MOLECULAR NUCLEAR IMAGING

1. MOLECULAR NUCLEAR IMAGING Current Status 성균관의대 핵의학교실 이 경한

2. AREAS OF DISCUSSION • What is Molecular Imaging ? • Why Molecular Nuclear Imaging ? • Current Status of Molecular Imaging • Prospects of Future Techniques

3. WHAT IS MOLECULAR IMAGING ?

4. Molecular Imaging: The Diagnostic Imaging Revolution — SM. Larson, MSKC Center • "You can’t make an omelet without breaking eggs." — V.I. Lenin • :The omelet is themolecular imaging approach to diagnosis, and the eggs are theold ways of thinking about anatomically based imaging • A paradigm shift away from traditional anatomically based imaging toward methods for imaging biochemical changes within cells

5. BACKGROUND • Tremendous advances in molecularbiology have revealed: • - sequence, structure, and functionof genes and proteins • - physicochemical properties ofligands and receptors • - crucial details cell signaling pathways • These discoveries have led to an increasedunderstanding of the fundamental mechanisms of disease and tothe development of genetically based therapies • Research inbiologic sciences combined with exploration in imaging sciencescould allow us to image the molecular basis of disease or imageresponses to therapy on a molecular level

6. Molecular imaging springs fromthe joining of two powerful forces • - On the one hand, there hasbeen an explosion of knowledge • regarding molecular biology • - On the other hand, there have been marvelousadvances in imaging • technology, based on improved electronics and new tracers for key • molecules in cell biology • Molecular imaging methods mentioned that are applicable to clinicalmedicine include gamma camera imaging, SPECT, PET, MRI, MRS, opticalimaging, and ultrasound  • Over 20,000 articles in Medline layclaim to "molecular imaging" as a component of their approach

7. DEFINITION • Noninvasive imaging of thekey molecules and molecular-based events that are fundamentalto the biology of human disease • An emerging field of study that deals withimaging of ds on a cellular or genetic level • New abilities of diagnostic imaging methods to detectand characterize cell biology in ds states • A growing research discipline aimed at developing and testing novel tools, reagents, and methods to image specific molecular pathways invivo, particularly those that are key targets in ds processes

8. WHY MOLECULAR IMAGING in NUCLEAR MEDICINE ?

9. “Advances in molecular biology begun now will dramatically impact medicine practiced tomorrow.” “Because nuclear medicine is inherently molecular, we are poised for a pivotal role in future medical advances.”

10. SNM, 2001

11. Pinwica Worms

12. ICMICs (P50s) Massachusetts General Hospital Ralph Weissleder, PI Memorial Sloan Kettering Cancer Center Ron Blasberg, PI University of California – Los Angeles Harvey Herschman, PI Biomedical Imaging Program (BIP) • NCI has recognized the great untapped potential of imaging technology and identified it as an area of extraordinary opportunity • NCI has awarded three grants to support "In vivo Cellular and Molecular Imaging Centers“ that will facilitate interaction among scientists from a variety of fields to conduct multidisciplinary research on molecular imaging

13. Pre-ICMICs (P20s) Duke University Ed Coleman, PI Case Western Reserve University James Willson, PI Indiana University Gary Hutchins, PI Johns Hopkins University Zaver Bhujwalla, PI Stanford King Li, PI University of California - Irvine Orhan Nalcioglu, PI University of California - San Diego Robert Mattrey, PI University of Iowa Michael Graham, PI University of Michigan Brian Ross, PI University of Missouri Wynn Volkert, PI University of Pennsylvania Jerry Glickson, PI University of Southern California Peter Conti, PI University of Texas Southwestern Ralph Mason, PI University of Wisconsin - Madison Tom Grist, PI Vanderbilt University David Piston, PI Washington University David Piwnica-Worms, PI The NCI has also funded 16 Pre-ICMIC planning grants which provide time and funds for investigators and institutions to prepare themselves, organizationally and scientifically, to establish an ICMIC

14. CURRENT STATUS

15. Weissleder, MGH GENE EXPRESSION IMAGING The influence of the Human Gene Project on diagnostic imaging will be widespread Weissleder R. Radiology, 2001:219

16. Delivery Vectors Swisher, MD Anderson GENE THERAPY

17. GFP gene --Gal gene Current Methods for Detecting Gene Expression • Northen Blot • Southern Blot • Western Blot for proteins • Immunostaining for proteins • Staining for b-galactosidase • Luminometric measurements for luciferase • Flurosecent imaging for GFP

18. HSV Thymidine Kinase Imaging Gambhir, UCLA

19. Receptor or Transporter Mediated Gene Imaging • Carcinoembryonic antigen gene: radioiodine COL-1 imaging • Dopaminetype 2 receptor gene: 11C-raclopride, 18F-FESPimaging • Sodium/Iodine Symporter gene: radioiodine imaging • Other specific cell surface receptor gene: Radioligand imaging

20. p<0.001 P<0.02 25000 40000 NGF Binding (cpm) 20000 35000 30000 15000 25000 20000 10000 15000 10000 5000 5000 0 0 TrkA TC on TC off Control TA-88 cells Gene Transfer and NGF Receptor Imaging KH Lee, 2001

21. Weissleder, 1999 MRI Methods for Gene Imaging

22. Weissleder, 1999 Optical Methods for Gene Imaging

23. HIV LTR promoter was activated with DMSO and topical application of substrate of half of the back of a LTR-luc Tg mouse Contag, Standford, 1997 Luciferase for Real-Time Indicator of Gene Activation

24. OPTICAL IMAGING • Source: fluorescence, absorption, reflectance, bioluminescence • Imaging • -Diffuse optical tomography • -Reflectance diffuse tomography • -Phase-array detection • -Confocal imaging • -Multiphoton imaging • -Intravital microscopy • Near-infrared fluorescence imaging: proteases (cathepsin D/H) • Fluorescent technique: GFP • Bioluminescence technique: Luciferase

25. Current Methods for In vivo Gene Imaging

26. ANGIOGENESIS IMAGING

27. Haubner R, Cancer Res 2001 [18F]Galacto-RGDPET of Melanoma Bearing Mice v

29. APOPTOSIS IMAGING • Apoptosis: a physiologic form of programmed cell death • Signaling – amplification of signals – activation of caspases – DNA fragmentation • Defective apoptosis : cancer, autoimmune ds, viral infection • Hyperactive apoptosis: AIDS, neurodegenerative ds, ischemia, stroke, myelodysplastic synd.  

30. In Vivo Detection of Phosphatidylserine Expression During Programmed Cell Death Blankenberg FG, PNAS USA 1998

31. Cytoxan Control Blankenberg FG, PNAS USA 1998

32. Detection of Apoptosis in Cardiac Tumor Tc-99m labeled Annexin-V, a high affinity molecule for phosphatidyl-serine which is expressed on cell surface in the terminal stages of apoptosis Hofstra L, JAMA. 2001

33. Labeled caspase-3 peptide substrates (asp-glut-val-asp sequence)

34. Imaging of Genetically Manipulated Animals • Development of transgenic/knockout mice to model human ds • Need for phenotyping imaging of small animals Micro-MR imaging - In vivo resolution 50 m in 3 hr (vs. 800 m for humans) Micro-CT - In vivo resolution of 50 m in 20 min - Ex vivo resolution of 4 um Micro-PET imaging - UCLA: resolution of 2 mm - MGH: resolution of 1 mm

35. Autoradiography Small Animal PET SNM, 2001

36. Ankyrin B (-/-)

37. Obese transgene

38. FUTURE PROSPECTS

39. Transgene Expression Imaging • Development of radiotracers for reporter gene imaging • Development of mutant surface receptors for reporter imaging • Development of new vectors for reporter gene imaging Endogenous Gene Expression Imaging • Imaging protein interactions of signal transduction pathways • Imaging of cell surface receptor regulation • Imaging of specific cell transporters • Imaging of gene expression with antisense oligonucleotides

40. Tumor Biology Imaging • Imaging tumor vasculature to assess angiogenesis • Imaging tumor oncogenes or proto-oncogenes • Imaging tumor suppressor genes • Imaging tumor apoptosis Tumor Therapy Resonse Monitoring • Imaging drug resistance • Imaging to assess chemotherapeutic response • Imaging to monitor gene therapy response • Imaging molecular therapy response

41. Cell Growth Factor Receptor Imaging • Imaging cell surface expressed growth factor receptors • Development of novel peptido-mimetics for imaging Cell Trafficking Imaging • In vivo tracking of progenitor or immune cells • In vivo tracking of viral delivery for gene therapy New Instrumentation • Integration of multi-modality equipment and techniques • Utilization of microPET in living animals

42. Construction of dual gene vectors for imaging IMAGING ENDOGENOUS GENE EXPRESSION M. Doubrovin, PNAS, 2001

43. Test virus in right shoulder, negative control in left shoulder, and positive control in the left thigh Imaging Transcriptional Regulation of p53-Dependent Genes with PET M. Doubrovin, PNAS, 2001

44. IMAGING DRUG RESISTANCE 99mTc-MIBI assessment of MDR1 overexpression in musculoskeletal sarcomas compared with therapy response Burak Z, Eur J Nucl Med. 2001

45. GOAL OF FUTURE EFFORTS 1. Develop new radioprobes that are SN to detect early abnormalities 2. Develop techniques that predict clinical course and tx response 3. Foster interaction and collaboration among imaging scientists and basic biologists, chemists, and physicists to advance imaging research 4. Create infrastructures to advance research in developing, assessing, and validating new imaging techniques and assessment methodologies

47. Molecular targets for therapeutic drugs will increase form a current 500 to an excess of 10,000 in the near future Imaging Downstream Weissleder, MGH

48. Interdisciplinary interactions SNM, 2001 “ It is expected that the fruits of todays molecular imaging research will have a direct effect on patient care within the next 5-15 years” - Weissleder, 2001