Small Animal Radionuclide Imaging:
Instrumentation, Performance, and Applications
Craig S. Levin, Ph.D.
Stanford University School of Medicine
Department of Radiology
Stanford
Stanford
University
University
MIPS
Molecular Imaging
Program at Stanford
School of Medicine
Department of Radiology
Small Animal Radionuclide Imaging
Outline of talk:
•Small Animal Positron Emission Tomography (PET)
Instrumentation requirements and challenges
Commercially available systems
New approaches
•Summary
Stanford University
MIPS
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Nuclear decays of interest for imaging
generate high energy photons
Gamma decay: Nuclear de-excitation
+
Example:
99mTc
+ e+ + ν
γ−ray
Stable
state of
nucleus
Short-lived
excited
nucleus
Positron decay: Nuclear transmutation
--> 99Tc + γ
Short-lived
unstable
nucleus
More
stable
isotope
Example:
18F
positron
--> 18O + e+ + ν
Annihilation Photons
Gamma Ray
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e+
Stanford University
School of Medicine
Department of Radiology
1
Small Animal PET System Design Wish List
•Reconstructed spatial resolution ≤ 1 mm
•Uniformity of spatial resolution
•Sensitivity (coincidence detection efficiency) > 10%
•Energy resolution ≤ 12% FWHM at 511 keV
•Coincidence time resolution ≤ 2 ns FWHM
•Live time > 95%
•Robust image reconstruction algorithm
•Accurate data correction and calibration
•Reasonable cost
Stanford University
MIPS
Molecular Imaging
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Limitations on PET Spatial Resolution
Positron Emitter
Variations in
positron trajectoryEffects on resolution
depend on isotope
Molecular
Probe
e+
Detector
Element
Variations in annihilation
photon non-collinearityEffects on resolution
depend on system diameter
Variations in photon
interaction locationEffects on resolution depend
on detector element size
Detector Gantry
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Spatial Resolution Limit for 18F PET
Positron
Range
Photon
Non-collinearity
Detector
Width
{
FWHM
0 cm
10 cm
20 cm
80 cm
System
Diameter
SPATIAL RESOLUTION (mm)
Blurring
Functions
6
FWTM
0 cm
10 cm
20 cm
80 cm
18F
5
4
3
2
1
0
0
1
2
3
4
5
DETECTOR ELEMENT WIDTH (mm)
~500µm spatial resolution (fwhm) is possible in theory
MIPS
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2
Non-Uniform Resolution Due to
Photon Penetration in Crystals
Upper Limit on Radial Resolution Blurring
(see drawing for definition of symbols):
Δd
detector
gantry
Δrupper ≈ Δxupper/2 = (Δd/2)·sinθi (FWHM)
θi
= (Δd/2) r / [R+(Δd/2)]
R
Δxupper
= r / [(D/Δd)+1]
r
(an “upper” limit since Δx is calculated
assuming two isolated crystals as shown;
the presence of other adjacent absorbing
detector crystals weights the calculation
towards shallower average interaction depth)
θi
crystal
finger
Stanford University
MIPS
Molecular Imaging
Program at Stanford
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Department of Radiology
Non-Uniform Resolution Due to
Photon Penetration in Crystals
Δrupper ≈ r / [(D/Δd)+1]
Δd
For a mouse positioned at
center with diameter of 3 cm,
at radial position r=1.5 mm,
and system depth resolution
Δd=10 mm, the
radial blurring contribution
Δr<1.5 mm FWHM
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Challenges for High Resolution PET Detectors
I. Getting light out of long,
skinny crystals
511 keV photon
Requirements for Crystal Arrays:
•Narrow (≤1 mm) for high spatial resolution
•Long (20-30 mm) and tightly packed
for high coincidence detection efficiency
•Need robust light signal for best coincident time resolution,
energy resolution, detection efficiency,
and crystal identification; These parameters determine
contrast resolution and quantitative accuracy.
MIPS
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3
Photon Count Sensitivity
(Coincidence Efficiency) for PET
High Geometric Efficiency
(Ω/4π):
High Intrinsic Detection
Efficiency (ε):
Photon detectors should be as
close to the body, cover as
large an axial FOV and be as
tightly-packed as possible:
511 keV photon detectors
should have high Z, high
density, and be thick for high
stopping power:
ε = (1-e -µx)×f
Ω ≈ 4π (A/D)×P
µ=attenuation coefficient
x=crystal thickness/length
f=fraction of events within
energy window
A=axial field-of-view
D=diameter
P=crystal packing fraction
Coincidence Detection:
ε2 = [(1-e -µx )×f]2
Sensitivity (%) ≈
100×(Ω/4π)×ε 2
= 100×(A/D)×P×[(1-e-µx)×f ]2
Stanford University
MIPS
Molecular Imaging
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Types of Coincidence Events
Front
view
Side
view
Random
Absorbed
single
photon
True
Escaped
single
photon
Scatter
Scatter and randoms are reduced with better energy and time resolutions
Stanford University
MIPS
Molecular Imaging
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Inorganic scintillation crystals for PET
Scintillator
“BGO” Bi4(GeO4)3
“LSO”
Lu2(SiO4)O:Ce
“GSO”
Gd2(SiO4)O:Ce
“LYSO”
Lu1.8Y0.2(SiO4)O:Ce
“Sodium Iodide”
NaI(Tl)
Effective
Z
Density
(g/cc)
75
7.13
1/e
attenuation
length at
511 keV
(cm)
1.06
66
7.4
59
Relative
light
yield
(%NaI)
Refractive
index
Decay
time
(ns)
Peak
emission
wavelength
(nm)
Rugged?
15
2.15
300
480
Yes
1.13
75
1.82
42
420
Yes
6.71
1.4
20
1.85
60
440
Yes
65
7.1
1.2
107
1.81
40
420
Yes
51
3.67
2.94
100
1.85
230
410
No
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4
Commercially Available Small Animal PET
Instrumentation
•Concorde Microsystems, Knoxville TN
“microPET” [Scintillation detectors (LSO), fiber-coupled]
•Oxford Positron Systems, Oxfordshire, UK
“HIDAC” [MWPC Detectors (lead converters, gas)]
•Philips Medical Systems, Philadelphia, PA
“Mosaic” [Scintillation detectors (GSO)]
•GE-Suinsa Medical Systems, Madrid, Spain
“eXplore Vista” [Dual-layer scintillation detectors (LSO-GSO)]
•Gamma Medica, Northridge, CA
“X-PET” [Scintillation detectors (BGO) + SPECT/CT]
•Advanced Molecular Imaging, Quebec Canada
“LabPET” [Scintillation detectors-Avalanche Photodiodes]
Stanford University
MIPS
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Concorde Microsystems microPET Focus
Detector cassette
PSPMT
1.5x1.5x10 mm3 LSO
Fiber
optics
Focus 120
Bore size
Axial FOV
Resolution
Coincidence Efficiency
Energy Resolution
Peak NEC
Focus
511 keV flood response
of detector block
Focus 220
120 mm
780 mm
1.3 mm
>6.5%
18%
>580kcps
R4 & P4
Energy spectrum in LSO
220 mm
780 mm
1.3 mm
>4.0%
18%
>700kcps
Stanford University
Courtesy of Stefan Siegel, Concorde Microsystems
MIPS
2.2x2.2x10 mm3 LSO
Molecular Imaging
Program at Stanford
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microPET Focus Performance
Reconstructed Image
point
source resolution
Resolution
5
Count rate performance
(mouse phantom)
•250-750 keV energy window
•10 ns timing window
FWHM ( mm )
4
800
•Fourier rebinning, 2D FBP
250-750 keV 10 ns
250-750 keV 6 ns
350-650 keV 10 ns
350-650 keV 6 ns
700
3
600
2
1
Focus Tangential
Focus Radial
Focus Axial
0
0
10
20
30
R4 Tangential
R4 Radial
R4 Axial
40
50
60
70
80
Radial Offset (mm)
Concorde P4, FBP
Concorde Focus, FBP
2.4 mm
NEC (kcps)
m
m
500
400
300
200
100
0
0
5
1.6 mm
4.0 mm
NEC =
1.2 mm
10
15
Activity (mCi)
3.2 mm
T2
T+S+2R
4.8 mm
T= “true” coincident rate
S= scatter coincident rate
R= random coincident rate
Fourier rebinning + 2D FBP /Ramp filter.
MIPS
Courtesy of Yuan-Chuan Tai, Washington University
Molecular Imaging
Program at Stanford
Stanford University
School of Medicine
Department of Radiology
5
microPET Focus Images
Cardiac Gated Images (Rat)
end-systole
end-diastole
non-gated
Neuro-receptor imaging
(mouse)
20 g mouse injected with 11C-CFT
362.6 g S.D. Rat
0.966 mCi 18FDG
1.8 hr P.I. 30 min scan
~23 ms frames
Courtesy of Douglas Rowland, Washington University
MIPS
Stanford University
Molecular Imaging
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GE-Suinsa eXplore Vista (Argus)
Dual-layer LYSO-GSO detectors
Spatial resolution in central slice:
1.45 mm radial
1.56 mm tangential
1.74 mm axial
3.9 mm3 Volume resolution
Coincidence timing resolution:
1.5 ns FWHM
Central point source sensitivity:
4.0% [250-700 keV]
5.7% [100-700 keV]
Peak NEC rate with mouse phantom:
185,000 cps [250-700keV] @ 15 µCi/cc
· Ring diameter: 11.8 cm
· Aperture: 8 cm
· Effective transverse field-of-view: 6 cm
· Axial FOV: drT: 4.6 cm (srT = 2.0 cm)
· Number of depth-of-interaction detector
modules: 36 (18) PS- PMTs
· Number of dual-scintillator depth-of-interaction
elements: 6,084 (3,042)
· Depth identification method: pulse shape
discrimination
· Crystal array pitch: 1.55 mm
· Total number of crystals: 12,168 (6,084)
· 3D (coincidences and singles)
· Total number of coincidence lines: 28.8 M (7.2M)
MIPS
Detector module
511 keV field flood
crystal pitch = 1.55 mm
Courtesy of Juan José Vaquero, Universitario Gregorio Marañón
Stanford University
Molecular Imaging
Program at Stanford
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GE-Suinsa eXplore Vista (Argus)
Imaging performance
µDerenzo Phantom
3D FORE/2D FBP
Awake Rat (F-18 FDG)
transverse
3.2 mm
2.4 mm
sagittal
coronal
cortex
cortex
cortex
4.0 mm
1.6 mm
4.8 mm
1.2 mm
spinal cord
ARGUS 3D OSEM reconstruction with resolution recovery
Courtesy of Juan José Vaquero, Universitario Gregorio Marañón
MIPS
Molecular Imaging
Program at Stanford
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6
Research Institutions Developing Small
Animal PET Instrumentation
MIPS
Brookhaven National Laboratory, USA
Clear PET Collaboration, Multi-national
Hamamatsu University, Japan
Hammersmith Medical Center, UK
Harvard University, USA
Indiana University, USA
King’s College UK
Montreal Neurological Institute, Canada
National Institutes for Health, USA
Stanford University, USA
Universitario Gregorio Marañón
University of California, Davis, USA
University of California, Los Angeles, USA
University of Julich, Germany
University of Munich, Germany
University of Pennsylvania, USA
University of Pisa, Italy
University of Sherbrooke, Canada
University of Texas, USA
University of Southwestern Texas, USA
University of Washington, USA
Washington University, USA
Molecular Imaging
Program at Stanford
Stanford University
School of Medicine
Department of Radiology
New Technologies for Small Animal
PET System Design
•Improved Scintillation Detectors
•Semiconductor Detectors
MIPS
Molecular Imaging
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Is it possible to build a high performance PET
system with 1 mm crystal pixels?
511 keV photon
Requirements for Crystal Arrays:
•Narrow (≤1 mm) for high spatial resolution
•Long (20-30 mm) and tightly packed for
high coincidence detection efficiency
and…don’t forget...
•Need high light extraction with low variation for best time resolution,
energy resolution, detection efficiency, and crystal identification;
these parameters will help to optimize contrast resolution and
quantitative accuracy by helping to reject background events.
MIPS
Molecular Imaging
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7
How can we collect >90% of light from tiny
array crystals?
A
Light Collection
Efficiency:
f ∝ (A/L)(1 - 1/n2)
+
+
+
+
Collect the
light from
the long side
n = refractive index
+
Instead of
collecting the
light from the
small end
(a small fraction of light
is collected)
+
+
L
+
+
(a high fraction of
light is collected)
+
+
+
+
+
+
+
+
+
+
Stanford University
MIPS
Molecular Imaging
Program at Stanford
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Department of Radiology
Light Collection Improvements (1x1 mm2 pixels)
20 mm long
10 mm long
6 mm long
1x1x20 mm 3
1x1x10 mm 3
LSO
BGO
LSO
GSO
100
100
90
90
80
80
70
70
60
60
50
50
40
40
30
30
20
BGO
GSO
20
10
10
0
GROUND SURFACE
WHITE REFLECTOR
POLISHED SURFACE
WHITE REFLECTOR
0
GROUND SURFACE
WHITE REFLECTOR
POLISHED SURFACE
WHITE REFLECTOR
For proposed scheme
•Nearly all available scintillation light is collected (≥95%)
•Light collection efficiency is independent of crystal length,
width and surface treatment
•Light collection efficiency is independent of the light origin
•Results in superior energy and time resolution
Stanford University
MIPS
Molecular Imaging
Program at Stanford
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Department of Radiology
How could we collect more light from arrays of
miniscule (1 mm) crystals?
Thin photodetectors
at crystal
sides
Photodetector
at crystal
ends
PSPMT
MIPS
Instead of this...
Molecular Imaging
Program at Stanford
Can we do this?
Stanford University
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Department of Radiology
8
New Approach for PET Detector Design
Scintillation detector arrays with “edge-on” position sensitive avalanche
photodiode (PSAPD) arrays between crystal planes
511 keV
photon
•~2 cm thick of LSO
detectors in two stacked
block modules
511 keV
photon
•Each module
comprises 8 layers
•Each layer comprises
3x8 arrays of 1x1x3
mm3 LSO crystals (left)
or 1 mm thick sheets
(right)
2 cm
thick
•This gives ~ 1-3 mm
interaction depth
resolution
•Thin PSAPDs required
1x1x3 mm3
LSO crystals
MIPS
9x9x1 mm3
LSO sheets
Need: extremely thin PSAPD
Stanford University
Molecular Imaging
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Selected Scintillation Light Sensor
Position sensitive avalanche photodiode (PSAPD)
•Made by RMD, Inc.
•8x8 mm2 area
•Gain ~1000
•Leakage Current ~1-2 µA
•Capacitance ~0.7 pf/mm2
~45 pf
•Noise ~130 e- rms
A
C
Scintillation
Light flash
Corner
contacts
X = (A+B)-(C+D)
A+B+C+D
Y = (A+C)-(B+D)
A+B+C+D
(X,Y)
B
D
Two sizes: 8 mm or 13 mm
Problem: Standard PSAPD is not thin enough for high crystal packing fraction in our
proposed detector design
Stanford University
MIPS
Molecular Imaging
Program at Stanford
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Department of Radiology
New Light Detector:
Position Sensitive Avalanche Photodiode (PSAPD)
Standard vs. Thin PSAPD
Standard chip and
ceramic package
Flex circuit
accomodates two
thin PSAPD chips
on a same plane
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Thin chip and Kapton
package (~230 micron thick)
Stanford University
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Department of Radiology
9
Novel “edge-on” detector configuration using
position sensitive avalanche photodiodes
Flex circuit
Flex circuit for
signal readout
and HV bias
2.2 cm
Electrica
l
traces
PSAPD chip
1.3mm interlayer
crystal pitch
511 keV
photons
1.0 mm intra-layer
crystal pitch
Polished
crystals
Ground
crystals
PSAPD + flex
circuit + reflector
(<300 µm total
thickness)
10 mm of LSO 1x1x3mm3
LSO crystals
Second PSAPD chip
location (not mounted)
Novel, ultra-thin (<300 µm) position-sensitive avalanche
photodiodes (PSAPD) are placed between the crystal
layers with incident 511-keV photons entering parallel to
the PSAPD plane (“edge-on”) as shown. This design
gives direct measurement of photon depth-of-interaction
and an effective 2-cm thickness of LSO crystal.
One layer of detector module
comprising PSAPD coupled to a 3x8
array of 1X1X3-mm3 LSO crystals.
Half ground and half polished crystals
were used to compare spatial, energy
and temporal resolution performance.
Stanford University
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Flood irradiation of 8x3 array of 1x1x3 mm3 crystals
side coupled to thin PSAPD
jin new12
x8 x1x3fld r30.l
Flood
histogram
3 1
Profile through center
200
Polished surfaces
Ground surfaces
50
25
{
{
100
150
150
20
200
250
15
100
300
10
350
50
400
5
No intercrystal reflectors450
No intercrystal reflectors
500
100
200
300
400
0
100
500
0 150
200
250
300
350
400
15:1 peak:valley ratio
Excellent crystal identification due to high light collection efficiency
Stanford University
MIPS
Molecular Imaging
Program at Stanford
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Spatial resolution of LSO-PSAPD detector layers
FWHM of the point spread functions
is measured to be about 1.0 mm.
Left figure shows the top view of
experimental setup used to measure
coincidence time resolution and point
spread function by edge-on scanning.
22Na
LSO
array
PMT
LSO
Scan direction
PSAPD
35
1000
900
50
30
100
800
25
150
200
20
700
600
250
15
300
500
1 2 3 4 5 6 7 8
400
350
12 3 4 5 6 7 8
400
10
450
500
100
200
300
400
1.04 mm
FWHM
300
5
500
0
200
100
0
0
5
10
15
Position (mm)
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Thin PSAPD: energy spectra of individual crystals
3x8 array of 1x1x3 mm3 LSO crystals
250
300
200
200
150
100
100
0
0
5
300
0
400
400
300
300
200
200
200
100
0
0
5
0
0
5
200
5
0
10
800
800
800
800
600
600
600
600
400
400
400
400
200
200
200
200
0
0
5
300
200
100
100
5
10
0
5
0
0
0
5
500
0
0
5
0
0
5
400
300
100
0
0
5
0
0
0
5
500
500
400
400
300
300
200
200
100
100
0
5
0
0
5
0
0
5
0
5
0
5
0
5
10
300
400
200
200
200
0
100
50
0
300
300
200
150
100
100
0
250
200
200
100
0
100
300
300
100
0
400
300
200
0
5
500
200
400
300
100
50
0
400
100
100
0
0
5
400
300
0
0
5
300
300
200
200
200
100
100
0
0
5
Ground crystals
0
0
5
100
0
0
5
Polished crystals
Stanford University
MIPS
Molecular Imaging
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Measured energy and time resolutions of
LSO-PSAPD modules
22Na
Energy Spectrum
Coincidence time spectrum
800
600
TAC Data
PSAPD START,
700
500
Gaussian Fit
PMT STOP
500
Counts
Counts
600
9.91%
FWHM at
511 keV
400
300
400
300
←
FWHM: 2.1 ns
200
200
100
100
0
0
1
2
3
4
5
6
7
8
9
10
40
45
50
55
60
65
70
Time difference (ns)
Voltage (v)
Experimental measurements show that the average energy resolution is 11.0±1%,
coincidence time resolution is 2.1±0.1 ns.
Stanford University
MIPS
Molecular Imaging
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Energy resolution comparison
conventional vs. proposed high res PET
Conventional µPET system:
LSO-Fiber-PSPMT
26.1%
fwhm
at 511 keV
Proposed PET system:
LSO-PSAPD
10.4%
fwhm
at 511 keV
These proposed energy resolution improvements will yield
enhanced sensitivity, image contrast and quantitative accuracy
MIPS
Molecular Imaging
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11
Summary
Great progress has been made in pre-clinical radionuclide imaging
instrumentation
PET:
•There are now six vendors for high resolution PET systems for small
animal imaging
•Over twenty research groups working on high resolution PET systems
world wide
•Sensitivity and spatial resolution, and energy resolution all continue to
improve
•Efforts to fuse this information onto high resolution CT and MR are being
made
In order for small animal imaging to assist existing drug development and
testing protocols, must push for highly accurate image data and means to
extract quantitative information that accurately characterize molecular
signals
MIPS
Molecular Imaging
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Department of Radiology
12