Molecular Imaging: from cell to man

Transcription

1 Molecular Imaging: from cell to man Torino, 24 November 2011 Advances in PET/SPECT technology for pre-clinical molecular imaging applications Alberto Del Guerra Dipartimento di Fisica "E.Fermi' Università di Pisa and INFN, Sezione di Pisa

2 CONTENTS MicroPET Technology MicroPET Tomographs MicroSPECT Technology MicroSPECT Tomographs MicroCT imaging Multimodality imaging

3 PET spatial resolution / 1 FWHM 1.2 d 2 2 b D 2 r 2 p 2 Crystal size Coding Non collinearity Positron Range Parallax error 1.2 : Degradation factor due to reconstruction d : Crystal pitch b : Coding error (range: 0-2 mm) D : Detector separation (i.e. gantry diameter) r : effective source size (including positron range) p : Parallax error * Derenzo & Moses, "Critical instrumentation issues for resolution <2mm, high sensitivity brain PET", in Quantification of Brain Function, Tracer Kinetics & Image Analysis in Brain PET, ed. Uemura et al, Elsevier, 1993, pp

4 From men to monkeys, to rats.. to mice Human PET human micropet *Images courtesy of Simon Cherry, UCLA mouse rat rat mouse infant monkey 4

5 Spatial resolution requirements 5

6 From the block detector to PSPMT s Block detector 1 st generation PSPMT Hamamatsu PS-PMT R mm Ø active area 16 x + 16 y anodes Small crystals can be used (down to d = 1mm) Used in the YAP-(S)PET (Univ of Ferrara Italy,1993) Large b Limitations on minimum d Flood field irradiation (511 kev) of a matrix of scintillator YAP:Ce, read by a Hamamatsu R2486 (resistive readout) 6

7 APD APD array Scintillator matrix (BGO/LSO) Coding problem: Individual coupling with APD s or light sharing with PSPMT s 2 nd generation PSPMT Hamamatsu PS-PMTR8520-C12 Active area 22 mm 22mm 6 x + 6 y anodes + High spatial resolution (b=0) + No Pile-up + No scattering in the crystals - Expensive - Many channels - Difficult tuning The detector module is composed by a matrix of 8 4 LSO crystals readout by a Hamamatsu S8550 (Pichler B., IEEE TNS 45 (1998) ) + Few channels to readout (resistive chain) + High gain and stability - Non negligible coding error - Pile-up increases with area - PS-PMT Hamamatsu R7600-C8 Matrix 8 8 square fibres 8 8 LSO matrix

8 Today: advanced light sharing photodetectors PET History PET Physics and technology light sharing technique: Hybrid position sensitive APD light sharing technique: Multi Anode flat panel PMT PSDs in PET: PMT PSDs in PET: solid state Advanced PET detectors: DOI and TOF Picture of a HPS-APD with four output connectors MA-PMT (8 8 ch s) Hamamatsu H8500 Active area 49 mm x 49 mm SiPMs for PET Conclusions Flood field image ( 241 Am, 60 kev ) obtained with a 4x4 and 8x8 CsI(Tl) scintillating matrices Flood field image (511 kev ) obtained with a 20x20 YAP:Ce scintillating matrix (resistive readout) 8

9 Spatial resolution of of commercial scanners Commercial scanners do not show large differences in spatial resolution YAP-(S)PET

10 Sensitivity requirements Requirements Imaging of low activity sources low uptake processes such as in gene research Possibility to study fast metabolic processes with characteristic time comparable with the scanning time Limitations Brain receptor saturation usually a maximum of 100 Ci can be injected to a mouse Limitation on the volume a maximum of 300 l can be injected to a mouse Solutions Utilization of radionuclides with a very high specific activity such as PET short half-life radioisotopes: 15 O (122 s), 13 N (10 min), 11 C (20 min), 18 F (110min) High geometry efficiency (large solid angle covered by detectors) High detection efficiency (e.g. for crystals: high/medium Z, high density) 10

11 Absolute sensitivity of commercial scanners Larger variations can be observed in the sensitivity figure of merit. YAP-(S)PET

12 SIEMENS micropet Focus 220 / Inveon PET 18 F-Paclitaxel biodistribution in rat MicroPET Focus 220 is a PET only scanner using the fiber technique Rat heart 18F-FDG The SIEMENS Inveon is dockable with a CT scanner 12

13 YAP-(S)PET II small animal scanner Scanner configuration Configuration: Four rotating heads Scintillator: YAlO 3 :Ce (YAP:Ce) Crystal size: 27 x 27 (1.5 x 1.5 x 20 mm 3 each) Photodetector: Position Sensitive PMT Readout method: Resistive chain (4 channels) FoV size: 40.5 mm axial 40.5 mm Ø Collimators (SPECT): Lead (parallel holes) Head-to-head distance: cm Scanner installed at the Institute of clinical Physiology (IFC-CNR) within the framework of the Center of Excellence AmbiSEN of the University of Pisa, Italy

14 Heart and bone metabolism in mouse with 18 F-FDG and 18 F - Mouse with 18 F-FDG Mouse with 18 F - (post-mortem) Horizontal slices: Gray and color scale injection of 11 MBq of 18 F -, 120 min. uptake time Step-and-shoot acquisition 128 views/180 (Acquisition time 60 min) Transaxial sections Horizontal section Total body (MIP) 120 min. uptake time (Acquisition time 100 min) Voxel size 375 m 375 m 750 m 3D ML-EM reconstruction 14

15 Small animal SPECT instrumentation development The use of pinhole-collimators allows a large magnification obtaining a high spatial resolution on medium-small field of view. The implementation of multi-pinholes increases the sensitivity Tipically based on large area NaI gamma camera similar to clinical one. ================ Other solutions based on solid state detectors are available. In this case the detector has a high intrinsic spatial resolution (smaller magnification allowed) and are characterized by a high energy resolution (multi-isotope imaging allowed)

16 Small animal SPECT collimator geometry Parallel hole pinhole D h L d System spatial resolution System spatial resolution D d L R 2 int 2 D 2 1 L e d L Rint d 2 System sensitivity System sensitivity D D D e 3 L D h 4d sin 16

17 Geom. Resol. FOV size Small animal SPECT Effect of collimator-to-target distance Sensitivity High sensitivity of pinholes only at small d (small FOV) d d Parallel hole Pinhole d 17

18 MILabs U-SPECT II Bone scan: rat Bone scan: mouse Detector active area Crystal Number of detectors Number and size of the pinholes 510 x 381 mm NaI(Tl), 9.5 mm thick Continuous 3 stationary 75 / mm FOV 28 mm x 140 mm 60 mm x 240 mm Spatial resolution mm FWHM Based on a standard three heads NaI gamma camera (no rotation) equipped with multi-pinhole collimators. Sensitivity >1500 cps/mbq 18

19 Bioscan NanoSPECT Features Detector active area 230 x 215 mm Crystal NaI(Tl), 9.5 mm thick continuous Number of detectors 4 (1,2 or 4) Also available as HiSPECT: transforms a clinical SPECT camera into an Animal Imager Number and size of the pinholes 36 / 1.0 mm FOV 26 mm x 20 mm Spatial resolution Sensitivity 0.8 mm FWHM 1640 cps/mbq Multi-pinhole with elical scanning 19

20 Siemens Inveon SPECT Detector active area 150 x 150 mm Crystal Number of detectors 2 or 4 NaI(Tl), 10 mm thick Pixilated (2.2 mm pitch) Mouse bone scan Number and size of the pinholes FOV Spatial resolution Sensitivity 1 or more / mm variable variable variable 20

21 GE explore speczt Full-ring solid-state detector small animal SPECT Utilizes a cadmium zinc telluride (CZT) detector High-energy resolution to enable dual or triple radionuclide imaging. Stationary, full-ring, 10 detector design Interchangeable, rotating cylindrical collimators - Multi-slit: 80mm axial FOV, full 360-degree coverage - Multi-pinhole: high resolution, full 360-degree coverage Detector active area Crystal Number of detectors Number and size of the pinholes FOV 124 x 124 mm ev-czt pixilated 10 full ring stationary Multi pinhole Multi slit 80 mm axial with multi slit 21

22 CT Dipartimento di Fisica e IFC-CNR 22

23 PET/CT image fusion PET Co-registration CT Advantages Anatomical repere: CT provides high resolution morphological information map The map is scaled at 511 kev and blurred at the YAP-(S)PET spatial resolution Better quantification: Attenuation correction of PET data CT may provide the shape and size of the target for recovery coeff. correction Additional information w.r.t. PET Using CT as a stand alone modality for stem cell imaging 23

24 Imaging PET/CT nel ratto

25 Whole body PET/CT (topo)

26 Multimodality systems Bioscan NanoSPECT/CT The BIOSCAN NanoSPECT is available also in combination with a CT module 26

27 Multimodality systems SIEMENS Inveon Available as integrated PET/SPECT/CT or dockable PET + SPECT/CT (only 2 SPECT heads available when in combination with CT) 27

28 GE Triumph (Gammamedica) X-SPECT : CZT based SPECT Sub-System LabPET : APD based PET Sub-System X-O : Fast, Low Dose CT Sub-System Triple isotope SPECT + CT 18F-FDG PET + CT CT 28

29 Rationale for PET/MR PET High sensitivity (10-11 /10-12 mol/l) Good spatial resolution (4mm for clinical system) Functional info and quantitation MRI Good sensitivity (10-3 /10-5 mol/l) Excellent spatial resolution (1mm isotropic for clinical system) Better soft tissue contrast with respect to CT Anatomical info (but also functional) No radiation dose COMBINED PET/MR 29

30 Technical Challenges in PET/MRI Interference on PET (photomultiplier and electronics) Static magnetic field Electromagnetic interference from RF and gradients Interference on MR (homogeneity and gradients) Electromagnetic radiation from PET electronics Maintaining magnetic field homogeneity Eddy currents Susceptibility artifacts General Challenges Space Environmental factors (temperature, vibration ) Cost 30

31 Effect of magnetic field on positron range A) B) 0 Tesla Tesla (X-Y plane) 86 Y (E max = 3.15 MeV) A). Influence of the magnetic field on positron range, for 86Y (Emax=3.15 MeV) in water,illustrated by Monte Carlo simulations obtained at 0 Tesla (top) and 10 Tesla (bottom) field. The 3-D tracks are projected onto a plane perpendicular to the direction of the magnetic field Distance (mm) B). Simulated positron range reduction for I-124 (Emax=2.14 MeV) in a 0 Tesla (top) and 9 Tesla (bottom) magnetic field. 31

32 PET/MRI solutions Artistic cross-view of various potential designs of combined PET-MRI systems a) tandem: The two scanners are mounted together back-to-back allowing sequential (like PET/CT) rather than simultaneous acquisition, b) insert: The PET scanner is inserted between the RF-coil and gradient set of the MR system, c) full integration: the two systems are fully integrated within the same gantry 32

33 Philips tandem PET/MRI PET MRI PET MRI PET-MRI Photograph of the Philips whole-body Ingenuity TF PETMR system design installed at Geneva University Hospital. A turntable patient handling system facilitates patient motion between the Achieva X-series 3T MRI system on the right and the time-of-flight PET system on the left. 33 Whole-body MRI, PET and fused PET-MRI images are also shown.

34 The advent of Solid State Photodetectors CdZnTe Used succesfully in SPECT by GE and used in SPECT/MR prototype APD = Avalanche Photodiode Criticity: High performance Amplifier Variation with T particularly relevant SiPM (Silicon Photomultiplier) Geiger-Muller APD DSiPM = Digital SiPM 34

35 Prototype combined solution Combined small animal PET/MRI developed by the University of Tuebingen (Germany). The PET insert is fully integrated into a 7 Tesla MRI system (ClinScan, Bruker): (a) Drawing of PET/MRI combination, showing the PET insert placed inside the MRI scanner, matching the centers of both fields of view. (b) Photograph of the MRI compatible PET insert, consisting of ten detector modules. (c) Single PET detector module showing the LSO scintillator block, APD-array, and preamplifier built into a MRI compatible copper shielding. 35

36 A Whole body PET/MRI solution from SIEMENS B (A) Showing the basic components of the system where the PET detector ring is placed between the RF coil and the RF body coil. (B) Configuration of the detector block consisting of 8 8 LSO crystals readout by a matrix of 3 3 APDs. (Courtesy of Siemens Medical Solutions). 36

37 Silicon Photomultiplier (SiPM) as a the most promising solid state photodetector SiPM are p-n diodes operating in Geiger mode, which means that the bias voltage is above the diode breakdown voltage. In this way output is independent from input: the surface is divided into -cells (~1000/mm 2 ) The SiPM has all of the characteristics: speed, QE, granularity, flexibility, robustness for a successful implementation in small animal instrumentation. Signal N cell of hit cells LSO slab Light guide SiPM array + High gain + Low noise + Good proportionality if N photon < N cell Triple layer detector block SiPM are insensitive to magnetic fields compatible with MRI 37

38 PET/MRI 38

39 Thank you!

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41 MRI based Attenuation Correction Whole-body MRI MR- map CT- map MRAC PET CTAC PET From left to right: - whole-body T1 weighted gradient echo MRI sequence co-registered to CT image of the same patient, - derived three-segment (soft tissue, lung and air) attenuation map (MRAC), - CT-based attenuation map (CTAC), - attenuation corrected PET images using MRAC -- attenuation corrected PET images using CTAC. 41

42 MRI based Attenuation Correction MR- map Modified MR- map CT- map LEFT: Attenuation correction maps derived from segmentation of T1 weighted MRI followed by assignment of known linear attenuation coefficients to the lung and soft tissue and addition of the scanner table template MIDDLE: same image shown on the left after non-rigid alignment to the CT attenuation map following removal of the PET-MR bed and addition of the CT scanner bed CT RIGHT: the CT-based attenuation map of the same patient. 42

43 Combined and simultaneous PET/SPECT with the YAP-(S)PET II One PET pair One SPECT pair Low energy shielding foil Thanks to the planar detectors and the YAP:Ce scintillator the YAP-(S)PET can perform SPECT imaging too on the same gantry by adding parallel hole collimators Removable collimators Cross contamination is reduced by: shielding the low energy single photons with a thin lead slab in front of the PET detectors With a dual window subtraction technique for selecting 99m Tc gamma s only in the SPECT data delguerra@df.unipi.it

44 Performance: Transaxial resolution Derenzo Phantom (SPECT) with 99m Tc 1.2 mm FBP (ramp filter) reconstruction was used on a mm 3 voxel space. Sinograms were build using kev energy window (37 cps/mbq). 1.5 mm thick slices delguerra@df.unipi.it

45 Dual tracer SPECT study (Myoview-Annexin) on rat heart 99m Tc-Annexin V (Apoptosis) 99m Tc-Myoview (Perfusion) Fusion 45 delguerra@df.unipi.it

46 Simultaneous PET/SPECT imaging with YAP-(S)PET SPECT ( 99m Tc) PET ( 18 F) 5:1 SPECT PET 10:1 30:1 Images of a section of an image quality phantom: the phantom is filled with 99m Tc while the two holes are filled with 18 F. ( 99m Tc/ 18 F activity ratio 30:1). 50:1 Images of two small cylinders simultaneously present in the FOV with different SPECT/PET isotopes activity concentration ratio Transaxial and coronal sections of a simultaneous PET/SPECT acquisition of two capillaries. The left one was filled with 18.5 MBq of 99m Tc, while the right with 370 kbq of 18 F ( 99m Tc/ 18 F activity ratio 50:1). delguerra@df.unipi.it

47 Molecular imaging technique for small animals A. PET Imaging on rats using 18 F-FDG showing glucose metabolism B. CT Imaging of a mouse abdomen after the injection of a contrast agent C. SPECT Imaging of a mouse abdomen after the injection of 99m Tc methylene diphosphonate showing the accumulation of the tracer in bones. D. Optical Imaging of a mouse showing the fluorescence of GFP from liver, abdomen, spinal chord and brain due to the presence of cancer cells. E. MRI image T2-weighted of a mouse brain. F. Bioluminescence optical imaging of a mouse superimposed to the picture of the animal. MULTIMODALITY