Positrons are the stable antiparticle of the electrons. Despite being stable, they are extremely rare in nature. When positrons combine with electrons, they quickly annihilate, leaving behind nothing but photon energy. The positrons that are used in nuclear cardiology originate from the decay of radionuclides, the most common of these being fluorine-18 (18F), carbon-11 (11C), oxygen-15 (15O), nitrogen-13 (13N), and rubidium-82 (82Rb). These radionuclides an excess number of protons; when the proton is converted to a neutron, an energetic positron is ejected from the nucleus of the atom.
Positron emission tomography (PET) relies on the annihilation of a positively charged particle (an antielectron or positron) with a conventional electron to produce two high-energy gamma rays traveling 180 degrees from each other. The existence of positrons was first proposed by Paul Dirac in 1928,1 and ultimately discovered in 1932 by Carl D. Anderson.2 Positrons, though stable in vacuum, annihilate almost immediately when they come in contact with electrons, producing a complete conversion of the mass of the two particles (511 keV/c2) into energy. This unique property of positrons, the complete conversion of the positron-electron pair into two photons of identical energies (511 keV), was recognized as potentially revolutionary for medical imaging. The first application of positron annihilation medical imaging was first explored by Brownell et al in 1953 for imaging brain tumors.3 This technique was later expanded to tomographic imaging in 1971.4
Before a positron can annihilate, it needs to come to rest in the medium (thermalization). This thermalization drift from the parent atom reduces the overall resolution of the image. For 18F, the maximum energy of the emerging positron is 633 keV, leading to a thermalization length of 0.239 cm.5 However for 82Rb, the maximum energy of the positron is 3.148 MeV, leading to a maximum thermalization length of 1.561 cm (Table 7-1).
| Half-Life | Beta Energy (max, mean) in MeV | Max Range (mm) | Mean Range (mm) | |
|---|---|---|---|---|
| 11C | 20.4 min | 0.96, 0.386 | 4.2 | 1.2 |
| 13N | 9.93 min | 1.199, 0.492 | 5.5 | 1.8 |
| 15O | 2.0 min | 1.732, 0.735 | 8.4 | 3.0 |
| 18F | 110 min | 0.634, 0.25 | 2.4 | 0.6 |
| 82Rb (no prompt, 81%) | 75 sec | 3.38, 1.535 | 17.0 | 7.1 |
| 82Rb (0.777 MeV prompt, 13%) | 75 sec | 2.601, 1.168 | 13.0 | 5.0 |
Though many atoms, such as 18F and 13N, decay to a stable nuclear state, some atoms, such as 82Rb, can decay to an unstable nuclear state. For these atoms, the decay to an unstable state results in the emission of a nuclear gamma ray (a “prompt gamma”) in addition to the two photons produced by the positron annihilation. In the case of 82Rb, 13% of all decays result in a prompt gamma ray (776 keV).5 These gamma rays can influence the scatter correction algorithms of the imaging system, producing significant artifacts.6,7
Several tracers are currently in use for measuring myocardial perfusion and blood flow, myocardial viability infection and inflammation including sarcoidosis. Unlike SPECT tracers, the radionuclides used have a relatively short half-life, ranging from 82Rb (75 seconds) to 18F (110 minutes). Because of these short half-lives, isotope production often must be produced on-site or at a nearby radio pharmacy.
The most common tracer used in cardiac PET nuclear cardiology is 82Rb. This agent has a 75-second half-life and is a potassium analog. As a potassium analog, 82Rb is used as a myocardial blood flow agent with similar biokinetics as thallium-201.8 Because of the short half-life of 82Rb, the agent must be produced using a generator encased in an infusion system. These generator infusion systems are capable of eluting the generator, performing the radioassay of the product and infusing the 82Rb directly into the patient with a single-button process (Figure 7-1).
Figure 7-1
Rb-82 Generator Provides a One-Button Process for Delivering a Radionuclide Dose to Patient. The system draws saline over the 82Sr coumn, collecting the free 82Rb ions. This solution is passed over a detector that assays the solution and the is transferred direction into the patient’s IV line.
82Rb is produced as a by-product of the decay of strontium-82 (82Sr). Because the atom itself is a blood flow tracer, no further radiochemistry is required before is it ready to use. 82Sr has a long half-life of 28 days, allowing clinical nuclear laboratories to use the generator for 4–6 weeks before needing to replace the expired generators.
The production of the 82Sr source requires a larger cyclotron capable of accelerating protons to more than 63 MeV. The process creates 82Sr, and two contaminants: 85Sr and 89Sr.9 These contaminants have a shorter half-life than 82Sr and must be allowed to decay before the 82Sr can be shipped.
13N-ammonia is a myocardial blood flow tracer that has been extensively studied for use in myocardial perfusion testing.10 With a 9.93-minute half-life, it either has to be produced on-site or within a short delivery distance from a radiopharmacy. For these reasons, it is a reasonable alternative to 82Rb only for those centers with a nearby cyclotron (Figure 7-2).
The most common method for producing 13N-ammonia is a process known as internal chemistry. In this process, a solution of water and ethanol are placed directly in the beam line of a cyclotron. 13N-ammonia is produced as a by-product of the reaction11:
Because this process is very simple, the high doses (>250 mCi) 13N-ammonia can be quickly extracted from the cyclotron, quality inspected, and packaged for delivery in minutes. This high dose at the time of packaging gives radiopharmacies up to 20 minutes to transport the product to a nuclear laboratory.
A process has also been introduced that uses a carbon target for producing the 13N. Though the process involves a more complicated chemistry, it has the advantage of requiring a lower energy cyclotron.11 Recent introduction of low energy, minicyclotrons using automated radiochemistry packages have opened the possibility of on-site production of 13N-ammonia without a full radiopharmacy (Figure 7-3). This option is discussed later.
18F-labeled compounds have the advantage of a relatively long nuclear half-life (110 minutes), allowing for longer distance delivery from the nuclear pharmacy. 18F-FDG synthesis begins with a cyclotron capable of producing protons with an energy >2 MeV. The high-energy protons produce 18F by bombardment of an 18O target. The 18F is then extracted from the 18O target using an anion separation process.11,12
The chemistry for FDG involves nucleophilic substitution using potassium carbonate. Finally, the FDG extract is purified to remove chelating agents and unreacted 18F. This entire process is performed in a chemistry synthesis box that automates the production. Given the long half-life of 18F, it can be shipped longer distances either by ground or air transportation.
18F-FDG (fluorodeoxyglucose) is a glucose analog capable of tracking glucose metabolism.13,14 Its most common application is in detection of cancer and following therapies. In nuclear cardiology, it can be used for the detection of myocardial viability, sarcoidosis, and infections, including devices or surrounding pockets.14–17
To use FDG for the detection of myocardial viability, glucose pathways often require activation via a process known as glucose loading. The methodology of clinical use of FDG for this purpose is discussed in Chapters 9, 10, and 11.
There has been considerable interest in developing an 18F myocardial perfusion tracer. The advent of such a tracer would allow unit dose delivery, higher count-higher resolution perfusion studies, and exercise testing. One such agent is 18F-flurpiridaz.18–21 This agent has been demonstrated to produce high-quality studies and that are well correlated with coronary anatomy.18 In addition, it is highly extracted at high flow rates, potentially exceeding the performance of 13N-ammonia.19 18F-flurpiridaz is a mitochondrial Complex 1 inhibitor that freely diffuses from the capillary bed into the cell with and extraction fraction of more than 90%.19 Once inside of the cell it is trapped in mitochondrial Complex 1. In addition to its favorable uptake in the myocardium, it also has favorable noncardiac uptake with moyocardial uptake exceeding liver uptake for rest, exercise, and pharmacological stress studies.20,21 The combination of favorable uptake characteristics, imaging properties, and convenience for 18F-flurpiridaz has the potential for revolutionizing cardiac PET. The greatest challenge for this agent will be expanding the network of radiopharmacies capable of production. The clinical data are discussed in Chapter 1.
