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Nuclear Medicine Michael R. Lewis, Ph.D. Associate Professor Department of Veterinary Medicine & Surgery Department of Radiology Nuclear Science & Engineering.

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Presentation on theme: "Nuclear Medicine Michael R. Lewis, Ph.D. Associate Professor Department of Veterinary Medicine & Surgery Department of Radiology Nuclear Science & Engineering."— Presentation transcript:

1 Nuclear Medicine Michael R. Lewis, Ph.D. Associate Professor Department of Veterinary Medicine & Surgery Department of Radiology Nuclear Science & Engineering Institute

2 Fisson/Reactor Products Cyclotron Products Generally decay by - emission because of excess neutrons Not many are useful for diagnostic imaging, but several are useful for radiotherapy Generally decay by + emission or electron capture because of excess protons Many are useful for diagnostic imaging (gamma scintigraphy or positron emission tomography)

3 Definition of Radiopharmaceutical Radioactive compound used for diagnosis and/or therapy of diseases In nuclear medicine, ~95% of radiopharmaceuticals used for diagnosis, while the rest are used for therapy Radiopharmaceuticals have no pharmacologic effect, since they are used in tracer quantities

4 Ideal Radiopharmaceutical for Imaging - Factors to Consider Administering to patients –What is the radiation dose to normal organs? –Radiochemical and radionuclidic purity must be extremely high –Regulatory approval required for human use Scope and limitations of instrumentation –Gamma scintigraphy vs. single photon emission computed tomography (SPECT) vs. positron emission tomography (PET)

5 Ideal Physical Characteristics of Imaging Radiopharmaceutical Decay Mode –gamma (gamma scintigraphy) or positron (PET) and - emitters avoided if at all possible; cause higher absorbed dose to organs and tissues Good Energy emissions of radionuclide –Easily collimated and shielded (lower dose to personnel) –easily detected using NaI crystals (e.g. Tc-99m decays by 140 keV photons which is ideal) –low radiation dose to the patient (no or )

6 Ideal Physical Characteristics of Imaging Radiopharmaceutical Ideal half-life –long enough to formulate RaPh and accomplish imaging study –short enough to reduce overall radiation dose to the patient –physical half-life of radionuclide should be matched well to biological half-life of RaPh Readily Available –geographic distance between user and supplier limits availability of short-lived radionuclides/RaPh –Generator-produced radionuclides are desirable

7 Ideal Biological Characteristics of Radiopharmaceutical Ideal biological half-life –long enough to complete the procedure (i.e. localize to target tissue while minimizing background) –short enough to reduce overall radiation dose to the patient High target:non-target ratio –rapid blood clearance –rapid localization in target tissue –rapid clearance from non-target tissues (liver, kidney, intestines)

8 Radioactive Decay Processes 1.alpha ++ 2.beta minus - 3.beta plus + 4.e - captureEC 5.isomeric transition 6.Internal conversionIC

9 Diagnostic Nuclear Medicine


11 Anatomic vs. Physiologic Imaging

12 How does Physiologic Imaging Work? Anatomy vs. Function in a broken leg

13 Anatomy vs. Physiology

14 Gamma Camera device most commonly used to obtain an image in nuclear medicine sometimes called a scintillation camera or Anger camera camera obtains an image of the distribution of a RaPh in the body (or organ) by detection of emitted -rays

15 Gamma Camera Consists of… A collimator sodium iodide crystal (detector) photomultiplier (PM) tube array position circuit summation circuit pulse height analyzer

16 Sodium Iodide Detector Gamma rays which interact in the crystal will deposit energy in the crystal to produce fast electrons with high kinetic energy Mechanisms of interaction are: –Photoelectric effect –Compton scatter –Pair production (not relevant to NM)

17 Sodium Iodide Detector, contd... As electrons slow down in crystal their KE is converted, in part, into light scintillations A relatively constant proportion of the light scintillations (produced by each -ray) will exit the crystal and hit the photocathode of the photomultiplier tube The crystals used in gamma cameras are typically 40-60 cm in diameter and 1 cm thick

18 Collimator The purpose of the collimator is to define a field of view each very small area of the detector sees only a small part of the organ to be imaged two basic types of collimators: –multi-hole (4000-10000 holes) (used more in modern gamma cameras) –single or pin-hole


20 Gamma Camera Basics * * JPNM Physics website

21 GE Whole Body Gamma Camera

22 SPECT Imaging

23 Mo-99/Tc-99m Generator Column Chromatography When saline is passed over column, the 99m TcO 4 - is dissolved and less strongly adsorbed to alumina.

24 Cardiac Infarction 201 TlCl Rest 99m Tc-Sestamibi Stress Test

25 Cardiac Ischemia 201 TlCl Rest 99m Tc-Sestamibi Stress Test

26 (MDP) (EDP) (HDP)

27 Normal Canine Bone Scan 99m Tc-MDP (Methylene Diphosphonate)

28 Rib Metastasis

29 11-year old boy with a one month history of right knee pain Increase activity in the right tibia Diagnosis: Osteosarcoma Juvenile Osteosarcoma

30 Metastatic Prostate Carcinoma Imaging 99m Tc-HDP

31 Principle of PET Imaging Each annihilation produces two 511 keV photons traveling in opposite directions (180 O ) which are detected by the detectors surrounding the subject

32 GLUTGLUT PLASMATISSUE FDG Fluorodeoxyglucose Metabolism

33 [ 18 F]Fluorodeoxyglucose (FDG)

34 PET Control Alzheimers Disease Center for Functional Imaging; Life Sciences Division; Lawrence Berkeley National Laboratory; Berkeley, CA. Brain Metabolism ([ 18 F]FDG)

35 [ 11 C]Raclopride PET Brain Study Normal Cocaine Abuser Courtesy BNL PET Project nCi/cc 1000 800 600 400 200 0

36 Therapeutic Nuclear Medicine


38 Fission products useful in nuclear medicine include: 99 Mo, 131 I, 133 Xe, 137 Cs and 90 Sr Mo-99 I-131

39 Differentiated Thyroid Carcinoma 5 mCi Na 131 I Imaging Treatment Planning 48 h p.i.

40 Differentiated Thyroid Carcinoma Therapy 105 mCi Na 131 I 27 h p.i.

41 Differentiated Thyroid Carcinoma Post Surgical Resection Therapy 57 Co Flood Source + 105 mCi Na 131 I

42 Differentiated Thyroid Carcinoma 201 TlCl and 99m Tc-Sestamibi Imaging 4 months after Na 131 I Therapy

43 Canine Osteosarcoma Tumor distal radius

44 Story of QuadraMet TM -- I 153 Sm identified as a useful nuclide for radiotherapy by MU researchers Development began in early 1980s at MU in collaboration with the Dow Chemical Company [phosphonate ligand complexes; 153 Sm-EDTMP] Successful in treatment of primary osteosarcoma in canine patients, with added bonus of 18% cure rate [MU College of Veterinary Medicine]

45 One of Our First Patients

46 Bone Scans of Canine Patient Before Treatment: 8/15/85After Treatment: 3/3/86

47 Results of Clinical Trial of 153 Sm-EDTMP in Canine Osteosarcoma Response# of Dogs (%)Survival (months) Disease Free7 (18%)11 - 60 Partial Response25 (62%)1 - 16 No Response8 (20%)0.5 - 1

48 Story of QuadraMet -- II Clinical trials began in late 1980s, with doses supplied by MURR for Phase I studies ~80% efficacy, with ~25% obtaining full pain remission Approved in U.S. for pain palliation of metastatic bone cancer in March, 1997

49 153 Sm-EDTMP [QuadraMet] 99m Tc-MDP 153 Sm-EDTMP N N PO 3 H 2 3 H 2 3 H 2 3 H 2 153 Sm +

50 Experimental Nuclear Medicine

51 1.Targeting vector (e.g., mAb, peptide hormone, small molecule, etc.) 2.Radionuclide (e.g., diagnostic – 99m Tc, 111 In, etc.; therapeutic – 188 Re, 90 Y, 177 Lu, etc.) 3.Bifunctional chelating agent (BCA) 4.Linker or spacer The design of an effective tumor-targeting radio- pharmaceutical involves appropriate selection of: Radiopharmaceutical Design Targeting Vector Linker Bifunctional Chelating Agent M Radiometal

52 Hypothesis 1 Non-invasive imaging of bcl-2 mRNA expression in lymphoma may aid in the identification of chemotherapy patient risk groups, who might respond better to targeted immunotherapy, radioimmunotherapy, or antisense therapy.

53 Receptor Targeting for Molecular Imaging and Therapy Radiometal chelation should be stable under physiological conditions. Chelate modification should not lower the receptor binding affinity.

54 Internalizing vs. Non-internalizing Receptors Bryan JN, et al. Vet. Comp. Oncol. 2004; 2:82-90Courtesy of Derek B. Fox, D.V.M., Ph.D.

55 Peptide Nucleic Acid

56 Cellular Delivery of PNA ChelatorPNA Peptide

57 DOTA-Tyr 3 -Octreotate *M = 111 In for gamma scintigraphy and single photon emission tomography (SPECT), 64 Cu for positron emission tomography (PET), or 177 Lu for targeted radiotherapy (TRT). N O N H D PheCysTyrDTrp Lys Thr CysThr N N N COOH COOH COOH S S * M HOOC

58 PNA and Peptide Conjugates

59 MicroSPECT/CT Using 111 In-labeled PNA and Peptide Conjugates (1 h, 48 h) Antisense Nonsense Ala TATE Jia F, et al. J. Nucl. Med. 2008; 49: 430-438

60 Bcl-2 mRNA Expression Levels in Mec-1 and Ramos Cells 3821 1 (Bcl-2 +) (Bcl-2 -)

61 MicroSPECT/CT Using 111 In-DOTA-anti-bcl-2-PNA-Tyr 3 -octreotate (48 h) Mec-1 Ramos

62 MicroPET/CT Using 64 Cu-DOTA-anti-bcl-2-PNA-Tyr 3 -octreotate Mec-1 Ramos 1 h 3 h 24 h 48 h

63 Hypothesis 2 Dogs with naturally occurring B-cell lymphoma will demonstrate tumor specific uptake of 111 In-anti-bcl-2-PNA- Tyr 3 -octreotate that correlates negatively with response to chemotherapy.

64 111 In-DOTA-Tyr 3 -Octreotate Scintigraphy Nodes 1 h post-injection4 h post-injection24 h post-injection

65 PNA Imaging of Normal Dog

66 Partial Remission Initial Scan Remission Scan

67 Complete Remission Initial Scan Remission Scan Relapse Scan

68 Hypothesis 3 Combined radionuclide and antisense therapy may act synergistically or additively with respect to cell proliferation and viability in an in vitro model of B-cell lymphoma.

69 Western Blot Analysis Tubulin bcl-2 1 2 3 4 5 1. Cells without treatment 2. Cells treated with 2 μg of DOTA-anti-bcl-2-PNA-Tyr 3 -octreotate for 48 h 3. Cells without treatment 4. Cells treated with 2 μg of DOTA-nonsense-PNA-Tyr 3 -octreotate for 48h 5. Cells treated with 2 μg of DOTA-anti-bcl-2-PNA-Ala for 48 h

70 Cell Viability Assay Day 2 p<0.002 Day 3 p<0.005

71 TUNEL Assays Anti-bcl-2 + Anti-FLIPAnti-bcl-2 + CH11Anti-bcl-2 Anti-FLIP + CH11 Anti-bcl-2 + Anti-FLIPAnti-bcl-2 + CH11Anti-bcl-2 Anti-FLIP + CH11 SH-SY5Y IMR-32

72 Acknowledgments Dr. Carolyn Anderson Washington University Dr. Henry VanBrocklin Lawrence Berkeley Lab Dr. Joanna Fowler Brookhaven National Lab Dr. Gregory Daniel University of Tennessee Dr. Alan Ketring University of Missouri Dr. Wynn Volkert University of Missouri

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