Molecular Imaging with Optical, Magnetic Resonance and Radioisotope Techniques Jonathan S. Maltz...

Molecular Imaging with Optical, Magnetic Resonanceand Radioisotope Techniques

Jonathan S. MaltzThomas F. Budinger

Department of Nuclear Medicine and Functional ImagingBerkeley Lab

University of California, Berkeley

BiologyAnatomyMetabolismReceptor bindingGene expressionCell traffickingCell death

ModalityX-rayCTSPECTPETMRIBioluminescenceFluorescence

Major diseasesCardiovascular diseaseCancerDepressionArthritisAlzheimer’s DiseaseParkinson’s disease

Overview

1. Review of Contrast Mechanisms2. Frontiers in Molecular Imaging

1. Hardware2. Reconstruction algorithms3. Imaging gene expression4. Imaging cell trafficking

Contrast Mechanisms in Medical Imaging

Planar X-ray, X-ray CT

PET,SPECT

Contrast Mechanisms in Medical ImagingFor ‘Transparent’ Animals Only

Contrast Mechanisms in Medical Imaging

Overview



Evolution of X-ray CT

1st - generation CT Later - generation CT Electron Beam CT

Spiral CT Multidetector CT

n > 8

Hardware: Evolution of X-Ray CT

Hardware: CT

High Resolution Spiral CTVisualizing vertebral foramena

Budinger et al., LBNL and NCSA

Vertebrae & Spinal Cord

MRI X-RAY CTF PET18

PET Resolution Has A Long Way To Go

Conventional PET

Position SensitivePhotomultiplier

Tube

Optical Fibers

Scintillator Crystal Array

MICROPETPSPMT:

330 mm PSPMT

PSPMT

PSPMT

Positron sensitive photoelectron multiplier tubes

A)

D) E) F)Photomultiplier Tube

Photodiode

Scintillator

(1"x 1")

10 cm

7.5 cm

7.5 cm

PSPMT

NIH

C)

PSPMT

Tier PET

B)

Hardware: Evolution of PET

6 mm8 mm

8 mm

4 mm

6 mm4 mm4 mm

5 mm

5 mm

6 mm

8 mm

8 mm

2 mm

Positron Emission Tomography Resolution Improvements

1970 1975 1980 1985 1990 19950

5

10

15

20

Year

Resolution (mm)

Phantom ImagePET Detector

37-Point Hot Spot Phantom used for Imaging

Research AchievementsLargest # of crystals (280 vs 60)First Dynamic StudiesFirst Gated Heart Studies

NaI Crystal

0

1

2

3

4

5

6

7

8

9

10

Centimeters

0

1

2

3

4

5

6

7

8

9

10

Centimeters

Research AchievementsPioneered use of BGO crystalsFirst use of Clam Motion

Phantom Image

PET Detector

BGOCrystal

Research AchievementsLargest # of crystals per ring (600 vs 400)Finest Resolution (2.6 mm)First Orbiting Transmission Source

0

1

2

3

4

5

6

7

8

9

10

Centimeters

Phantom ImagePET Detector

BGOCrystal

Lawrence Berkeley National Lab, Berkeley, CA

Spatial Resolution Away From Center

1 cm

Near tomograph center 14 cm from tomograph center

Point Source Images in 60 cm Ring Diameter Camera

Resolution degrades significantly...

Radial Elongation

• Penetration of 511 keV photons into crystal ring blurs measured position.

• Effect variously known as Radial Elongation, Parallax Error, or Radial Astigmatism.

• Can be removed (in theory) by measuring depth of interaction.

Radial Projection

Tangential Projection

LBNL Detector Module Design

25 mm

25 mm

30 mm

Photomultiplier Tube

64 Photodiodes

64 LSO Crystals(3x3x30 mm)

•PMT Provides Timing Pulse and Energy Discrimination•PD Array Identifies Crystal of Interaction

•PD+PMT Measures Energy Deposit•PD / (PD+PMT) Measures Depth of Interaction

Custom IC(64

Channels)

Moses et al., LBNL

< 0.5 T

1.5 - 8 T

12 T1 ppm

12 T

0.04 T

Magnetic Resonance DevelopmentsHardware: Evolution of MRI

MRI Imaging of Anatomy

High Resolution MRI

Markers of Alzheimer’s Disease:Hippocampal Atrophy

Receptivity

39K

1H19F31P23Na

13C

35Cl

2. Spectral dispersion increases with field increase.

Other Reasons for High Field

1. SNR increases with field increase

If the field goes from 1.5 T to 12T the time required to achieve a given SNR would be reduced from 5 hours to 5 minutes.

Human Noninvasive Studies Enabled by 12 TExamples

Cellular and extracellular concentrations of Na, K, Cl with relevance to mental disorders, hypertension and cancer

Role of the pentose monophosphate shunt in cancer, congestive heart failure and ischemic heart disease

Glutamate / Glutamine metabolism in the normal CNS and in stroke and trauma

Amyloid plaque concentration changes on the CNS in neurodegenerative disorders

Carbohydrate and fatty acid metabolism in obesity and nutrition

80

100

120

140

160

180

-20 0 20 40 60

Time (min)

Reperfusion20 min

Reperfusion40 min

Globalischemia

23

Na NMR TQF signal (%)

- 20 min Ischemia

- 40 min Ischemia

23Na NMR TQF Signal in Isolated Rat Heart Clamp Global Ischemia at 37° C

(n = 6)

(n = 6)

Enabling Technology: Nb3Sn Superconductors

Overview



Reconstruction Algorithms for Dynamic Imaging

Algorithms: Making Movies with SPECT 99m Tc-teboroxime Reconstruction

Dynamic ECT Reconstruction Algorithms

Studies Enabled:Improve SNR by developing:1. Dynamic imaging using low-cost widely deployed instrumentation2. Slow rotation contour studies - increased sensitivity

e.g. 123 Xe imaging for pulmonary embolism3. Low photon count studies benefit from enforced kinetic model conformity

head

foot

chest back

Extent of Contractile MotionBase moves 9-14 mm towards apexWalls thicken from 10 mm to 16 mm

Transverse Coronal Sagittal

chest

back

right left

head

foot

right left

Contractile Compensation Results

Single Time FrameEnd-Diastole

(noisy)

Motion CompensatedGated Sum

Ungated Sum(motion blur)

ShortAxis

LongAxis

Klein et al., LBNL

Overview



Imaging Gene Expression

Tracer Trapping MethodsInserting reporter genesApproaches:1. Create transgenic animals:

-all cells contain transgenes-animal studies only

2. Insert genes later using:-plasmids-adenoviruses-retroviruses-adeno-associated viruses-lentiviruses


Tracer Trapping MethodsEnzyme trapping

Trapping Mechanisms (PET, SPECT)

1. PhosphorylationHSV1-TK traps radiolabeled acyclovir(nucleotide-5’-monophosphates cannot cross plasma membrane)

2. DeaminationCytosine deaminate traps radiolabeled 5-fluorocytosine

Contrast Activation Chemistry

PET


Tracer Trapping MethodsLigand reporter probes

Trapping Mechanisms

-Reporter gene expression leads to dopamine D2 receptor production. Traps dopamine antagonist spiperone.

-Expression of transferrin receptors traps ion-oxide nanoparticlesbonded to transferrin.

MicroPET Example of Enzyme and Receptor Trapping

Gambhir et al., UCLA

MRIContrast Activation Chemistry

Galactopyronosecap

-galactosidase

Meade et al., Caltech

Imaging Gene Expression in African Clawed Frog Embryo

Meade et al., Caltech

Contrast Activation Chemistry

Firefly Sea pansy

Bioluminescence

Luciferin/coelenterazine Luciferase oxidation product

Overview



*CD15 receptor

* * * ***

*****

*

Neutrophil Lymphocyte*

**** * *

***

****CD4

receptor glycoproteins

Cell Trafficking: Targeting Surface Proteins

2 hrs post injection 18 hrs post injection 36 hrs post injection

111In - Oxine Labelled Lymphocytes (ex-vivo)

Liver Spleen

Nodes

Nodes

Nodes

111In-Oxine Labeled Lymphocytes (Ex-Vivo)Hodgkin’s Disease

Thakur et al., Thomas Jefferson University and LBNL

Targeting Cell Surface Antigens

99mTc-VIP

Left lateral breast

Anterior chest

MIBI

Targeting Surface Proteins with Aptamers

Feigon et al., UCLA

Acknowledgements

Katie BrennanMatthew DarmalingumJamie Eberling Greg KleinBill MosesScott Taylor

Non-Invasive Measurement ToolboxPET, SPECT, MRI, CT, Bioluminescence, Fluorescence

Functional Imaging:AnatomyBloodflow: myocardial viability, cerebral perfusionMetabolism: glucose utilization, oxygen consumptionReceptor binding: cholinergic (Alzheimer’s), serotonin (depression), dopamine (Parkinson’s)Gene expression: monitoring gene therapy, monitoring cancers, cell physiologyCell trafficking: inflammation, angio genesis, metastasisCell death: apoptosis, monitoring cancer therapy, degenerative disease

BloodflowMyocardial ViabilitySPECT evaluation of myocardial viability is the most common clinical study in Nuclear Medicine

Quest for the Ideal Flow Tracer

125 I-rotenone

Get chem. diagramThought to specifically target Complex I of mitochondria

125 I-rotenone

0

0.2

0.4

0.6

0.8

11 Minute

0 0.5 1 1.5 2 2.5 3 3.5 4

Enet

(t)

A.

.

.

0

0.2

0.4

0.6

0.8

1

0 0.5 1 1.5 2 2.5 3 3.5 4

26 Minutes

Enet

(t)

Flow (ml·min-1 ·g LV-1 )

B.

Retension in isolated rabbit heart

125 I-rotenone

Tracer extraction

Get graph

Receptor Binding

Depression Affects XxxxYet there is no seratonin-transporter specifictracer for SPECT/PET

Imaging Time-Variation ContrastRadiolabeling anti-depressives fluoxxx and sertraline inactivates binding ability

N NNH

O2NI

5-iodo-6-nitro quipazine

O

I

OOO

H

H

MeOOMe

iodorotenone

KT

[123I]INQUIP* - SPECT

[125I]INQUIP* - Autioradiography

Magnetic Resonance ImagingMonkey Coronal Images Equivalent

Human brain slice

* INQUIP is a safe chemical probe specific for studies of the serotonin

system

Three Frontiers in Medical Imaging

Improving ContrastImprove SNR by developing:1. More sensitive detectors2. More specific tracers3. Improved tracer kinetics

Imaging Time-Variation Contrast1. Better temporal resolution2. Algorithms for dynamic image reconstruction

New Contrast Mechanisms1. Expression of specific gene2. Concentration of specific enzyme3. Presence of a specific receptor inside/on a cell4. Rate of specific metabolic process5. Rate of fluid flow

12 Tesla Whole Body Magnet

NbTi outer coils

13.2 Tpeak

Nb3Sn center coils

12 T1 ppm

Molecular Imaging with Optical, Magnetic Resonance and Radioisotope Techniques Jonathan S. Maltz...

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Transcript of Molecular Imaging with Optical, Magnetic Resonance and Radioisotope Techniques Jonathan S. Maltz...