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 b- emission because of excess neutrons
Not many are useful for diagnostic imaging, but several are useful for radiotherapy
Generally decay by b+ 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)
a and b- 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 a or b)

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- capture EC
5. isomeric transition 
6. Internal conversion IC

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 g-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, cont’d...
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 g-ray) will exit the crystal and hit the photocathode of the photomultiplier tube
The crystals used in gamma cameras are typically 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 ( 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 99mTcO4-
is dissolved and less
strongly adsorbed to
alumina.

24. Cardiac Infarction
201TlCl Rest
99mTc-Sestamibi
Stress Test

25. Cardiac Ischemia
201TlCl Rest
99mTc-Sestamibi
Stress Test

26. (MDP)
(EDP)
(HDP)

27. Normal Canine Bone Scan
99mTc-MDP (Methylene Diphosphonate)

28. Rib Metastasis

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

30. Metastatic Prostate Carcinoma
Imaging
99mTc-HDP

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

32. Fluorodeoxyglucose Metabolism
PLASMA
TISSUE G L U T
FDG

33. [18F]Fluorodeoxyglucose (FDG)

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

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

36. Therapeutic Nuclear Medicine

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

39. Differentiated
Thyroid
Carcinoma
5 mCi Na131I
Imaging
Treatment Planning
48 h p.i.

40. Differentiated
Thyroid
Carcinoma
Therapy
105 mCi Na131I
27 h p.i.

41. Differentiated Thyroid Carcinoma Post Surgical Resection Therapy
57Co Flood Source mCi Na131I

42. Differentiated Thyroid Carcinoma 201TlCl and 99mTc-Sestamibi Imaging
4 months after Na131I Therapy

43. Canine Osteosarcoma
Tumor distal radius

44. Story of QuadraMetTM -- I
153Sm identified as a useful nuclide for radiotherapy by MU researchers
Development began in early 1980’s at MU in collaboration with the Dow Chemical Company [phosphonate ligand complexes;153Sm-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
-Veterinary nuclear medicine imaging facilities at MU allowed us to diagnose and monitor the bone cancer in patient dogs
Before Treatment: 8/15/85
After Treatment: 3/3/86

47. Results of Clinical Trial of 153Sm-EDTMP in Canine Osteosarcoma
Response
# of Dogs (%)
Survival (months)
Disease Free
7 (18%)
Partial Response
25 (62%)
1 - 16
No Response
8 (20%)
-First documented cures of dogs with bone cancer, without amputation, reported in the literature.

48. Story of QuadraMet™ -- II
Clinical trials began in late 1980’s, 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. 153Sm-EDTMP [QuadraMet] + 153Sm 99mTc-MDP 153Sm-EDTMP N PO H 3 2
The development Quadramet exemplifies the translational research capabilities at MU: from the and production of the radioisotope (Sm-153) and the identification of the phosphonate comppound, (EDTMP) which targets bone cancer to the initial clinical trials in human patients.

50. Experimental Nuclear Medicine

51. Radiopharmaceutical Design
The design of an effective tumor-targeting radio-pharmaceutical involves appropriate selection of:
Targeting vector (e.g., mAb, peptide hormone, small molecule, etc.)
Radionuclide (e.g., diagnostic – 99mTc, 111In, etc.; therapeutic – 188Re, 90Y, 177Lu, etc.)
Bifunctional chelating agent (BCA)
Linker or spacer
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; 2:82-90
Courtesy of Derek B. Fox, D.V.M., Ph.D.

55. Peptide Nucleic Acid

56. Cellular Delivery of PNA
Chelator
PNA
Peptide

57. * DOTA-Tyr3-OctreotateN O H D P h e C y s T r p L S * M
*M = 111In for gamma scintigraphy and single photon emission tomography (SPECT), 64Cu for positron emission tomography (PET), or 177Lu for targeted radiotherapy (TRT).

58. PNA and Peptide Conjugates

59. MicroSPECT/CT Using 111In-labeled PNA and Peptide Conjugates (1 h, 48 h)
Antisense
Nonsense
Ala
TATE
Consistent with the biodistribution study that kidneys were the primary organ of accumulation of the PNA conjugates.
Jia F, et al. J. Nucl. Med. 2008; 49:

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

61. MicroSPECT/CT Using 111In-DOTA-anti-bcl-2-PNA-Tyr3-octreotate (48 h)
Mec-1
Ramos

62. MicroPET/CT Using 64Cu-DOTA-anti-bcl-2-PNA-Tyr3-octreotate
Mec-1
Ramos
1 h h h h

63. Hypothesis 2 Dogs with naturally occurring B-cell
lymphoma will demonstrate tumor
specific uptake of 111In-anti-bcl-2-PNA-
Tyr3-octreotate that correlates
negatively with response to
chemotherapy.

64. 111In-DOTA-Tyr3-Octreotate
Scintigraphy
Nodes
1 h post-injection
4 h post-injection
24 h post-injection

65. PNA Imaging of Normal Dog
This is an scintigraphy scan of a normal healthy patient. There appears to be no specific imaging agent uptake.

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-Tyr3-octreotate
for 48 h
3. Cells without treatment
4. Cells treated with 2 μg of DOTA-nonsense-PNA-Tyr3-octreotate
for 48h
5. Cells treated with 2 μg of DOTA-anti-bcl-2-PNA-Ala for 48 h
Analysis of protein inhibition. Quantitive analysis showed 51.0% of bcl-2 protein inhibition by the treatment of 2 ug of DOTA-anti-bcl-2-PNA-Tyr3-Octreotate

70. Cell Viability Assay Day 2 p<0.002 Day 3 p<0.005
The viability curve shows a general decrease through out the study however days two and three demonstrate statistically significant mass effects p=0.005 and p=0.002 respectively further at day3 these levels are well below those found for Lu-DOTA-TATE 70

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