1. Novel High resolution SPECT Instrumentation and Techniques for Molecular Imaging of Small Animals
F. Garibaldi - ISS-NIH, Rome, 4-6 June 06
Molecular imaging with radionuclides :the in vivo characterization and measurement of biologic processes at the cellular and molecular level
Collaboration between ISS, JHU(B. Tsui), Jefferson Lab (S. Majewski)
It sets forth to probe the molecular abnormalities that are the basis of disease rather than to image the end effects of these molecular alterations
specific task
-detecting vulnerable plaques in mice
what you need
-high resolution high sensitivity detectors
key parameters:
- SNR
- FOV
- Sensitivity
- Spatial Resolution
- simulations, prel. measurements
The rat and mouse host a large number of human diseases. Therefore one can study disease progression and therapeutic response under controlled conditions
PET (microPET) cannot attain the needed performances !
MRI doesn’t have the needed sensitivity
Summary and outlook

2. Molecular Imaging Modalities
Ultrasound
Structure A F
Doppler
0.1 mm
Optical
(Bioluminescence, fluorescence) A
Topography M
~103 cells
 quantitative
µm to mm CT
Tissue Density, Z A
20-50 µm
Unique !!
MRI A
H Concentration M F
BOLD, DCE
0.1 mm
Aujourd’hui, en altérant le génome nous pouvons manipuler le métabolisme et recréer les conditions qui mènent au développement de différentes maladies.
L’intérêt ici est de pouvoir suivre l’expression de ces gènes dans le temps et au travers de différentes conditions.
C ’est dans des cas ici que les méthodes d ’imagerie prennent toute leur importance car elles permettent de visualiser ce qui se passe dans l’animal d ’une manière non invasive et non létale.
Presque toute les méthodes d’imagerie clinique sont maintenant disponibles pour l’imagerie animale, ce qui permet de faire des parallèles entre les études cliniques et les études animales.
PET/SPECT
Radiotracer M
~1-2 mm
<10-12 mole
= quantitative F
-galactocidase
0.1 µmole H / µmole 31P

3. γ Imaging: Single Photon Detector Module
Patient injected with radioactive drug.
Drug localizes according to its metabolic properties.
Gamma rays, emitted by radioactive decay, that exit the patient are imaged.
Collimator
Only gammas that are perpendicular to imaging plane reach the detector
Readout Electronics
Amplify electrical signal and interface to computer
Scintillator
Convert gammas to visible light
Computer decoding procedure
Elaborate signal and gives image output
Photomultiplier
Convert light to electrical signal

4. High Resolution High Sensitivity Detectors
key parameters
SNR (and contrast)
(spatial resolution)
FOV
S = counts in ROI,
BKG = background
Max = max. counts
in tumor ROI
they are correlated
Gamma Emission X position
Light Spread Function (LSF)
Diffusive Wall
FWHM = 7.4 mm
Absorbing Wall
FWHM = 5.4 mm
energy resolution plays only a secondary additional role in imaging breast under compression

6. Important parameters for detectability/visibility
efficiency
detector and collimation
SNR
- Contrast
time (and modality)
uptake (radiopharmacy)
scintillator
spatial resolution
detector intrinsic properties
pixel dim/n.of pixels
modality (compression)
electronics, DAQ
. Uniformity of p.h.response
(affecs the overall en res.
and the energy window sel.)
CsI(Tl)
Bialkali PMT
Bialkali PMT
fotofraction

7. Importance of pixel identification
good pixel identification is fundamental for correct digitization affecting spatial resolution and contrast
C8 strips
M16 (4 x 4) mm2
M64 (2 x 2) mm2

8. Projective coordinate electronics
1024 ch, 2 KHz
Under study
4096 Ch. -> 8192 Ch. ( kHz)

9. measurements confirm simulation
tumors: (5, 6, 7, 8,9,10,12)
uptake 1:10; breast 6 cm
NaI(Tl) 1.5 pitch; H8500 (6x6 mm2)
measurements
6 mm
8 mm
7 mm
X (H9500)
NaI(Tl) 1.3 pitch; H8500(6x6 mm2)
6 mm tumors visible
NaI(Tl) 1.2 pitch
H9500 (3x3 mm2)
measurements confirm simulation
smaller scintillator pixel, higher SNR
but
anode pixel has to be small
tum 8 mm

10. Trying to Image apoptosis by proper tracer (e.g.99mTcINIC-Annexin-V)
Performances not good enough for imaging biological process in vivo in small animals (mice)
Man
Rat
Mouse
Body weight
~70 kg
~200 g
~20 g
Brain
~105 mm
~10 mm
~6 mm
Heart
~300 g
~1 g
~0.1 g
Aorthic cannula
~ 30 mm
1.5 – 2.2 mm
mm (0.5 mm)
man
rat
Trying to Image apoptosis by proper tracer (e.g.99mTcINIC-Annexin-V)
Geant 4 simulation
detector area: 100 x 100 mm2
aorta: ~ 2 mm diameter
plaque size: 0.5 x 1 x 4 mm3
- pixellated CsI(Tl) ( mm pitch)
LaBr3 continuous (3 mm thick, different surface(s) treatment(diffusive vs absorptive)
6 x 6 mm2, 3 x 3 mm2, 1.5 x 1.5 mm2
(PMT anode pixel size)
spatial resolution: ~ 500 m
system sensitivity: ~ 10 cps/Ci
1000 counts/view/resol.elem.
1 plaque = 10 mCi,10resol.elem.

11. LaBr3 to be carefully evaluated
Summary of CsI(Tl), pixellated
0.6 mm pitch H9500
0.6 mm pitch Burle
What about CsI(Na) ??
LaBr3 to be carefully evaluated

12. Scaling down (100 mm, 0.8 mm --> 50 mm, 0.4 mm)
1/4 of detector area, 1/4 number of channels
but
0.4 mm is very small !!
mouse doesn’t scale !

13. multiply by ~ 4 (multipinhole) x 4(8) ( n. of modules)
simulation summary
snr calculation
sensitivity too small
but
multiply by ~ 4 (multipinhole) x 4(8) ( n. of modules)
 snr = 30 ( 60 ) ===> plaque “visible”

14. sensitivity smaller than required
A  G = d then
A  G = Ô, in fact
There are decoding patterns G allowing:
Coded apertures
Ô = R  G = ( O × A )  G = O * (A  G) = O * PSF
Submillimeter spatial resolution (FWHM=0.93 mm) AND
High sensitivity (~850cps/MBq)
30 time pinhole already obtained
recostruction possible in a deepth of focus as large as large as 4 cm !!
Both spatial resolution and
sensitivity still to be improved
F. Cusanno et al. NIM A
Smaller scintillator pixels (0.8 --> 0.6 mm) ==> smaller photodetector anode pixels

15. Measurements
60Co source, 122 keV
CsI(Tl) 1.0 pitch
H9500 (6 x 6mm2)
CsI(Tl) 1.25 pitch
H9500 (3 x 3mm2)
NaI(Tl) 1.25 pitch
H8500 (6 x 6 mm2)
measurements confirm simulations: small anode pixel is needed for small scintillator pixel (0.8 --> 0.6 mm --> high number of channels 1024 for 1 module! )

16. 1.5mm thick LaBr3 attached to a H9500 PSPMT
LaBr3 continuous 1.5 mm thick + H9500 (3 x 3 mm2 anode); 3 mm thick + H8500(6 x 6 mm2)
Image of a 0.25mm slit. Chipped edge seen at left. Non-uniformities to correct.
1.5mm thick LaBr3 attached to a H9500 PSPMT
Measured energy resolution ~ 8% keV
Projection of the image of the slit.
FWHM = 0.65mm
Mcarlo FWHM = 0.615
3 mm mm thick LaBr3 attached to a H8500 PSPMT
Active area
0.75 mm FWHM
Mcarlo FWHM = 0.8
Dead area
1.4 mm FWHM

17. Preliminary pinhole SPECT reconstruction results from the CsI detector
Images are displayed as MIP (maximum-intensity-re-projections) animations
Please use slide show mode to see the animation
2 point sources
APOE mouse (kidneys shown)
Sample
projection
image
Flood image

18. scaling down (50 x 50 mm2, 0.4 mm pitch, Burle photodetector (3x3 mm2)
Conclusions
A solution for this challenging problem exists:
- good results with CsI(Tl) 1 mm pitch + H pixels, spatial resolution 0.53 mm mm, FOV=33-25,  (22-39) cps/MBq
improvements needed?
scaling down (50 x 50 mm2, 0.4 mm pitch, Burle photodetector (3x3 mm2)
->more compact, much less expensive
- 100 x 100 mm2 CsI(Tl) 0.8 (0.6) mm pitch with individual readout
careful evaluation of LaBr3 option (the advantage is better energy resolution
(very important if multilabeling shows to be possible and useful)
Fov, surface treatment, thickness, availability, cost
decision to be taken on the base of SNR obtained with measurements (phantoms)
Measurements for CsI(Na) mm pitch, LaBr3 3 mm thick
10 x 10 cm2 vs 5 x5 cm2 (scaling down) (tomographic reconstruction will be decisive)
Final layout on two steps next two years (if funding allows)

19. Invited talks Invited talks a Congressi Internazionali
1.F. Cusanno. “High Resolution, High Sensitivity detectors for Molecular imaging with Radionuclides: the Coded Aperture option”. Milos (Grecia). Imaging technologies in Biomedical Sciences. September 2005
2. F. Garibaldi. “High Resolution, High Sensitivity Detectors”, Advanced Molecular Imaging Techniques in the Detection, Diagnosis, Therapy, and Follow-Up of Prostate Cancer, Rome, 6-7 December
3. Magliozzi ML et al “High Resolution, High Sensitivity Detectors for Molecular Imaging of Small Animals and Tumor Detection”. International Conference of Advanced Detectors. Como (Italy), October17-21, 2005
4. F. Garibaldi, “Molecular imaging: high resolution detectors for early diagnosis and therapy of breast cancer”. Milos (Grecia). Imaging technologies in Biomedical Sciences. September 2005
5. "Molecular Breast Imaging: first results from Italian National Health Institute clinical trials", to be presented at the International Conference "Fist European Conference on Molecular Imaging Technology (EUROMEDIM2006)”
Marseille, France, May 2006
6. E. Cisbani, “Imaging with radionuclides: a powerful means for studying biological processes in vivo",  Fist European Conference on Molecular Imaging Technology (EUROMEDIM2006)", Marseille, France, May 2006
- Cuba ?

20. Publications
1. F. Garibaldi et al. “A PET scanner employing CsI films as photocathode”, Nucl. Instr. Meth., 2004, A525,
F. Garibaldi et al. “Novel design of a parallax free Compton enhanced PET scanner”, Nucl. Instr. Meth., 2004, A525,
3. R. Pani, M.N. Cinti, F. Cusanno, F. Garibaldi et al“Imaging detector designs based on Flat panel PMT”, Nucl. Instr. Meth., 2004, A527,
F. Cusanno et al. “Molecular imaging by single-photon emission”, Nucl. Instr. Meth., 2004, A527,
F. Cusanno et al. “Preliminary Evaluation of Compact Detectors for Hand-Held Gamma Cameras”, Physica Medica, 2004, XX (2), 65
Pani R. Cinti, M.N., Cisbani, E.; Colilli, S.; Cusanno, F.; De Vincentis 6. Preliminary study of metabolic radiotherapy with 188-Re via small animal imaging, A. Antoccia, G. Baldazzi, M. Bello, D. Bernardini, P. Boccaccio, D. Bollini, F. de Notaristefani, F. Garibaldi, G. Hull, U. Mazzi, G. Moschini, A. Muciaccio, F.-L. Navarria, V. Orsolini Cencelli, G. Pancaldi, R. Pani, A. Perrotta, M. Riondato, A. Rosato, A. Sgura, C. Tanzarella, N. Uzunov, M. Zuffa Nuclear Physics B, Volume 150, January 2006, Pages
Small animal imaging by single photon emission using pinhole and coded aperture collimation, Garibaldi, F.; Accorsi, G.; Fortuna, A.; Fratoni, R.; Girolami, B.; Ghio, F.; Giuliani, F.; Gricia, M.; Lanza, R.; Loizzo, A.; Loizzo, S.; Lucentini, M.; Majewski, S.; Santavenere, F.; Pani, R.; Pellegrini, R.; Signore, A.; Scopinaro, F.; Veneroni, P.; IEEE Transaction on Nuclear Science, Volume 52, Issue 3, Part 1, June 2005 Page(s):573 – 579
New Devices for Imaging in Nuclear Medicine, Cancer Biotherapy & Radiopharmaceuticals, 19(1), , 2004
A PET scanner employing CsI films as photocathode, Nucl Instr Meth A525, 2004,
10. Novel design of a parallax free Compton enhanced PET scanner Nucl Instr Meth A525, 2004,

21. 11. A study of intrinsic Crystal-pixel light-output spread for discrete scintigraphic imagers modeling, Scafe, R.; Pellegrini, R.; Soluri, A.; Montani, L.; Tati, A.; Cinti, M.N.; Cusanno, F.; Trotta, G,Pan Pani, R.;Garibaldi,F.,IEEE Transaction on Nuclear Science, Volume 51, Issue 1, Part 1, Feb Page(s):
12. Custom breast phantom for an accurate tumor SNR analysis, Cinti, M.N.; Pani, R.; Garibaldi, F.; Pellegrini, R.; Betti, M.; Lanconelli, N.; Riccardi, A.; Campanini, R.; Zavattini, G.; Di Domenico, G.; Del Guerra, A.; Belcari, N.; Bencivelli, W.; Motta, A.; Vaiano, A.; Weinberg, I.N.; IEEE Transaction on Nuclear Science, Volume 51, Issue 1, Part 1, Feb Page(s):

22. Publications
- Molecular imaging by single-photon emission”, Nucl. Instr. Meth., 2004, A527,
- Preliminary Evaluation of Compact Detectors for Hand-Held Gamma Cameras”, Physica Medica, 2004, XX (2), 65-70
- Small Animal Imaging by Single Photon Emission Using Pinhole and Coded Aperture Collimation”, IEEE Tran Nucl Sci, 2005, 52(3),
- Tumor SNR Analysis in Scintimammography by Dedicated High Contrast Imager”, IEEE Trans Nucl Sci, 2003, 50(5),
Custom breast phantom for an accurate SNR analysis, IEEE Trans. N.S., Vol 51, N.1 Feb. 2004
- Molecular imaging: high resolution detectors for early diagnosis and therapy monitoring of breast cancer,
To be published on NIM, Milos
High Resolution, High Sensitivity Detectors for Molecular Imaging with Radionuclides: the Coded Aperture Option, to be published on NIM
Euromedim Francesco
Euromedim Evaristo
Euromedim Carrato
A. Dragone

23. 1. “A PET scanner employing CsI films as photocathode”, Nucl. Instr
1. “A PET scanner employing CsI films as photocathode”, Nucl. Instr. Meth., 2004, A525,
2. “Novel design of a parallax free Compton enhanced PET scanner”, Nucl. Instr. Meth., 2004, A525,
3. “Imaging detector designs based on Flat panel PMT”, Nucl. Instr. Meth., 2004, A527,
4. “Molecular imaging by single-photon emission”, Nucl. Instr. Meth., 2004, A527,
5. “Preliminary Evaluation of Compact Detectors for Hand-Held Gamma Cameras”, Physica Medica, 2004, XX (2),
6. “Small Animal Imaging by Single Photon Emission Using Pinhole and Coded Aperture Collimation”, IEEE Tran Nucl Sci, 2005, 52(3),
7. Milos code apertures
8. Milos breast?
9. Prostate Rome, in preparation
10. Invited talks at Euromedim (titoli anche se non so se mettere il breast)
11. Deleo et al (la PET del CERN sottomesso a NIM)
12. altri lavori (recenti) di PET CERN)
13. lavori dei nostri amici del pin diodes (IEEE CD?? )
14. altra roba recente di Pani in cui ha messo solo me?
15. Como M.Lucia
Invited talsk (presentazione a congressi):
1. Milos 2005
2. Milos 2005
3. Prostate Conference
4. Euromedim a Maggio
5. What else? (dal 2004)?
6. Como MLuci
7. Cuba?

24. Positron
Emission
Tomography
microPET

25. Internal Compton Probe
Detection coincident events between two detectors
Compton scatter equation relates scatter angle and Eo and Ere
Photon direction is determined within conical ambiguity
Imaging Distance
10 cm
Compton Probe
High-Sensitivity Coll.
High-Resolution Coll.
Efficiency Resolution
1.8e mm
1.11e mm
4.00e mm
Internal Compton Probe