advances in in vivo nuclear imaging technologies
TRANSCRIPT
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"
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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 ~
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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