Advances in In Vivo Nuclear Imaging

Technologies Simon R. Cherry, Ph.D.

Departments of Biomedical Engineering and Radiology

Center for Molecular and Genomic ImagingUniversity of California, Davis"

Probing Tissue with Radiation"Ultrasound

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E = hν = hc /λ c = λν

MRI X-ray/CT Nuclear Optical

Freq

uenc

y (H

z) W

avel

engt

h (m

)

In Vivo Biomedical Imaging"

Anatomic " Physiologic " Metabolic " Molecular"

PET/SPECT"

x-ray CT"

MRI "

ultrasound"

optical imaging

Radionuclides for Nuclear Imaging"Single Photon Emission Computed Tomography (SPECT)"67Ga " "3.26 days "electron capture, γ "93, 185, 300 keV"99mTc " "6.02 hours "internal transition "140 keV"111In " "2.81 days "electron capture, γ "172, 247 keV ""123I " "13 hours "electron capture, γ "159 keV"125I " "60.2 days "electron capture, γ "27-31, 35 keV"131I " "8.04 days "β–, γ " " "364 keV"

Positron Emission Tomography (PET) "11C " "20.4 mins "β+ (positron emission) "511 keV"18F " "110 mins "β+ (positron emission) "511 keV"64Cu " "12.7 hours "β+, β–, EC " "511 keV"124I " "4.18 days "β+ (positron emission) "511 keV"

Radiotracers/Radiopharmaceuticals"•  Usually introduced by i-v injection"•  Agent must have access to target"

–  Stable in plasma"–  For extravascular targets, passive diffusion or active

transport into extracellular space"–  For targets in the brain, cross blood-brain barrier"–  For intracellular targets, must get across cell membrane"

•  Agent must be modified by interaction with target"–  Binding, trapping, …."

•  Unmodified agent must be cleared away"–  Efficient clearance and excretion from body"

•  Many parallels with drug design, but some important differences as well"

Classes of Radiolabeled Agents"•  Ions"

–  Neuronal tract tracing, bone metabolism…"•  Small molecules"

–  Substrates for enzymes, receptor ligands, drugs…"•  Peptides"

–  Receptor targeted, enzyme substrates…"•  Antibodies"

–  Fragments, minibodies, diabodies "•  DNA/RNA"

–  Gene delivery vectors, oligos, SiRNA, naked DNA…"•  Cells"

–  T-cells, stem cells…"•  Pathogens"

–  Viruses, bacteria…"•  Particles"

–  Liposomes, lipospheres, nanoparticles…"•  Reporter Proteins "

–  Promoter activity, regulation of gene expression…"~20-100 nm

~10 x 2 nm

~1-5 nm

~1 nm

Single Photon Emission Computed Tomography"

pinhole collimator

Detector

Types of Collimation"

Pinhole Collimation Parallel-Hole Collimation

Clinical SPECT and SPECT/CT Scanners"

Images courtesy Siemens and Philips

Clinical SPECT Applications"

Dopamine transporter, 123I-Ioflupane

99mTc-MDP bone scan (courtesy Siemens)

Myocardial perfusion, 99mTc-sestamibi (courtesy Siemens)

Preclinical SPECT and SPECT/CT Scanners"

Courtesy of MILabs and Bioscan

Molecular Imaging with SPECT"

Myocardial perfusion, 99mTc-sestaMIBI(Bioscan)

Tumor targeting, 125I-teledendrimer loaded with paclitaxel (Kit Lam, UC Davis)"

99mTc-HIDA kinetics in liver (Freek Beekman, TU Delft)"

Dopamine transporter, 123I-Ioflupane (MILabs)

Positron Emission and Annihilation"

511 keV photon

511 keV photon

Electron Positron

Positron trajectory

Radiolabeled molecule

Atom decaying by β+ (positron) emission

Annihilation

subject

Ring of detectors

Sensitive volume for a pair of detectors

Positron Emission Tomography"

Biomedical Cyclotron"18F (110 mins)"11C (20 mins)"13N (9.9 mins)"15O (120 secs)"

Courtesy of Siemens

Some Examples of Radiopharmaceuticals for PET"

•  18F-FDG ([18F]fluoro-2-deoxy-D-glucose)"–  Targets glucose transporters and hexokinase"–  Rate of glucose utilization"

•  18F-FLT (3’-deoxy-3’-[18F]fluorothymidine)"–  Targets thymidine kinase 1"–  Proliferation (thymidine uptake and phosphorylation)"

•  18F-FMISO ([18F]fluoromisonidazole)"–  Targets hypoxic tissue"

•  18F-FHBG (9-(4-[18F]fluoro-3-hydroxymethylbutyl)guanine)"–  HSV-tk transgene expression "

•  64Cu or 124I-labeled biomolecules"–  Peptides, antibdodies, nanoparticles and cells"

Important Performance Characteristics"

•  Spatial Resolution"–  Closest two objects can be located and still resolved"

•  Sensitivity"–  Fraction of radioactive decays converted to a valid detected

coincidence event"•  Timing Resolution"

–  Precision with which arrival times of annihilation photons can be determined"

•  Energy Resolution"–  Precision with which energy of detected photon can be determined"

•  Counting Rate Performance"–  Event rate that can be sustained without significant deadtime"

Scintillation Detector"•  Scintillator"

–  Emits light when radiation strikes it"–  Amount of light released is proportional

to amount of energy deposited"–  Amount of light released is small (104-105

photons per MeV)"

•  Sensitive Photodetector"–  Converts light into an electrical signal"

•  Photomultiplier Tubes (PMTs)"•  Photodiodes, Avalanche Photodiodes"

511 keV annihilation

photon

Scintillators for PET"

Detector Technology Used in PET"

PSPMT

scintillator scintillator

array of PMTs

Considerations: Photomultiplier tubes (PMTs) are fast, have high gain but are very sensitive to magnetic fields

position-sensitive PMT

Early PET Scanner Design"

Detector Technology Used in PET"

PSPMT

scintillator scintillator

array of photomultiplier tubes

position-sensitive photomultiplier tube

Conventional “Block” Detector"

€

X =(A + B) − (C +D)A + B +C +D

Y =(A +C) − (B +D)A + B +C +D

Position-Sensitive PMTs"Advantages: Equivalent to many PMTs in a single compact package

Disadvantages: moderately expensive active area non-uniform position resolution depends on light level unusable regions at edges of tubes

Clinical PET and PET/CT Scanners"

Courtesy of GE Healthcare and Philips Healthcare

.

Tomography"

•  Produces images of slices through the body"

•  Imaging system takes views at different angles around the patient and reconstructs the images using mathematical algorithms"

Angular Projections in PET"

Reconstruction in PET/SPECT"

Attenuation Map

PET Applications"

Images courtesy of GE Medical Systems

[18F]-fluoro-2-deoxy-D-glucose"

(FDG)"11C-PIB

AMYLOID PLAQUE BURDEN

PET/CT Imaging in Cancer"

Images courtesy of Philips Healthcare

Preclinical PET and PET/CT Scanners"

Courtesy of Siemens, Bioscan, Gamma Medica, GE Healthcare,

Mouse Model of Breast Cancer FDG microPET"

Dr. Craig Abbey

Measuring Drug Pharmacokinetics with microPET

Dr. Katherine Ferrara

.

Radiation Doses"Activity Radiation Dose

Average background in USA 3 mSv per year

Additional dose from SFO-JFK-SFO 0.05 mSv

Chest X-ray 0.1 mSv (10 days)

Mammogram 0.7 mSv (3 months)

Chest CAT scan 8 mSv (3 years)

Nuclear Medicine studies 1.5 - 15 mSv (6 months-5 years)

Annual limit for general public 1 mSv per year

Nuclear Imaging"•  Advantages:"

–  High sensitivity (nM-pM)"–  Labeling of small molecules with little or no change in

biological action"–  Whole body 3D volumetric imaging (tomographic)"–  Quantitative"–  Straightforward translation from mouse to man "

•  Disadvantages"–  Involves ionizing radiation"–  Access to radiolabeled molecules, especially for short half

life radionuclides"–  Limited spatial resolution (~0.5 mm SPECT, ~ 1 mm PET)"

Time-of-Flight PET"

Improving performance using timing information"

Time of Flight PET"

•  Speed of light is "– 3 x 108 m/s"– 30 cm/ns"

•  5 mm spatial resolution would require 33 psec timing resolution!"

Time of Flight Constraint"

without time-of-flight with time-of-flight

noise reduction ~

€

2Dc Δt

Timing Resolution of Scintillators"

0

5000

10000

15000

20000

25000

30000

35000

-1000 -500 0 500 1000

Co

un

ts /

14.2

5 p

s B

in

Time (ps)

221 ps fwhm

Material Coinc. LSO 221 ps LaBr3:30% Ce 165 ps CeBr3 198 ps LuI3:30% Ce 195 ps

Data courtesy of:

Bill Moses

Marcus Ullisch

Kanai Shah

Time of Flight Gains"

•  Favorable scenario: 40 cm diameter patient, 300 ps timing resolution"– Effective increase in signal-to-noise ~ x 3"

•  Less favorable scenario: 30 cm diameter patient, 600 ps timing resolution"– Effective increase in signal-to-noise ~ x 1.8"

Whole-Body FDG with TOF"

Data courtesy of Joel Karp

PET scanner LYSO: 4 x 4 x 22 mm3

28,338 crystals, 420 PMTs 70-cm bore, 18-cm axial FOV ~ 600 ps timing resolution

CT scanner Brilliance 16-slice

non TOF

TOF Philips Gemini TF

Dedicated Breast PET/CT"•  Advantages"

– Higher spatial resolution"– Higher sensitivity"– Should translate to better

image quality"•  Detection of smaller lesions?"

•  Disadvantages"– Limited to imaging breast"– Difficulty visualizing chest wall"

Ramsey Badawi and John Boone, Radiology, UC Davis

49-yo woman, palpable mass in right upper outer quadrant. Invasive mammary carcinoma confirmed at biopsy.

Whole-body PET/CT

Dedicated breast PET/CT

Images courtesy of Spencer Bowen, UC Davis

Dedicated PET/CT for Molecular Imaging of Arthritis "

4-5 weeks Baseline

Abhijit Chaudhari, Radiology, UC Davis

PET/MRI - motivation"•  Like PET/CT provides:"

–  “Near-perfect” registration of image data"–  Anatomically-guided interpretation of PET data"–  Anatomic priors for reconstruction and data modeling"

•  Additional Advantages"–  No additional radiation dose"–  Can exploit soft-tissue contrast of MRI"–  Can be combined with advanced MRI techniques such

as fMRI, MRS, DWI and MR molecular imaging methods"•  Additional Disadvantages"

–  Does not directly provide attenuation correction for PET"–  Technically more difficult and more expensive"

Approaches to PET/MRI"

magnet

magnet

magnet

magnet

“tandem” PET/MRI “integrated” PET/MRI

PET

+ interference easier to avoid + largely use existing hardware + least expensive

+ simultaneous PET/MRI possible + higher throughput + best image registration

PMT Sensitivity to Magnetic Fields"

3T = 30,000 gauss; 7T = 70,000 gauss!

PMT-based PET/MRI"

56 mm ring diameter

72 2x2x25 mm LSO scintillators

200 g Rat - 18F-FDG Brain Study

Shao Y, Cherry SR, Farahani K et al. Phys Med Biol 42: 1965-70 (1997)

Avalanche Photodiodes"•  compact Si devices"•  electric field high enough

for multiplication of e-h pairs"

•  magnetic field insensitive"•  range of sizes"•  APD arrays available"

•  compared with PMTs"–  lower gain"–  sensitive to temperature

and bias voltage"

p+ drift region

avalanche region n+ Si substrate +V

APD-based PET/MRI"Number of modules Ring diameter Axial FOV Transaxial FOV Number of crystals Insert length Insert outer diameter

16 60 mm 12 mm 35 mm 1024 55 cm

11.8 cm

Clinical PET/MRI"Biograph mMR, clinical whole body PET/MRI system at 3 Tesla

•  APD based LSO block detector (4x4mm2) •  Fully integrated with MRI system •  Shared cooling system

LSO array"

3x3 APD array & electronics"

Crystal"APD"

Cooling"

Courtesy of Siemens Courtesy of Henrik Michaely & Alex Guimaraes, MGH

In Vivo Imaging with Cerenkov Radiation"

Light emitted when a charged particle (can be produced by radioactive decay) passes through a dielectric medium at a speed greater than the speed of light in that medium."

Blue glow around nuclear reactors comes from Cerenkov radiation"

Used for many years as an alternative assay to liquid scintillation counting for beta-emitting radionuclides."

Pavel Alekseyevich Cerenkov (1904-1990)

(Nobel prize in 1958)

[Advanced Test Reactor, Idaho National Laboratory]

Faster than the Speed of Light…"

vacuum

tissue η~1.4

Constructive Interference Leads to Cerenkov Radiation"

http://www.sheffield.ac.uk/physics/teaching/phy411/coherent.html

Cerenkov Threshold"

An electron or positron travelling in a medium with refractive index n will produce Cerenkov radiation when its energy E exceeds the value given by:

€

n 1− 1E(MeV )0.511

+1

⎛

⎝

⎜ ⎜ ⎜

⎞

⎠

⎟ ⎟ ⎟

2

>1

Biomedical Radionuclides"

Radio-nuclide

Decay Endpoint energy

Use

11C β+ 960 keV PET 18F β+ 630 keV PET

64Cu β+ 650 keV PET 68Ga β+ 1890 keV PET 32P β– 1710 keV therapy 90Y β– 2270 keV therapy 131I β– 606 keV therapy/imaging

186Re β– 1070 keV therapy

Nuclide Half-Life Decay (major emissions, average β energy) Cerenkov Signal

C-11 20.4 min β+ (0.386 MeV), EC weak

N-13 9.97 min β+ (0.492 MeV), EC moderate

O-15 122 sec β+ (0.735 MeV), EC moderate

F-18 110 min β+ (0.250 MeV), EC weak

P-32 14.3 day β– (0.695 MeV) moderate

Cu-64 12.6 hr β+ (0.278 MeV), EC β– (0.190 MeV) weak

Ga-67 78.3 hr EC negligible

Ga-68 68 min β+ (0.836 MeV), EC strong

Zr-89 3.3 day β+ (0.396 MeV), EC weak

Rb-82 82 sec β+ (1.523, 1.157 MeV) EC strong

Y-90 64 hr β– (0.935 MeV) strong

Mo-99 66 hr β– (0.133, 0.443 MeV) moderate

Tc-99m 6.02 hr Isomeric transition none

In-111 2.83 d EC none

I-123 13.2 hrs EC negligible

I-124 4.2 day β+ (0.686, 0.974 MeV), EC moderate

I-125 60.1 day EC none

I-131 8.04 day β– (0.192 MeV) weak

Xe-133 5.2 day β– (0.101 MeV) negligible

Tl-201 3.04 day EC none

Beta-Decay Energy Spectra"

!

18F (β+) 90Y (β–)

Monte Carlo Simulation of Spatial Distribution of Emitted Photons

Mitchell et al, Phil Trans A (in press) 2011

Monte Carlo Simulation Results Cerenkov Luminescence in Water

(400-800 nm)"radionuclide" decay" visible light "

photons produced"per beta decay"

F-18" β+, Emax = 630 keV" 1.35"N-13" β+, Emax = 1.20 MeV" 14.35"P-32" β–, Emax = 1.7 MeV" 32.7"Y-90" β–, Emax = 2.28 MeV" 56.5"

Cerenkov Imaging of PET Radiotracers: 18FDG"

T=1.5 min T= 2.7 min T= 5.8 min T=16.9 min

Time series imaging of 4T1-luc2 tumor-bearing mouse on right flank, injected with 315 µCi of 18F-FDG.

Model: nu/nu mouse with U87 (glioma) cells expressing engineered antibody 2D12.5/G54C as a reporter gene

Tracer: yttrium-(S)-2-(4- acrylamidobenzyl)-DOTA (90Y-AABD) as a reporter probe

Cerenkov Imaging of 90Y-AABD

previously published reporter approach, see: LH Wei, et al. (2008) J Nucl Med 49 1828–1835

N N

N N

COOH

COOHHOOC

HOOCHN

O

+H3N

R1SS

N N

N N

COOH

COOHHOOC

COOHHN

O

NH

R1SS

OH2N

O

N N

N N

COOH

COOHHOOC

HOOCHN

O

N N

N N

COOH

COOHHOOC

HOOCHN

HN

S

1

2

3

4

5N N

N N

COOH

COOHHOOC

COOHHN

O

NH

R1SS

ON

O

HO

HO

OH

OHOH

HO

8 µCi 90Y-AABD injected

Pharmacokinetic Optimization

90Y-AABD (version 2)

90Y-AABD (version 1)

U87 glioma cell line, 10 µCi injected activity, imaging at 48 hrs

Other Developments"•  Detector materials"

–  New scintillators (e.g. LuI3)"–  Dense semiconductors (e.g. TlBr)"

•  Fast, massively parallel electronics"•  Larger axial field of view PET scanners"•  Organ-specific PET and SPECT systems"•  Improved and faster reconstruction algorithms"•  Multimodal image analysis/quantification"•  …"

Acknowledgments"Simon Cherry Yongfeng Yang Gregory Mitchell Junwei Du Changqing Li Emilie Roncali Martin Judenhofer Kun Di Yu Ouyang Ruby Gill Katherine Byrne Julien Bec Jeffrey Schmall Xiaowei Bai

Jinyi Qi Guobao Wang Jian Zhou Nannan Cao Li Yang Mengxi Zhang

Ramsey Badawi and Abhijit Chaudhari Jonathan Poon Jessica Saiz Andrea Ferraro Felipe Godinez

Douglas Rowland David Kukis Steve Rendig Jennifer Fung Michelle Connell Lina Planutyte David Boucher

Agile Engineering Keith Vaigneur

Radiation Monitoring Devices Kanai Shah (RMD Inc.) Richard Farrell (RMD Inc.) Purushottam Dokhale (RMD Inc.)

Collaborators Richard Leahy (USC) Russell Jacobs (Caltech) John Boone (UC Davis) Robbie Robertson (Takeda-Millennium) Selected Lab Alumni Ciprian Catana (MGH/Harvard) Bernd Pichler (U. Tübingen) Yiping Shao (MD Anderson) Hongjie Liang (Philips Medical) Huini Du (Toshiba Medical) Yibao Wu (Digirad) Sara St. James (MGH/Harvard)

Funding: National Institutes of Health R21 CA143098 R01 CA134632 R01 CA121783 R01 EB000993 R01 EB006109 Department of Energy DE-SC0002294 DE-FG02-08ER64677