1. New techniques for early detection of diseases: imaging of small biological structures with amplifying PET/SPECT probes using SiPm photodetectors 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. Spin-off from new progress in technologies developed for and by the nuclear physics and high energy physics communities (developments in new scintillators, photodetectors, solid state materials, fast electronics, fast data acquisition systems, fast computer algorithms, etc,) play a special, important role in transferring and implementing the potentially successful instrumentation technologies to this field. The design of imaging systems (especially for small animals) is very challenging due to the concurrent requirements of high spatial resolution and sensitivity. We discuss the characteristics and performances needed for human studies and the role of different radionuclide techniques. Few examples will be given of issues related to human disease diagnosis (breast and prostate) The emphasis will be on the challenge to integrate different imaging modalities. M. Baiocchi 1), E. Cisbani 1), N. Clinthorne 13),L. Cosentino 7), E. Cossu 9), F. Cusanno 2), R. De Leo 4), G. De Vincentis 3), P. Finocchiaro 7), R.Fonte 6) 10) A. Gabrielli, F. Garibaldi 2), M.L. Magliozzi 1), S. Majewski 10), G. Marano 1), B. Maraviglia 3), F.Meddi 2), P.Musico 5), M.Musumeci 1),O. Schillaci 9), G. Simonetti 9), M. Moszynski 12), 12),S. Torrioli 1), B. Tsui 13), L. Vitelli 1) M. Baiocchi 1), E. Cisbani 1), N. Clinthorne 13),L. Cosentino 7), E. Cossu 9), F. Cusanno 2), R. De Leo 4), G. De Vincentis 3), P. Finocchiaro 7), R.Fonte 6) 10) A. Gabrielli, F. Garibaldi 2), M.L. Magliozzi 1), S. Majewski 10), G. Marano 1), B. Maraviglia 3), F.Meddi 2), P.Musico 5), M.Musumeci 1),O. Schillaci 9), G. Simonetti 9), M. Moszynski 12), T. Szczesniak 12), S. Torrioli 1), B. Tsui 13), L. Vitelli 1) 1) 1)) I.S.S. ROMA (I); 2) INFN ROMA1, Roma(I), 3) University La Sapienza ROMA 4) INFN Bari, 5) INFN Ge, 6) INFN CT, 7) INFN LNS, 8) INFN Bo; 9) University of Tor Vergata, Roma, 10) West Virginia University; 11) Johns Hopkins University, 12) Szoltan Institute, Varsavia, 13) Michigan State University

2. Molecular Imaging Modalities CT Tissue Density, Z A 20-50 µm  -galactocidase 0.1 µmole H / µmole 31 P MRIA H Concentration MF BOLD, DCE 0.1 mm UltrasoundStructure A F Doppler Optical (Bioluminescence, fluorescence) A Topography M ~10 3 cells  quantitative µm to mm PET/SPECTRadiotracer M ~1-2 mm <10 -12 mole = quantitative F “ … the in vivo characterization and measurement of biologic processes at the cellular and molecular level.” 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.

3. Breast cancer

4. Anger camera doesn’t work for small tumors, smaller, high resolution detector close to the breast is needed !

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

6. MCP (Burle) 1.5x1.5 mm2 LaBr 3

7. Importance of pixel identification good pixel identification is fundamental for correct digitization affecting spatial resolution and contrast. Correct sampling and possibly individual readout electron ics is needed C8 strips M16 (4 x 4) mm 2 M64 (2 x 2) mm 2 Individual readout means better pixel identification(betterimage)

8. Geant4 simulations 1 detector - p.h. collimator - NaI(Tl) 1.5 mm pitch(the smallest pixel in this applications (~13000 pixel in 150 x 200 mm2) - H8500 (6 x 6) mm2 anode pixel -Individual channles electronics but - most cancers are in the upper part of the breast  2 detectors Sensitivity dominates the visibility, so we have to try to get closer to the lesion and modify collimation and modality

9. 8 – Fotomoltiplicatori H 9500 H 8500 " Italian Patent Pending No. RM2008A000541". a novel dual detector setup Better compression (smaller detector) and the right collimation (pinhole) allows getting closer to the lesion, increasing efficiency and spatila resolution, so the SNR,= and contrast  detectability focusing the lesion by the amplifying probe, imaging the whole organ by abother detector allows to increase SNR and contrast  detectability. Moreover the small detector (with very good energy resolution (LaBr3 scintillator)) can be colser to the lesion also when is close to the chest

10. Paziente A MLO 10 clinical trials, University of Roma2 (TOV) in comparison with a dedicated high RESOLUTION DETECTOR. IDENTICAL RESULTS: 1 SMALL TUMOR (< 10 MM), 2 BIG TUMORS 7 “NEGATIVE”, SUSPICIOUS TO MAMMOGRAPHY, NEGATIVE (OR POSITIVE IN SOME CASE) ULTRASOUND AND MRI,\ - In one case only our detector detected the tumor

11. PSA SENSITIVITY 83% SPECIFICITY 17% CT Selective indication :  PSA > 10 ng/ml  cT3  Gleas on score > 7 diagnosis is made from tissue obtained on a blind biopsy Need to consider fundamental changes in the approach to diagnosing prostate cancer In the future, multimodality imaging approach tailored to each patient PSA  DRE  TRUS  biopsy Prostate cancer is the most common cancer and the second leading cause of cancer death. No diagnostic techniques available. Only PSA, qualitative

12. Limited space for the PET detector PET detector must not use magnetic materials  Could distort MR image PET detector must not emit in MR frequency  Could produce MR image artifacts MR-compatible PET shielding materials  Could distort MR image  MR gradient field-eddy currents  Could produce noise in detector  Could heat detector  MR RF transmit  Could produce false PET events  MR materials  Will produce more gamma attenuation PET/MR Design Challenges -CITRATE that is present in the normal prostate -CREATINA that may increase in the phlogosis and all the proliferative processes -COLINE more specific for a neoplastic transformation PET MRI & MRS

13. Requirements for radionuclide imaging - radiotracer (high specificity) - high sensitivity - practical consideration, cost Dedicated high resolution high sensitivity PET probe for prostate imaging Detector goals - 3D photon position capability - spatial resolution ~ 1mm - high coincidence photon efficiency - energy resolution ~ 12% or better - TOF ~ 300 ps or better drawback of the standard PET - detectors far away from prostate - poor spatial resolution (6 – 12 mm) - poor photon detection efficiency (<1%) - activity ouside the organ -> poor contrast resolution - relative high cost per study

14. Dedicated PET detector ring (Moses) Better than standard scannner but still limited. Endorectal probe: PET coupled to a dedicated detector or to a standard PET scanner. Spatial resolution and sensitivity dominated by the small detector close to the prostate huge background from the bladder !! Could we reduce or eliminate it?

15. Signals from Different Voxels are Coupled  Statistical Noise Does Not Obey Counting Statistics Signals from Different Voxels are Coupled  Statistical Noise Does Not Obey Counting Statistics If there are N counts in the image, SNR = TOF provides a huge Performance Increase! SiPm are needed for TOF !

16. Timing resolution depends on -scintillator (kind (n.of photons, decay time, geometry (light path)) -photodetector (time jitter, capacitance, PDE etc) -coupling (light collection efficiency) -electronics (in our case has to be very compact  ASIC) - front end - readout architecture

17. Surti, Karp et al. LaBr3 + PMT A big advantage of SiPMs in a fast timing is a low time jitter, below 100 ps. However, a fast timing is limited by rather low photon detection efficiency (PDE), not exceeding 10 – 20%, depending on the number of pixels. This is of particular importance in timing with slow scintillators, like LSO, with the decay time constant of about 40 ns. Thus the expected time resolution is a direct function of sqr(n.p.e.) (PDE of SiPM). Thus, the application of SiPMs to TOF PET detectors requires a number of optimizations related to the size of the device, its PDE, number of pixels and finally its capacitance. Moszynski Some results with PMT and SiPm SiPm vs PMT- role of the capacitance

18. Array SiPm Endorectal (SPECT and) PET [(2.5 x 5 (6) mm2] probe in multimodality with MRI DOI Majewski -1.2 mm Layout has to be optimized to avoid undersampling and to optimize DOI (sandwitch)

19. Detection of vulnerable atherosclrotic plaques in genetic modified mice Monitoring effects of stem cell therapy SPECT Spatial resolution 300-800  (tradeoff with efficiency ( ~35 cps/MBq)) Next measurements: efficiency ~30 times. It can be improved adding detectors Small animal imaging of cardiovascular diseases To be integrated in a multimodality platform (optical and MRI). This is impossible with anger canera based detectors, that have also limitations in intrinsic spatial resolution It would be impossible to inject the tracer through the tail vein in infarction mice models for months. A new deliverey route of delivery(intraperito neal injection) has been proposed. It works !. 8 detectors can be installed around the animal: half of them with large FOV imaging the whole animal to be able to see the homing and fate of the stemm cells, the other fosucing the hearth to imager the perfusion, in order to extract information (ejection fractio) on the possible effects of the therapy

20. Probe close to artery  high spatial resolution & high efficiency transaxial view high 2D resolution (~2mm) compact PET imaging modules ~1mm 3D resolution compact PET Probe artery with plaque modules and probe can be moved around the neck on a gantry Two components: High 3D resolution (~1mm) compact PET probe with 2”x2” FOV High 2D resolution ( = 5x15cm) 1) Imaging (“zoom”) probe: double-sided SiPM modules with 1x1x15mm LYSO arrays 2) Modular imager: three or more SiPM based modules with 5cm x 5cm x 15-20mm thick LYSO crystal plates or arrays

21. T. Zeniya et al ”Conceptual design of high resolution SPECT system for Imaging a selected small ROI of huma brain magnifying probe for brain

22. Summary and conclusions - Molecular imaging is a powerfull tool for diagnosis and follow up of diseases (multidisciplinarity) - Radioncuclide technique have an important specific role - Focusing on small object and imaging at the same time the whole organ -Multimodality is mandatory in most cases (practical problems, cost etc) -Dedicated devices are frequently needed (room for research groups/small companies -Important role of nuclear and high energy physics concepts and technique -The biological/medical problem has to be well understood first!!

23. Italian National Health Institute and INFN Roma1 TESA: E. Cisbani, S. ColilliF. CusannoR. Fratoni, F. Garibaldi M. Gricia, M. Lucentini, M.L. Magliozzi F. Santavenere, S. Torrioli Farmaco: G. Marao, M. Musumeci Oncologia: M. Baiocchi, L. Vitelli Johns Hopkins University, B.Tui, Y Wang Jefferson Lab;S. Majewski, D. Weisemberger, B. Kross, J. Proffit Department of Radiology-University of Rome – La Sapienza G. De Vincentis Collaboration University of La Sapienza Roma B. Maraviglia, F. Giove Michigan State University: N. Clinthorne Soltan Institute for Nuclear Studies: M. Moszinsky University of Tor Vergata- Roma: E. Cossu, O Schillaci, G. Simonetti INFN Genova: P. Musico INFN Bari: R. De Leo, A Ranieri INFN Catania: L. Cosentino, P. Finoccchiaro INFN LNS:R. Fonte INFN Bologna:A. Gabrielli INFN Roma1: F. Meddi

24. TOF in PET: Why? 2009 Pisa Meeting on Instrumentation La Biodola, Italy – May 24 - 30, 2009 Thomas C. Meyer/CERN-PH24 From HEP we know: Event patterns congested by background; “Space” points help to remove confusion and improve reconstruction efficiency; Charge division, Stereo view, delay lines, cathode readout are known methods; In PET similar problems arise: Count rate contaminated with scattered and random photons; TOF reduces randoms and increases sensitivity. Data courtesy of J. S. Karp, IEEE, Trans. Med. Imag. Vol. 10 (D denotes patient diameter) D = 27cm D = 35cm Lesion Detectability APD SiPM “S”catter “R”andom “T”rue