# Presentation: 563802

## Molecular Imaging with Optical, Magnetic Resonanceand Radioisotope Techniques

- Jonathan S. Maltz
- Thomas F. Budinger
- Department of Nuclear Medicine and Functional Imaging
- Berkeley Lab
- University of California, Berkeley

- Biology
- Anatomy
- Metabolism
- Receptor binding
- Gene expression
- Cell trafficking
- Cell death

- Modality
- X-ray
- CT
- SPECT
- PET
- MRI
- Bioluminescence
- Fluorescence

- Major diseases
- Cardiovascular disease
- Cancer
- Depression
- Arthritis
- Alzheimer’s Disease
- Parkinson’s disease

## Overview

- Review of Contrast Mechanisms
- Frontiers in Molecular Imaging
- 	1. Hardware
- 	2. Reconstruction algorithms
- 	3. Imaging gene expression
- 	4. Imaging cell trafficking

## Contrast Mechanisms in Medical Imaging

- Planar X-ray,
- X-ray CT

- PET,
- SPECT

## Contrast Mechanisms in Medical ImagingFor ‘Transparent’ Animals Only

## Contrast Mechanisms in Medical Imaging

## Overview

- Review of Contrast Mechanisms
- Frontiers in Molecular Imaging
- 	1. Hardware
- 	2. Reconstruction algorithms
- 	3. Imaging gene expression
- 	4. Imaging cell trafficking

## Hardware: Evolution of X-Ray CT 

- Hardware: Evolution of X-Ray CT

## Hardware: CT

- High Resolution Spiral CT
- Visualizing vertebral foramena

*Budinger et al., LBNL and NCSA*

## PET Resolution Has A Long Way To Go

## Hardware: Evolution of PET

## Slide 12

## Spatial Resolution Away From Center

- 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.

## 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*

## Hardware: Evolution of MRI 

- Hardware: Evolution of MRI

## MRI Imaging of Anatomy

- High Resolution MRI

- Markers of Alzheimer’s Disease:
- Hippocampal Atrophy

## Receptivity

## Other Reasons for High Field

- 2. Spectral dispersion increases with field increase.

- 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 TExamples

- 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

## Enabling Technology: Nb3Sn Superconductors

## Overview

- Review of Contrast Mechanisms
- Frontiers in Molecular Imaging
- 	1. Hardware
- 	2. Reconstruction algorithms
- 	3. Imaging gene expression
- 	4. Imaging cell trafficking

## Reconstruction Algorithms for Dynamic Imaging

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

## Dynamic ECT Reconstruction Algorithms

- Studies Enabled:
- Improve SNR by developing:
- Dynamic imaging using low-cost widely deployed instrumentation
- Slow rotation contour studies - increased sensitivity
- 	e.g. 123 Xe imaging for pulmonary embolism
- 3.	Low photon count  studies benefit from enforced kinetic model conformity

## Extent of Contractile MotionBase moves 9-14 mm towards apexWalls thicken from 10 mm to 16 mm

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

- Transverse

- Coronal

- Sagittal

## Contractile Compensation Results

- Single Time Frame
- End-Diastole
- (noisy)

- Motion Compensated
- Gated Sum

- Ungated Sum
- (motion blur)

- Short
- Axis

- Long
- Axis

*Klein et al., LBNL*

## Overview

- Review of Contrast Mechanisms
- Frontiers in Molecular Imaging
- 	1. Hardware
- 	2. Reconstruction algorithms
- 	3. Imaging gene expression
- 	4. Imaging cell trafficking

## Imaging Gene Expression

- Tracer Trapping Methods
- Inserting reporter genes
- Approaches:
- Create transgenic animals:
- 	-all cells contain transgenes
- 	-animal studies only
- Insert genes later using:
- 	-plasmids
- 	-adenoviruses
- 	-retroviruses
- 	-adeno-associated viruses
- 	-lentiviruses

## Imaging Gene Expression

- Tracer Trapping Methods
- Enzyme trapping

## Imaging Gene Expression

- Tracer Trapping Methods
- Enzyme trapping

## Imaging Gene Expression

- Tracer Trapping Methods
- Enzyme trapping

## Trapping Mechanisms (PET, SPECT)

- Phosphorylation
- HSV1-TK traps radiolabeled acyclovir
- (nucleotide-5’-monophosphates cannot cross plasma membrane)
- Deamination
- Cytosine deaminate traps radiolabeled 5-fluorocytosine

## Contrast Activation Chemistry

- PET

## Imaging Gene Expression

- Tracer Trapping Methods
- Ligand reporter probes

## Imaging Gene Expression

- Tracer Trapping Methods
- Ligand reporter probes

## Imaging Gene Expression

- Tracer Trapping Methods
- Ligand reporter probes

## Trapping Mechanisms

- -Reporter gene expression leads to dopamine D2 receptor
- production. Traps dopamine antagonist spiperone.
- -Expression of transferrin receptors traps ion-oxide nanoparticles
- bonded to transferrin.

## MicroPET Example of Enzyme and Receptor Trapping

*Gambhir et al., UCLA*

## Contrast Activation Chemistry

- Galactopyrono_x0008_se
- cap

- -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

- Review of Contrast Mechanisms
- Frontiers in Molecular Imaging
- 	1. Hardware
- 	2. Reconstruction algorithms
- 	3. Imaging gene expression
- 	4. Imaging cell trafficking

## Cell Trafficking: Targeting Surface Proteins

## 111In-Oxine Labeled Lymphocytes (Ex-Vivo)

- 111In-Oxine Labeled Lymphocytes (Ex-Vivo)

- Hodgkin’s Disease

*Thakur et al., Thomas Jefferson University and LBNL*

## Targeting Cell Surface Antigens

## Slide 49

## Targeting Surface Proteins with Aptamers

*Feigon et al., UCLA*

## Acknowledgements

- Katie Brennan
- Matthew Darmalingum
- Jamie Eberling
- Greg Klein
- Bill Moses
- Scott Taylor

## Non-Invasive Measurement Toolbox

- PET, SPECT, MRI, CT, Bioluminescence, Fluorescence

- Functional Imaging:
- Anatomy
- Bloodflow: myocardial viability, cerebral perfusion
- Metabolism: glucose utilization, oxygen consumption
- Receptor binding: cholinergic (Alzheimer’s), serotonin (depression),
- dopamine (Parkinson’s)
- Gene expression: monitoring gene therapy, monitoring cancers,
- cell physiology
- Cell trafficking: inflammation, angio genesis, metastasis
- Cell death: apoptosis, monitoring cancer therapy, degenerative disease

## Bloodflow

- Myocardial Viability
- SPECT evaluation of myocardial viability is the most
- common clinical study in Nuclear Medicine

## Quest for the Ideal Flow Tracer

## 125 I-rotenone

- Get chem. diagram
- Thought to specifically target Complex I of mitochondria

## 125 I-rotenone

- Retension in isolated rabbit heart

## 125 I-rotenone

- Tracer extraction

- Get graph

## Receptor Binding

- Depression Affects Xxxx
- Yet there is no seratonin-transporter specifictracer for SPECT/PET
- Imaging Time-Variation Contrast
- Radiolabeling anti-depressives fluoxxx and sertraline inactivates binding ability

- 5-iodo-6-nitro quipazine

- iodorotenone

## KT

** ****[****123****I]INQUIP********* - ****SPECT**

** ****[****125****I]INQUIP********* - ****Autioradiography**

** ****Magnetic Resonance Imaging**

**Monkey Coronal Images**

**Equivalent **
**Human brain slice**

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

## Imaging Gene Expression

## Three Frontiers in Medical Imaging

- Improving Contrast
- Improve SNR by developing:
- More sensitive detectors
- More specific tracers
- Improved tracer kinetics
- Imaging Time-Variation Contrast
- Better temporal resolution
- Algorithms for dynamic image reconstruction
- New Contrast Mechanisms
- Expression of specific gene
- Concentration of specific enzyme
- Presence of a specific receptor inside/on a cell
- Rate of specific metabolic process
- Rate of fluid flow

## 12 Tesla Whole Body Magnet