the near future
Imaging Downstream
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“ It is expected that the fruits of todays molecular imaging research will have a direct effect on patient care within the next 5-15 years” - Weissleder, 2001
SNM, 2001
Interdisciplinary interactions