Outline Chapter 14 • Introduction Nuclear Medicine • Radiopharmaceuticals • Detectors for nuclear medicine Radiation Dosimetry I • Counting statistics • Types of studies Text: H.E Johns and J.R. Cunningham, The • Absorbed dose from radionulides physics of radiology, 4th ed. http://www.utoledo.edu/med/depts/radther 1 2 Introduction Radiopharmaceuticals • The field involving the clinical use of non-sealed radionuclides is referred to as nuclear medicine • Radiopharmaceuticals are medicinal formulations • Most of the activities are related to containing one or more radionuclides – the imaging of internal organs – the evaluation of various physiological functions • Once administered to the patient they can localize to – to a lesser degree treatment of specific types of disease specific organs or cellular receptors • Typical procedures use a radioactive material • Properties of ideal radiopharmaceutical: (radiopharmaceutical or radiotracer), which is injected – Low dose radiation => appropriate half-life into the bloodstream, swallowed, or inhaled as a gas – High target/non-target activity ratio • This radioactive material accumulates in the organ or – Low toxicity (including the carrier compound, shelf-life) area of the body being examined, where it gives off a – Cost-effectiveness (available from several manufacturers) small amount of energy in the form of gamma rays 3 4 Radiopharmaceuticals Mechanisms of localization • Compartmental localization (leakage points to abnormality) • Phagocytosis (normal vs cancer cells) • Cell sequestration (spleen imaging) • Passive diffusion (often through membranes, e.g., BBB) • Active transport (membranes with pumps) • Metabolism (glucose-like molecules, F-18 labelled FDG) • Capillary blockade/Perfusion • Receptor binding (e.g., antibody-antigen) • Shielded vial used to hold reconstituted radiopharmaceuticals • Others • Using long forceps to handle a vial containing radioactivity Comprehensive review at: http://pharmacyce.unm.edu/nuclear_program/freelessonfiles/Vol16Lesson4.pdf 5 6 1 Radiopharmaceuticals Radiopharmaceuticals production production: Tc-99m generator • Mo-99 (th=66h) is produced in the fission reaction, it is then chemically purified and shipped in Tc-99m (th=6h) generators 2− • Molybdate, MoO4 is passed on to an anion exchange column of alumina (Al2O3); acid pH promotes binding • As Mo-99 decays it forms pertechnetate TcO4−; because of its single charge, • Cyclotron it is less tightly bound to the • Nuclear reactor (fission or neutron activation) alumina. Pouring normal saline solution through the • Radionuclide generators column of immobilized 99Mo 99m From: Ziessman, et al., Nuclear Medicine: the http://www.gedrytec.com/design/technical_ elutes the soluble Tc Requisites In Radiology, 3d ed., Elsevier, 2006 features_annotations.php 7 8 • Recent development: US- based North Star started Radiopharmaceuticals production of Tc-99m (South Africa) generators, brand name production: Tc-99m generator RadioGenix System, in 2018 (Wisconsin) • A technetium generator can be eluted several times a day for • Uses neutron capture: ~1 week before it needs to be replaced with a fresh generator Mo-98(n,g)Mo-99, no 5 Uranium involved Tc-99m (th~ 6h) decays to Tc-99 (th~ 10 y) with emission of 140.5keV g-ray https://www.nap.edu/read/23563/chapter/6#55 TABLE 3.2 Reactors That Irradiate Targets for Global Mo-99 Suppliers as of June 2016 Start of Reactor Country Power (MWt) Fuel Type Target Type Operation (year) BR-2 Belgium 100 HEU HEU 1961 HFRe Netherlands 45 LEU HEU 1961 Czech LVR-15 10 LEU HEU 1957 Republic Maria Poland 30 LEU HEU 1974 Left. Plot of typical Mo-99 and Tc-99m activity Right. Image acquired from a Tc-99m cerebral blood flow brain scan of a NRU Canada 135 LEU HEU 1957 person with Alzheimer’s disease. The arrows indicate areas of diminished blood flow due to the disease. OPAL Australia 20 LEU LEU 2006 From: Molybdenum-99/Technetium-99m Production and Use, NRC 2009 https://www.ncbi.nlm.nih.gov/books/NBK215133/ SAFARI-1 South Africa 20 LEU HEU/LEUc 1965 9 10 Detectors in nuclear medicine Geiger counter • The standard methods for the detection and • Counter filled with a special measurement of radiation are not sensitive enough gas mixture, at p=10 cm of Hg to detect the emission of a single particle arising • Operated at high voltages, from the disintegration of a nucleus where the passage of each particle creates a controlled • Special gas-filled, scintillating, or semiconductor avalanche, resulting in a gain detectors are used almost exclusively of ~105-106 • For visualization of the distribution of activity use • A single particle can produce a computer-aided signal processing (PET scanners, pulse of charge in the detectable range (10-10 C) gamma cameras, etc.) 11 12 2 Geiger counters Scintillation detectors • Scintillating material coupled with a photomultiplier (PM) • X-rays → electrons within the scintillator → optical photons within the scintillator → photoelectrons from the photocathode of the PM → secondary electrons from each dynode → collected at the final anode of PM • Efficiency of gamma counter is very low, ~5% • PM multiplication factors ~106 • Efficiency of beta counters is ~100%; their configuration • Pulse size is proportional to the depends on the energy of particles to be detected energy of the initial x-ray 13 14 Scintillation detectors Semiconductor detectors 662keV 412keV • Ionization produced within the sensitive volume of semiconductor detector is converted directly into a measurable electric pulse • Pulse height distributions always have Gaussian • Fewer losses result in much sharper pulse height spectra shaped peaks and low-energy tails • Sensitivity is typically lower compared to scintillators 15 16 Stochastic quantities Statistics of isotope counting • Radiation is random in nature, associated physical • The probability of observing quantities are described by probability distributions the value N when the • For a “constant” radiation field a number of x-rays expected value is a: observed at a point per unit area and time interval aN e−a P = follows Poisson distribution N N! • For large number of events it may be approximated • For each measurement there is always an error due to by normal (Gaussian) distribution, characterized by statistical fluctuations: standard deviation for a single measurement – Standard deviation = Ne N = N 100 100 100 – Probable error % = = p = 0.67 N Ne Ne N The PE defines the middle 50% of the normal distribution 17 18 3 Statistics of isotope counting Standard deviation • In a normal distribution • Standard deviation can be estimated from a 68.3% of all measured values fall within 1 sample mean value a determined from a interval on either side of series of measurements, = a the mean a, 95.5% to be • The sample standard deviation can be within 2, and 99.7% to be constructed from a series of N measurements within interval 3 of a variable x • These are not device- N 2 (xi − a) related fluctuations = i=1 s N −1 The probable error p defines the middle 50% of the normal distribution 19 20 Example 1 Example 2 • If the average number of counts in a region of a • Concerning the Poisson distribution, which one of the planar gamma camera image is 25 counts per following statements is false? pixel, what is the percent standard deviation per pixel, assuming Poisson statistics? A. It is an approximation to the binomial distribution for small sample sizes B. It describes rare and random events A. 0% C. Radioactive decay as a function of time fits the Poisson distribution B. 10% D. The standard deviation is approximaly equal to the square root of the number of counts for large numbers C. 20% E. The percent standard deviation decreases as the number of counts D. 50% increases 21 22 Resolving time and loss of counts Resolving time and loss of counts • Most of detectors become unresponsive for a short • To determine the resolving experimentally, can time after receiving each pulse use two sources of similar activities – For Geiger counters resolving time t ~100 ms • For measured number of counts per second NA, – Scintillators t <10 ms NB, NAB, the corrected number of counts • At high counting rates some pulses can be missed N N N A + B = AB • For observed number of counts per second N0, the 1− N At 1− N Bt 1− N ABt corrected number of counts • The resolving time: N0 N + N − N Nc = t = A B AB 1− N0t 2N A N B 23 24 4 Uptake and volume studies Example 3 • A radioactive sample is counted for 1 minute and • Activity of a sample (P) is compared with a produces 900 counts. The background is counted for standard source (S) measured in the same geometry 10 minutes and produces 100 counts. The net count • Thyroid uptake of I-131 taken orally rate and net standard deviation are about __ ,__ counts. P - P %Uptake = bkg 100 A. 800, 28 Ncorr = 900 /1−100 /10 = 890 S-Sbkg B. 800, 30 N N • Plasma volume determination by injection of RISA = 2 + 2 = c + bkg = C. 890, 28 c bkg tc tbkg (radioactive iodine-tagged, I-125, serum albumin) D. 890, 30 900 100 S-Sbkg E. 899, 30 + = 30 Vol = Vol dilution 1 10 P - Pbkg 25 26 Imaging using radioactive materials: Example 4 Rectilinear scanner • A wipe test over a countertop yields a count rate of Electronics PMT 1000 counts per minute in a nuclear medicine clinic Scintillator that uses 99mTc only. If the background is 40 counts Collimator per minute and the detector efficiency is 0.8, the activity of the 99mTc source corresponding to this surface is ___Bq. A. 5 B. 10 N = (N − N ) / = (1000− 40)/ 0.8 = C. 20 corr