Presentation on theme: "Nuclear Medicine Michael R. Lewis, Ph.D. Associate Professor"— Presentation transcript:
1Nuclear Medicine Michael R. Lewis, Ph.D. Associate Professor Department of Veterinary Medicine & SurgeryDepartment of RadiologyNuclear Science & Engineering Institute
2Fisson/Reactor Products Cyclotron Products Generally decay by b- emission because of excess neutronsNot many are useful for diagnostic imaging, but several are useful for radiotherapyGenerally decay by b+ emission or electron capture because of excess protonsMany are useful for diagnostic imaging(gamma scintigraphy or positron emission tomography)
3Definition of Radiopharmaceutical Radioactive compound used for diagnosis and/or therapy of diseasesIn nuclear medicine, ~95% of radiopharmaceuticals used for diagnosis, while the rest are used for therapyRadiopharmaceuticals have no pharmacologic effect, since they are used in tracer quantities
4Ideal Radiopharmaceutical for Imaging - Factors to Consider Administering to patientsWhat is the radiation dose to normal organs?Radiochemical and radionuclidic purity must be extremely highRegulatory approval required for human useScope and limitations of instrumentationGamma scintigraphy vs. single photon emission computed tomography (SPECT) vs. positron emission tomography (PET)
5Ideal Physical Characteristics of Imaging Radiopharmaceutical Decay Modegamma (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 radionuclideEasily 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)
6Ideal Physical Characteristics of Imaging Radiopharmaceutical Ideal half-lifelong enough to formulate RaPh and accomplish imaging studyshort enough to reduce overall radiation dose to the patientphysical half-life of radionuclide should be matched well to biological half-life of RaPhReadily Availablegeographic distance between user and supplier limits availability of short-lived radionuclides/RaPhGenerator-produced radionuclides are desirable
7Ideal Biological Characteristics of Radiopharmaceutical Ideal biological half-lifelong enough to complete the procedure(i.e. localize to target tissue while minimizing background)short enough to reduce overall radiation dose to the patientHigh target:non-target ratiorapid blood clearancerapid localization in target tissuerapid clearance from non-target tissues (liver, kidney, intestines)
8Radioactive Decay Processes 1. alpha ++2. beta minus -3. beta plus +4. e- capture EC5. isomeric transition 6. Internal conversion IC
14Gamma Cameradevice most commonly used to obtain an image in nuclear medicinesometimes called a scintillation camera or Anger cameracamera obtains an image of the distribution of a RaPh in the body (or organ) by detection of emitted g-rays
15Gamma Camera Consists of… A collimatorsodium iodide crystal (detector)photomultiplier (PM) tube arrayposition circuitsummation circuitpulse height analyzer
16Sodium Iodide Detector Gamma rays which interact in the crystal will deposit energy in the crystal to produce “fast electrons” with high kinetic energyMechanisms of interaction are:Photoelectric effectCompton scatterPair production (not relevant to NM)
17Sodium Iodide Detector, cont’d... As electrons slow down in crystal their KE is converted, in part, into light scintillationsA relatively constant proportion of the light scintillations (produced by each g-ray) will exit the crystal and hit the photocathode of the photomultiplier tubeThe crystals used in gamma cameras are typically cm in diameter and 1 cm thick
18Collimator 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 imagedtwo basic types of collimators:multi-hole ( holes) (used more in modern gamma cameras)single or pin-hole
44Story of QuadraMetTM -- I 153Sm identified as a useful nuclide for radiotherapy by MU researchersDevelopment 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]
46Bone Scans of Canine Patient -Veterinary nuclear medicine imaging facilities at MU allowed us to diagnose and monitor the bone cancer in patient dogsBefore Treatment: 8/15/85After Treatment: 3/3/86
47Results of Clinical Trial of 153Sm-EDTMP in Canine Osteosarcoma Response# of Dogs (%)Survival (months)Disease Free7 (18%)Partial Response25 (62%)1 - 16No Response8 (20%)-First documented cures of dogs with bone cancer, without amputation, reported in the literature.
48Story 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 remissionApproved in U.S. for pain palliation of metastatic bone cancer in March, 1997
49153Sm-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.
51Radiopharmaceutical 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 spacerTargetingVectorLinkerBifunctionalChelating AgentMRadiometal
52Hypothesis 1Non-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.
53Receptor Targeting for Molecular Imaging and Therapy Radiometal chelation should be stable under physiological conditions.Chelate modification should not lower the receptor binding affinity.
54Internalizing vs. Non-internalizing Receptors Bryan JN, et al. Vet. Comp. Oncol. 2004; 2:82-90Courtesy of Derek B. Fox, D.V.M., Ph.D.
57* DOTA-Tyr3-Octreotate NOHDPheCysTrpLS*M*M = 111In for gamma scintigraphy and single photon emission tomography (SPECT), 64Cu for positron emission tomography (PET), or 177Lu for targeted radiotherapy (TRT).
59MicroSPECT/CT Using 111In-labeled PNA and Peptide Conjugates (1 h, 48 h) AntisenseNonsenseAlaTATEConsistent 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:
60Bcl-2 mRNA Expression Levels in Mec-1 and Ramos Cells 38211(Bcl-2 +)(Bcl-2 -)
61MicroSPECT/CT Using 111In-DOTA-anti-bcl-2-PNA-Tyr3-octreotate (48 h) Mec-1Ramos
62MicroPET/CT Using 64Cu-DOTA-anti-bcl-2-PNA-Tyr3-octreotate Mec-1Ramos1 h h h h
63Hypothesis 2 Dogs with naturally occurring B-cell lymphoma will demonstrate tumorspecific uptake of 111In-anti-bcl-2-PNA-Tyr3-octreotate that correlatesnegatively with response tochemotherapy.
64111In-DOTA-Tyr3-Octreotate ScintigraphyNodes1 h post-injection4 h post-injection24 h post-injection
65PNA Imaging of Normal Dog This is an scintigraphy scan of a normal healthy patient. There appears to be no specific imaging agent uptake.
68Hypothesis 3Combined 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.
69Western Blot Analysis Tubulin bcl-2 1 2 3 4 5 1. Cells without treatment2. Cells treated with 2 μg of DOTA-anti-bcl-2-PNA-Tyr3-octreotatefor 48 h3. Cells without treatment4. Cells treated with 2 μg of DOTA-nonsense-PNA-Tyr3-octreotatefor 48h5. Cells treated with 2 μg of DOTA-anti-bcl-2-PNA-Ala for 48 hAnalysis 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
70Cell 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-TATE70
72Acknowledgments Dr. Carolyn Anderson Washington University Dr. Henry VanBrocklin Lawrence Berkeley LabDr. Joanna Fowler Brookhaven National LabDr. Gregory Daniel University of TennesseeDr. Alan Ketring University of MissouriDr. Wynn Volkert University of Missouri