In-vivo Diagnostic agentsSpring 2003 :1 In-vivo Diagnostic agentsSpring 2003 Contrast or Radio-imaging agents Radioisotopes MRI contrast agents


In-vivo Diagnostic Agents :2 In-vivo Diagnostic Agents What is medical imaging? – The non-invasive or non-surgical visualization of internal organs or processes X-rays, Magnetic resonance imaging (MRI), radionuclide or nuclear medicine, ultrasound Radionuclides are nuclei that decay by dissipating excess energy (parent) to become stable (daughter) by energy emission in form of particulate or electromagnetic radiation Modes of decay or ionizing radiation: a Alpha particle – parent nucleus releases a helium nucleus without its electrons, largest mass of the particles therefore no penetration, if daughter is in an excited state then the excess energy is released as a g-ray b Beta particle – mass of an electron, parent nucleus releases either a negative electron (negatron b-) or a positive electron (positron b+)----anti-matter. When a b+ interacts with matter, an annihilation reaction occurs that produces 2 g-rays at 180 degrees to each other with energy = 0.511 MeV, used in PET imaging


Slide 3:3 In-vivo Diagnostic Agents EC or electron capture – occurs when an electron drops from a K shell electron cloud to the nucleus where a proton is converted into a neutron producing a X-ray (source is outside the nucleus) Cathode ray tube of an X-ray machine– range of energies g Gamma ray – no mass, source is from inside nucleus, most ionizing and penetrating, most important type of decay used in medicine, does considerable damage to matter, a few properties of matter---photons IT or isomeric transition – Where a high energy nucleus loses energy by emitting a g-ray-------no particle is emitted or captured----called metastable state, example: 99mTc (parent) decays to 99Tc plus a g-ray Sources: X-ray: a film is exposed Fluoroscopy: a fluorescent screen detects g- or X ray which is imaged by a TV camera to afford real time images of organs in motion by using contrast agents----PCTA CAT – Computed axial tomography – takes advantage of small differences in tissue radiographic density to create an image


Slide 4:4 In-vivo Diagnostic Agents Characteristics of the “ideal” radioisotope: Decays by g-rays alone Half-life of 6-12 hours Readily available-----Generators Readily incorporated into a carrier molecule Product is relatively stable Important: most rapidly reproducing cells are affected most by ionizing radiation – reproductive organs, fetus, bone marrow, hair follicles Units to express activity or the rate of radioactive decay Curie – Ci, mCi or mCi, 1 Ci = 3.7 x 1010 dps dps – disintegrations per second, 1 dps – 1 Bq (becquerel)


In-vivo Diagnostic Agents :5 Types of medical imaging available: Angiography – an X-ray film or radiographic study of the vascular system Urography – radiographic study of the urinary tract Pyelogram – pelvis and the kidney and ureters Cystogram – urinary bladder Bronchography – radiographic study of the lungs and bronchi Upper GI series or “Barium Swallow” – radiographic study of the pharynx, esophagus, stomach, duodenum, small intestine Lower GI series or Barium enema – radiographic study of the large bowel (colon) and rectum Cholecystography – radiographic study following introduction of contrast agents either orally or IV of the structure of the gall bladder and bile ducts Myelography – radiological study of the spinal cord Salpingography – radiological study of the fallopian tubes In-vivo Diagnostic Agents


Slide 6:6 Types of medical imaging available continued: Hysterosalpingography – radiographic study of the uterus and fallopian tubes Sialography – radiological study of the salivary glands and ducts Arthrography – radiological study of the joints Discography – radiological study of the joints of the spine Cisternography – radiological study of CSF flow patterns CAT scan –Computerized Axial Tomography– a computerized method of resolution of a series of x-ray pictures into a “cross-section” of the body or part of the body. Some procedures do benefit from the use of a contrast agent. NMR scan or MRI – Magnetic Resonance Imaging – A computerized method of resolution of a series of radio-frequency scans of tissues into a “cross-section” of the body or body part. This method visualizes composition of areas rather than density as in the CAT scan. What is actually measured is the “relaxation time” of water. This “relaxation time” is different depending on the type of tissue. In-vivo Diagnostic Agents


Slide 7:7 In-vivo Diagnostic Agents How do you calculate the “activity” of a radioisotope at the present time? Anow = At=0 e-lt l = decay constant for a particular element l = 0.693/half life t1/2 = Half life is characteristic of the radioisotope under discussion NOTE: t = time elapsed since original activity determination-----This elapsed time MUST include time zone information


Slide 8:8 In-vivo Diagnostic Agents Biological effects of radiation on tissue Major differences between radiation types is the ability to penetrate matter b particles – few millimeters, particle delivery is highly localized producing primarily ionization based damage X- and g-rays – several centimeters, radiation delivery is more uniform and less concentrated primarily producing free radicals Radiation damage mechanisms Direct radiation effect – absorption occurs directly at the critical biological site or target – primarily damage on DNA which leads to cell death Indirect radiation effect – primarily radiolysis of water since it is the most abundant target to produce hydroxide radical-----reaction with DNA produces non-lethal damage and mutations


Slide 9:9 In-vivo Diagnostic Agents Technecium (Z = 43) Chemistry and the Technecium generator – 85% of all medical diagnostic scans Artificial element, 22 isotopes with 8 nuclear isomers, NO STABLE isomers Easily forms metal-electron donor complexes or chelates in the presence of a reducing agent Electronegative chelating groups – SH thiols, CO2- carboxylates, NH amines, PO4- phosphate, CNOH oximes, OH hydroxyls, P Phosphines, NC isonitriles Virtually ideal properties for imaging with a g-camera: 140 KeV g-ray (89% abundance), half-life of 6 hours – adequate to synthesize chelate, determine purity, inject and image with a minimum radiation exposure How does a 99mTc generator work?


Slide 10:10 In-vivo Diagnostic Agents Technecium (Z = 43) Chemistry and the Technecium generator – 85% of all medical diagnostic scans TcO4- will not chelate electronegative groups unless in the presence of a reducing agent such as ascorbic acid or stannous salts Following elution of TcO4- from the generator it is placed in a vial containing the desired chelating ligand and a reducing agent such as SnCl2, SnF2 or stannous tartrate Product is then assayed/purified by either paper chromatography, thin-layer chromatography, column chromatography or solvent extraction A new generator is purchased weekly by the hospital Types of products available: Technecium tagged Chelated 2. Bifunctional chelated – covalent linkage group coupled to a targeting moiety such as a antibody, peptide or hormone and a chelating group for the metal


Slide 11:11 In-vivo Diagnostic Agents Technecium products available: Technecium albumin – used in heart imaging to determine wall motion and ejection fraction – CAD, bypass surgery, heart failure, pre- and post transplant, cardiomyopathy and damage from cardiotoxins (doxirubicin) Technecium albumin aggregate – pulmonary microcirculation imaging to determine occlusions due to emboli Technecium albumin colloid – imaging to determine perfusion and clearance rate of the colloid by the reticuloendothelial cells of the liver and spleen, used in cases of abdominal trauma, tumor metastisis, and liver dysfunction such as in cirrhosis Technecium Biscisate – imaging to determine brain perfusion in stroke and lesion determination


Slide 12:12 In-vivo Diagnostic Agents Technecium products available: 5. Technecium Disofenine – imaging of the liver after hepatocytes take up the product followed by excretion into the gall bladder and common bile duct and finally the duodenum----used to separate acute from chronic cholecystitis (acute – the cystic duct is blocked preventing bile from getting to the gall bladder) 6. Technecium Exametazine – Brain imaging - agent of choice to determine brain death in life support patients, Brain scans - localize seizure foci, dementia, strokes; major use is radiolabeling of leukocytes to located intra-abdominal infections and inflammatory bowel disease


Slide 13:13 In-vivo Diagnostic Agents Technecium products available: Technecium Medronate – imaging of the skeletal system – bone scans are the most common procedure: cancer metastasis to bone in breast and prostate cancer, osteomyelitis, Paget’s disease, fracture, stress fracture diagnosis 60% localizes in bone based on metabolic activity, take scan 3 hours after injection, abnormality appears as hot spots due to increase bone metabolism and cold spots indicate necrosis Technecium Mertiatide – imaging of kidney function and urine outflow


Slide 14:14 In-vivo Diagnostic Agents Technecium products available: Technecium Gluceptate – radiolabeling of monoclonal antibodies 10. Technecium Pentetate – imaging of the brain for brain tumors and death, renal studies and glomerular filtration rates 11. Technecium pyrophosphate – heart imaging to determine diagnosis of recent MI with normal cardiac enzymes 12. Technecium labeled red blood cells – imaging in cardiac studies, localize pre—operatively the site of active lower GI bleeding, heat wrinkled cells are used for spleenic tissue damage diagnosis


Slide 15:15 In-vivo Diagnostic Agents Technecium products available: Technecium Sestammibi - Cardiolite® - myocardial perfusion imaging, pre-operative localization of parathyroid adenoma and early breast cancer diagnosis Technecium Succimer – determination of functional renal parenchyma in cases of trauma, cysts and scarring Technecium sodium pertechnate TcO4-Na+ - similar in size and charge to I- : concentrated in thyroid, salivary glands, kidney, stomach and choroid plexus in the brain (blood-brain barrier) Preferred agent for thyroid scans unless 131I is indicated – cold spot indicates non-functional tissue such as a tumor or cyst Technecium sulfur colloid – imaging of bone, liver, spleen to determine reticuloendothelial cell function, primary agent used in determining GI emptying time and GER (gastroesophegeal reflux) Technecium Tetrofosmin - Myoview® - myocardial perfusion imaging Others


Slide 16:16 Bioconjugate Chemistry Vol. 13 370-377 (2002) Rennen, van Eerd, Oyen, Corstens, Edwards and Boerman Department of Nuclear Medicine, University Medical Center Nijmegen, Nijmegen, The Netherlands Effects of Coligand Variation on the In Vivo Characteristics of Tc-99m-Labeled Interleukin-8 in Detection of Infection


Slide 17:17 In-vivo Diagnostic Agents Other Radiolabel Generators available: 90Sr (strontium) – 90Y (Yttrium) 2. 62Zn – 62Cu (copper) 68Ge (germanium) – 68Ga (Gallium) 4. 82Sr – 82Rb (Rubidium) Other radiolabeled compounds: Gallium 67Ga citrate – imaging to localized inflammation and infection sites 18F-2-fluoro-2-deoxy-D-glucose – used in PET scanning (positron emission tomography), used in determining metabolic rate: brain, heart and cancer management (neoplasms have a high glycolytic rate) – most often used for this


Slide 18:18 © 1994-2000 Crump Institute for Molecular Imaging          UCLA School of Medicine NH3 perfusion study 18FDG metabolic study Both flow and metabolic studies show a matching defect in the antero-septal wall Consistent with a perfusion deficit in this wall The hypometabolism supports little viable tissue in the wall of this patient Myocardial Viability – Matching two methods to confirm disease For a complete tutorial on Clinical PET imaging with cardiology applications see: http://www.crump.ucla.edu/lpp/clinpetcardio/mismatch.html


Slide 19:19 In-vivo Diagnostic Agents Other radiolabeled compounds: Iodine radiolabels Iobenguane sulfate 131I – used to image and locate functional neuroblastomas and pheochromocytomas Sodium 123Iodine – thyroid imaging Sodium 131Iodine – total thyroidectomy and treatment of functional thyroid cancer metastatic carcinoma Indium 111In radiolabels – utilized to radiolabel monoclonal antibodies and peptides via bifunctional chelating agents Indium chloride – behaves similar to Fe+3 – imaging of tumors, bone marrow, and abscesses (white blood cell labeling) Indium satumomabpendetide – labeling of monoclonal antibodies


Slide 20:20 In-vivo Diagnostic Agents Indium 111In radiolabels continued: Indium Oxine – (8-hydroxyquinoline) – used to replace 67Ga due to better specificity and better image quality, labeling of platelets and leukocytes for infection localization and for platelet studies (thrombosis location, life span) and kidney transplantation Indium pentetate – imaging of the spinal canal and CSF spaces in the brain Indium Pentreotide – whole body imaging for the diagnosis of somatostatin receptor rich neuroendocrine tumors and metastasis


Slide 21:21 In-vivo Diagnostic Agents 5. Thallium 201Tl Chloride – cardiac imaging of viable myocardium – similar uptake into tissue as seen with K+, perfusion studies in conjunction with stress testing via treadmill, adenosine or dipyridamole, cold spots indicated poor perfusion 6. Xenon gas – 133Xn – inhalation and lung scans to localize obstructed regions, b-emitter producing a low energy g-ray therefore not very sensitive or efficient Radiological Contrast Agents – goal is to increase the opaqueness or contrast of poorly contrastable regions or tissues (typically an X-ray film or fluoroscopy as in PTCA) 5 radiographic densities of increasing contrast: air, fat, fluid (soft tissue), bone, metallic Oral and rectal use: Barium sulfate – totally insoluble in water so the toxicity of barium does not occur---no absorption


Slide 22:22 In-vivo Diagnostic Agents Radiological Contrast Agents continued: Iodine based compounds – water soluble, viscous organic iodides Iodine atoms absorb x-rays effectively and produces a “bone-like” density on an x-ray film or fluorometer screen Elimination is primarily via liver metabolism and intestinal excretion Adverse reactions: N/V, pain, warm feeling at injection site, flushing, urticaria, possible anaphylaxis and death (be sure they have epinephrine and a crash cart available immediately if needed)


Slide 23:23 In-vivo Diagnostic Agents Radiological Contrast Agents continuned: Iodine based compounds:


Slide 24:24 In-vivo Diagnostic Agents Radiological Contrast Agents continuned: Iodine based compounds: Cholangiography and Cholecystography Urography, CT and angiography


Slide 25:25 In-vivo Diagnostic Agents Radiological Contrast Agents continuned: Iodine based compounds: Angiography, myelography, CT, urography, Angiocardiography, ventriculography, cisternography Angiography


Slide 26:26 In-vivo Diagnostic Agents Radiological Contrast Agents continuned: Iodine based compounds: Angiography Iodixanol – Visipaque® – Angiography Isosulfan Blue – Lymphazurin® – lymphography to visualize lymph drainage Pentetreotide – OctreoScan® – imaging and locating neuroendocrine tumors possessing somatostatin receptors


Slide 27:27 In-vivo Diagnostic Agents Magnetic Resonance Imaging Contrast Agents – Alters the relaxation time of water in tissues being imaged Gadolinium Gd+3 chelated compounds OTHERS


Slide 28:28 In-vivo Diagnostic Agents New for 2002 - Ultrasound Contrast Agents – used for contrast enhancement during ultrasound enhancement procedures in blood Injectable Perflexane Lipid microspheres for IV use - Imagent® Kit consists two basic components: Perflexane – n-perfluorohexane gas 2. 1,2-Dimyristoyl-sn-glycero-3-phosphocholine (DMPC) - Synthetic Indication: Improvement of left ventricular endocardial border in patients with suboptimal echocardiogram No improvement in ejection fraction determinations Eliminated within 5 hours, DMPC eliminated by normal phospholipid metabolism