MOLECULAR

NUCLEAR IMAGING

성균관의대 핵의학교실 이 경한

Current Status

AREAS OF DISCUSSION

What is Molecular Imaging ?

Why Molecular Nuclear Imaging ?

Current Status of Molecular Imaging

Prospects of Future Techniques

WHAT IS

MOLECULAR IMAGING ?

"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

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

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

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

WHY

MOLECULAR IMAGING

in NUCLEAR MEDICINE ?

“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.”

SNM, 2001

Pinwica Worms

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

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

CURRENT STATUS

GENE EXPRESSION IMAGING

Weissleder R.Radiology, 2001:219

Weissleder, MGH

The influence of the Human Gene Project on diagnostic imaging will be widespread

Vectors

GENE THERAPY

Delivery

Swisher, MD Anderson

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

HSV Thymidine Kinase Imaging

Gambhir, UCLA

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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5000

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25000

Control TrkA

NG

F B

indi

ng (

cpm

)

p<0.001

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5000

10000

15000

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25000

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TC on TC off

TA-88 cells

P<0.02

Gene Transfer and NGF Receptor Imaging

KH Lee, 2001

Weissleder, 1999

MRI Methods for Gene Imaging

Weissleder, 1999

Optical Methods for Gene Imaging

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

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

Current Methods for In vivo Gene Imaging

ANGIOGENESIS IMAGING

v

[18F]Galacto-RGD PET of Melanoma Bearing Mice

Haubner R, Cancer Res 2001

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

In Vivo Detection of Phosphatidylserine Expression During Programmed Cell Death

Blankenberg FG, PNAS USA 1998

Cytoxan Control

Blankenberg FG, PNAS USA 1998

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

Labeled caspase-3 peptide substrates (asp-glut-val-asp sequence)

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

Autoradiography Small Animal PET

SNM, 2001

Ankyrin B (-/-)

Obese transgene

FUTURE PROSPECTS

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

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

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

IMAGING ENDOGENOUS GENE EXPRESSION

Construction of dual gene vectors for imaging

M. Doubrovin, PNAS, 2001

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

99mTc-MIBI assessment of MDR1 overexpression in musculoskeletal sarcomas compared with therapy response

IMAGING DRUG RESISTANCE

Burak Z, Eur J Nucl Med. 2001

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

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

“ 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