1. Characterization of LaBr3:Ce scintillator optimized for spatial resolution in low-energy gamma detection F. Cusanno, E. Cisbani, S. Colilli, R. Fratoni, F. Garibaldi *, F. Giuliani, M. Gricia, M. Lucentini, M.L. Magliozzi, G. Marano, M. Musumeci, S. Palazzesi, F. Santavenere, P.Veneroni Italian National Institute of Health and INFN-Roma 1, gr. Sanita, Rome, Italy S. Majewski, J. Mckisson, V. Popov, S. Stolin, B. Welch Jefferson Lab, newport News, VA, USA Y. Wang, G.S.P. Mok, B. M. W. Tsui Johns Hopkins University, Baltimore, MD (USA)

2. Motivations An important component of molecular medicine is molecular imaging, where the molecular identification of cellular components, receptors and ligands may allow the detection of early or hidden lesions allowing a new approach to diagnoses and cure of diseases. Strong integration is needed between preclinical and clinical studies. In this framework a key role is played by techniques employing radionuclides that allow imaging of biological processes in vivo with very high sensitivity (picomolar level) providing that a suitable detection system is available. The design of imaging systems (especially for small animals) is challenging due to the concurrent requirements of high spatial resolution and sensitivity. Moreover many research have to be performed on mice that have many advantages: small size, rapid gestation period large litter size, low maintenance costs. Moreover, the mouse genome has been extensively characterized. Gene-targeted "knock- out" and transgenic overexpression experiments are performed using mice, rather than rats, so submm spatial resolution and “good” sensitivity are needed. For this reason we focus on the SPECT modality. In fact PET has intrinsic limitations and doesn’t allow multilabeling that allows looking at different biological processes at the same time. This makes the design of the detectors challenging. In fact dedicated detectors have to be designed for this kind of researches. Multimodality is often mandatory For these reasons careful optimization is needed for the different components of the imaging systems. In this paper we focus on the optimization of the intrinsic properties of the detectors, namely with the choice and the design of the scintillator.

4. pet Compton Camera collimation Multipinhole or

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

6. Improving the intrinsic perfrmances. Spatial resolution. Importance of pixel identification good pixel identification is fundamental for correct digitization affecting spatial resolution and contrast C8 strips M16 (4 x 4) mm 2 M64 (2 x 2) mm 2

7. MCP (Burle) 1.5x1.5 mm2 or LaBr3 continuous CsI(Tl) 0.4 -1.0 mm pitch SiPm ?

8. Optimizing intrinsic performances - Layout : 8 detectors around the animal - Single module detector dimension: 100 x 100 mm 2 - Pinhole (or multipinhole) is mandatory, to get submm spatial resolution With M=3, we get a FOV = 33 x 33 mm 2 (significant portion of mouse) we are looking for spatial resolution of ~ 0.5 mm, so we need intrinsic spatial resolution of ~ 0.5 mm 0.2 0.4 0.6 0.8 1.0 1.2 1.6 1.8 r t (mm) r i (mm)

9. CsI(Tl) (3 mm thick, 0.4 mm pitch, BURLE MCP (1.5 x 1.5 mm 2 “anode”)

10. simulations (GEANT4)

11. CsI(Tl) (3 mm thick, 0.6 mm pitch, H9500 (3 x 3 mm 2 “anode”)

12. CsI(Tl) (3 mm thick, 0.6 mm pitch, BURLE MCP (1.5 x 1.5 mm 2 “anode”)

13. Labr3 Continuous different performances for different window treatment, diffusing (a), absorbing (b) a b

14. 0.6 mm pitch Burle

15. CsI(Na) is an interesting option. Unfortunately arrays with pixels smaller than 0.8 mm pitch cannot be built. It is igroscopic, so a window is needed (with spatial resolution degradation) or the integral line layout has to be used. Careful evaluation of the different options has to be done validating the simulations by measurements first. Then, decision to be taken on the SNR evaluation base looking at the specific application Tradeoff spatial resolution/efficiency/ energy resolution summarizing

16. 1024 Ch. ~ 2 kHz 8192 Ch. (20 kHz) role of readout resistive chain projectivecoordinatesindividual channels

17. LaBr 3 3 mm thick (white) coupled to two H8500 (6 x 6 mm 2 ) Active area 0.75 mm FWHM Dead area 1.4 mm FWHM FOV = 40 mm ! LaBr3 3 mm thick 80% black FWHM = 0.55 mm M64 (2 x 2 mm2 anode) white vs black entrance window measurements simulation vs measurement black scintillator entrance window improves spatial resolution and FOV but worsens energy resolution

18. Labr3 continuous, 3 mm thick, coupled to 4 H9500 CsI(Tl) 0.8 mm pitch coupled to PSPMT H9500 (raw image) LaBr3 continuous vs CsI(Tl pixellated LaBr3: good sampling of light also in the dead area. Spatial resolution ~ 0.8 mm (see simulations). CsI(Tl) (preliminary), raw image: The image would improve significantly using smaller anode size PSPMTs probably loosing few pixels in the dead area)

19. Cardiovascular diseases - Stem cell therapy? we should try to understand better……….

20. 10 cm 2.5 cm High Resolution Upper Head: Pin Hole: 0.5 mm Scintillator: NaI(Tl), 1.5 pitch 6 mm thick Photodetector: H8500 (2×2) R t ~ 0.8 mm, Eff ~ 0.5 cps/μCi M ~ 3, FoV ~ 33 mm High Sensitivity Lower Head: Pin Hole: 1.0 mm Scintillator: NaI(Tl), 1.2 pitch 6 mm thick Photodetector: H8500 (4+4) R t ~ 1.4 mm, Eff ~ 1.7 cps/μCi M ~ 2.7, FoV ~ 37 mm DUAL HEAD DETECTOR only one used for the measurement

21. Let’s start - evaluating the effects of the therapy: 1. perfusion on “normal” mice 2. infarction model (multilabeling) 2.1 perfusion (mibi- 99 Tc) 2.2 monitoring of the injected stem cells diffusion ( 111 In) Preliminary measurement of perfusion on normal mouse with 1 detector module : - Pin Hole: 0.5 mm - Scintillator: NaI(Tl), - 1.5 pitch, - 6 mm thick - Photodetector: (2x2) H8500 - M ~ 3 - FoV ~ 33 mm - R t ~ 0.8 mm, - Eff ~ 0.5 cps/  Ci

22. Reconstruction Images of Mouse Perfusion Scan (I) OS-EM, 6 subsets, 2 iterations, post-smoothed by Butterworth filter (cutoff=0.12, order=8), voxel size = 0.25 mm, image dimension 90x90. Trans-axial Axial Reconstruction Images of Mouse Perfusion Scan (II)

23. Extrapolation to different number of detectors (maximum 8) Spatial resolution ~ 300 - 400  possible (to be traded with sensitivity) - sensitivity ~ 0.2 % - spatial resolution ~ 0.4 mm 1 detector 8 detectors with multipinhole (factor 32)

24. Conclusions - molecular imaging: crucial role of radionuclides techniques - compact high resolution flexible system - optimization needed for all the components - role of the scintillator but LaBr3 continuous seems the best candidate allowing both good spatial and energy resolution and (multilabeling possible) but problems with fragility, dimension, reduction of FOV, cost but - CsI(Tl) (or CsI(Na) pixellated (0.8 mm pitch) is the alternative but problems with sampling in the dead area (to be carefully evaluated)

25. Outlook - stem cells studies (multilabeling): - selecting “right” cells - monitoring diffusion, differentiation, grafting etc - looking at the effects of the therapy ===> multimodality ( optical, SPECT, MRI, ) - the challenge: 120 pixel/100 mm, 8 modules 150 X 100 mm 2 -> FOV 50 x 33 (M=3)) “ideal” - multidisciplinary approach mandatory ---> “new” photosensors (SiPm?)