Perspectives in Molecular Imaging

New Roads to Molecular Imaging

Prepared by Bertrand LOUBATONDirector, Pharmaceutical & Academic CollaborationGE Healthcare InternationalBertrand.loubaton@ge.com

Disclaimer

The concepts and technologies presented within this presentation are proprietary to GE. Additionally, these concepts are being presented in an educational forum and are not, and may never, become products. Further, none of these concepts are being offered for sale, or have been cleared/approved by the FDA for commercial availability.

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Trend Towards Molecular Imaging

HaemodynamicsVascular permeability

Tissue oxygenation/hypoxiaCNS activityMetabolites

pH

Physiologicalimaging

Mechanism

Molecularimaging

Functional receptorimaging

Target specificcontrast agents

PharmacoKinetics

Target

Anatomicalimaging

MorphologyMorphometry

Structure

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Molecular Imaging… Innovation occurs at the intersection of disciplines: INTEGRATION is KEY

Innovation

Physicists

Animal Research

Biologists

Mathematicians

Physicians: NM, oncology, cardiology, neurology

ComputerScientists

Chemists

MechanicalEngs

Patient centric

Development IP

Patients

Research Centers

SocietiesBiotechnology IP

BIOMARKERS…

PRACTICAL REALITY…

Hardware + Wetware + Software

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“Molecular Imaging is a technique which directly or indirectly monitorsand records the spatiotemporal distribution of molecular and cellularprocesses for biochemical, biologic, diagnostic or therapeuticapplications.”Thakur and Lentle, J. Nucl. Med. 2005: 46:11N-13N

F-PIB

Molecular Imaging is key to monitoring “specific” therapies

F-Dopa F-Angiogenesis Acetate FLT

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Our Mission at GE Healthcare…

If you can DETECT it here,

it may NEVER appear here.

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• Molecular Diagnosticsü Genomics to assess risk factors in individuals

ü Biomarkers for early/accurate disease detection and

characterization

Identifies high risk populations for imaging

• Molecular ImagingDirectly or indirectly monitors cellular/molecular processes via PET/CT, Nuclear, Optical or MR imaging

ü Can precisely locate diseased cells in the body

ü Allows for appropriate treatment to be planned

ü Can monitor response to treatment

Keys to Early Health

Allows for better targeting and molecular based therapies (Pharma)

Hardware + Wetware + Software

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Biology and Technology Molecular concentrations and functions

Anatomy

Biology

MRS

SPECT, PET

MRI

CT

X Ray Angio

Ultrasound

X Ray

Optical

MetabolismReceptors

Heart and lung

function

Perfusion

Gene expression

Signal transduction

Zeptomolar

Femtomolar

Picomolar

Micromolar

Millimolar

Nanomolar

Attomolar

Physiology

BiochemistryfMRI

Concentration

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External protein

Aggregates

Alzheimer’s

Cellular

Transporter

DatScan/ FDG

External enzyme systems

Coagulation

Inflammation

Oncology

Internal enzyme

systems

Hypoxia

FDG

DNAmRNA ProteinmRNA

Receptor

Systems

Angiogenesis

Imaging targets

Cell

proliferation

DNA/protein

Local Environmental

changes

Temperature

pH

vascular permeability

Surface

proteins

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Before 2 days 8 days

GIST response to Glivec measured by 18FDG

Personalized Medicine a reality

Select for treatment

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PET synthesis PlatformDriving Tracers validation

From: To:

FASTlab cassette based synthesis system

Technology…opening the door to consistent and predictable Molecular Imaging

What it means…

ü GE industrializing PET chemistry and Molecular Imaging

ü Speeds evolution of cancer, cardiovascular and neurological research/ drug development

ü Enables PET diagnostics to be more accessible to patients

ü cGMP compliance easier to achieve Cassette designed for future PET imaging agents

Hyperpolarized 3He/129Xe Lung Imaging&13C Metabolic MR imaging

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What is hyperpolarization?

• The hyperpolarization is part of the “activation” of the agent prior to injection

SNR 5(37 h, 168 000

excitations)

Conventional MR

SNR=400

(0.8 s, 1 excitation)Enhancement ~4400

Hyperpolarized MR

Ardenkjaer-Larsen JH et al, PNAS 103(30) (2003)

• Hyperpolarization enhances the NMR signal ~100 000 times over 3 T MRI

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Possible nuclei for polarized MR imaging

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Conventional MRI of the Chest

Signal Source is H2O

Lung tissue not visualized

HelispinTM

MRI of the Chest

Signal Source is 3He gas

Major airways and air space visualized

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Polarization Device…

Magnetic Field +

Microwave Source

C13-Labeled Agent Dopedwith Unpaired Electrons

Hyper-polarized Agent

Standard 3.0TMR Scanner

Hyper-Polarized 13 C MR: a way for MR to become metabolic

Vision:Measure biochemical “fingerprint” of tissue for earlier diagnosis, improved staging and influence treatment decisions.

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Why 13C MR?

• 13C is a stable (non-radiating) and magnetically active isotope of carbon

• 13C is only naturally abundant at 1.1%, but can be enriched chemically in specific positions

• The signal frequency is specific to the chemical environment and identifies the compound

• When labeled in the appropriate position the life time is sufficiently long

• MRI Spectroscopy but in millimolar concentration

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The Concept

3D anatomy of the whole body obtained in seconds is a reality today with 1H MRI

In the future:

Combined with hyperpolarized 13C Metabolic MR the diagnosis may be improved by providing information about the disease process at the cellular level

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With 13C – Pyruvate

Lactate over

pyruvate contrast

highlights the

tumor.

•Quickly metabolized

•Branch point molecule of glycolysis

•Converted to Alanine, Lactate and Bicarbonate

•Lactate indicator of anaerobic glycolysis

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Real-Time Metabolic Imaging with 13C-Pyruvate

0 10 20 30 40 50 60 70 80

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1000

2000

3000

4000

5000

6000

7000

8000

0

500

1000

1500

2000

Time (s)

Ag

en

t (P

yru

va

te)

Co

nc

en

tra

tio

n Me

tab

olite

Co

nc

en

tratio

n

Pyruvate

Proton Image

AlanineLactate

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Metabolic MR with Hyperpolarized 13C

Cancerous tissue has a marked elevated metabolism of Pyruvate into Lactate compared to Healthy tissue.

Canine Prostate - Metabolic MR images Kurhanewicz, Vigneron & Nelson at UCSF

Vision:Measure biochemical “fingerprint”of tissue for earlier diagnosis, improved staging & influence treatment decisions starting with prostate cancer

With [1-13C] pyruvate

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Monitoring response to treatment with 13C Metabolic MR (13C-labelled bicarbonate)

8.6

0.0

Untreated

8.6

0.0Treated

8.6

0.0

Untreated

8.6

0.0Treated

Lactate-Pyruvate-Ratio 30 seconds post-injection

U of Cambridge - Mouse EL4 lymphoma In Vivo

Apoptosis

Necrosis

FDG

Pyr-lac exchange

Day SE et al. (2007) Nature Medicine 13, 1382 – 1387Tim Witney, ISMRM, Toronto 2008

Next step PET & MRI imaging

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Molecular Quantitative Translation Cost Ease of Use

CT

Optical

PET/MI

MR

SPECT

Ultrasound

Combinations of techniques will give us the best outcome…

Molecular Imaging is not limited to a unique modality…..

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GLD sum image 0-6 minPCA1 image 0-6 min

Pain paradigm right thumb

Courtesy, Prof. Bengt Långström, WIP, Uppsala University, Sweden

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acknowledgement

I would like to express my profound gratitude to my

mentor in MI the Pr Bengt Langstrom Uppsala University

Thank you for your attention

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