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:
Nuclear Medicine Michael R. Lewis, Ph.D. Associate Professor Department of Veterinary Medicine & Surgery Department of Radiology Nuclear Science & Engineering Institute
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)
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
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)
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 )
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
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)
Radioactive Decay Processes 1.alpha ++ 2.beta minus - 3.beta plus + 4.e - captureEC 5.isomeric transition 6.Internal conversionIC
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
Gamma Camera Consists of… A collimator sodium iodide crystal (detector) photomultiplier (PM) tube array position circuit summation circuit pulse height analyzer
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)
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
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
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]
Bone Scans of Canine Patient Before Treatment: 8/15/85After Treatment: 3/3/86
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
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
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 +
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
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.
Receptor Targeting for Molecular Imaging and Therapy Radiometal chelation should be stable under physiological conditions. Chelate modification should not lower the receptor binding affinity.
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.
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
MicroPET/CT Using 64 Cu-DOTA-anti-bcl-2-PNA-Tyr 3 -octreotate Mec-1 Ramos 1 h 3 h 24 h 48 h
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.
111 In-DOTA-Tyr 3 -Octreotate Scintigraphy Nodes 1 h post-injection4 h post-injection24 h post-injection
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.
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
Cell Viability Assay Day 2 p<0.002 Day 3 p<0.005
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