What is PET?
Positron emission tomography (PET) imaging is a functional imaging modality utilizing short- lived positron-emitting radiopharmaceuticals to characterize physiological processes. The physio- logical process or function imaged is dependent on the radiopharmaceutical employed. The attri- butes of PET are defined by the three Rs—the positron-emitting radionuclides, radioactive decay, and radiopharmaceuticals.
Positron-emitting radionuclides The major positron-emitting radionuclides are carbon-11, nitro- gen-13, oxygen-15, and fluorine-18, all atomic species that are components of biological molecules, analogues, and drugs. These four radionuclides require a cyclotron, a type of particle accelerator (protons or deuterons), for their production. A limited number of other positron-emitting radionu- clides are available from generator systems (e.g., rubidium-82 (82Rb), gallium-68 [68Ga]) similar to the technetium (99mTc) generator utilized for the preparation of radiopharmaceuticals used in nuclear medicine (Table 9.1).
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Positron emission Positron-emitting radionuclides are neutron-deficient. For example, carbon- 12 is the stable isotope of carbon with 6 protons and 6 neutrons. Carbon-11 has 6 protons but only 5 neutrons and decays by positron-emission to boron-11. A positron is a positive electron, an antimatter particle. An electron is the matter counterpart of the positron. When a positron and electron meet (i.e., matter–antimatter reaction), an annihilation occurs producing two colinear 511 keV gamma rays. These gamma rays (photons) are the form of energy detected by PET scan- ners to create the PET emission images (Figure 9.1). PET scanners use coincidence circuitry to
Table 9.1 Positron-emitting radionuclides (Madsen & Ponto, 1992).1
Radionuclide Half-life Production
11C 20.3 minutes Cyclotron
13N 10.0 minutes Cyclotron
15O 122 seconds Cyclotron
18F 109.8 minutes Cyclotron
82Rb 75 seconds Generator
68Ga 68.3 minutes Generator
Figure 9.1 Schematic representation of how positron emission tomography (PET) works.
165 Positron Emission Tomography (PET) Imaging
define the line on which the annihilation occurred and for time-of-flight scanners to mathemat- ically determine where on this line the event occurred. All of the events are reconstructed into three-dimensional images of the concentration of the radiopharmaceutical = PET emission scan.
PETemissiondata is corrected for photon attenuation (i.e., reduction in the signal due to absorp- tion of some of the energy by the body) by eithertransmissionimaging (for PET-only scanners) or computed tomography (for PET/CT scanners); therefore, the images are quantitative with the resulting concentrations (i.e., kBq/cc) accurate representations of the radiotracer in the tis- sues. Tissue concentrations can be determined at a single time point, referred to as astaticimage, or for a series of time points, referred to asdynamicimages. The PET-based concentration data can be used as input into pharmacokinetic models for the generation of kinetic parameter values on aglobal, regional, tissue, orvoxel-by-voxel basis. Images derived from the pixel-by-pixel or voxel-by-voxel application of a pharmacokinetic model are referred to as parametric images (Table 9.2).
Table 9.2 Definitions of imaging terms.
Term Definition
Static image
Transaxial
Coronal
Sagittal
“Snapshot”= single image (generally one bed position [15–20 cm field-of-view]) acquired over a specified time period. Images are generally displayed as orthogonal planes designated as coronal, sagittal, or transaxial slices.
Whole-bodyimage Series of static images, spatially contiguous, combined into a single multibed position frame of data. Although acquired over a period of time, the images are decay- corrected to the start of the first acquisition in the series.
Dynamicimaging
166 Laura L. Boles Ponto
Table 9.2 (Continued)
Term Definition
Wash-in
50 min
0.5 min Wash-out
“Movie”= multiple frames of data acquired over a single bed position. The length of frames can vary but are temporally contiguous.
Parametricimage Image with the pixel values derived from the application of a mathematical function to calculate a“parameter”value on a pixel-by-pixel basis (e.g., blood flow image [mL/
min/100mL tissue]).
Field-of-view (FOV) Field-of-view (FOV) is the amount of tissue covered by an imaging modality. The illustration defines the FOV for a single bed position of a typical PET scanner (i.e.,15 cm) overlaid on a co-registered magnetic resonance image (MRI).
Orthogonalimages Images at right angles—transaxial (transverse), sagittal, and coronal.
Transaxial Coronal Sagittal
Region-of-interest (ROI) Regions over a tissue of interest in a plane (2D)
Volume-of-interest (VOI) Regions over a tissue of interest in a volume (3D).
167 Positron Emission Tomography (PET) Imaging
Positron-emitting radiopharmaceuticals Because radioactive forms of carbon, nitrogen, oxygen and fluorine exist, theoretically a radioactive version of any organic molecule is possible. However, there are practical constraints on the synthesis of useful positron-emitting radiopharmaceuticals. Syn- thesis and quality assurance testing of the radiopharmaceutical must be accomplished within approx- imately 2–3 half-lives. Therefore, for example, an agent labeled with carbon-11 needs to have these tasks accomplished and available for administration within approximately one hour. The longer half- life of fluorine-18-labeled agents not only provides an expanded time period for synthesis and quality assurance testing procedures but also for delivery of the radiopharmaceutical to imaging centers remote from the cyclotron and radiochemistry facilities. Currently, a number of F-18 labeled agents are commercially available radiopharmaceuticals, manufactured under the auspices of US Food and Drug Administration (FDA) regulations (21 CFR Part 212) by centralized nuclear pharmacies and distributed on a regional basis to PET imaging centers or by FDA-approved in-house facilities equipped with a cyclotron and chemistry facilities. All PET radiopharmaceutical manufacturing facil- ities must meet cGMPs (current Good Manufacturing Practices). All PET radiopharmaceuticals must be an FDA-approved agent (NDA [new drug application]) or an investigational agent used under an IND (investigation new drug) protocol or under local RDRC (research drug review com- mittee) approval. The production of PET radiopharmaceuticals entails a sizeable investment in equipment and qualified personnel associated with a significant regulatory burden. Therefore, these expenses are incorporated in the cost for using this technology. However, the reputation that PET is inherently an expensive modality, limiting its clinical application, is not universally true. Because of the widespread availability of F-18 fluorodeoxyglucose (FDG) for oncology uses, in many centers FDG brain studies are competitively priced with brain MRI and some SPECT studies.
The specific PET radiopharmaceutical employed determines the physiological process that will be imaged. Hundreds of PET radiopharmaceuticals have been described in the literature for the imaging of a variety of physiological processes such as blood flow, metabolism (glucose, amino acids, nucleic acids, fatty acids), receptor binding,β-amyloid, and tau. The Molecular Imaging and Contrast Agent Database (MICAD) is a useful resource for identifying agents with literature describing their use in animals and/or humans. This information was compiled between 2004 and 2013 and is searchable via PubMed (http://www.ncbi.nlm.nih.gov/
books/NBK5330). Figure 9.2 provides an example of a monograph available for agents listed in the MICAD database. Although numerous agents have been investigated, only a handful of PET radiopharmaceuticals have documented utility and, now, FDA approval. These agents are listed in Table 9.3.
Because PET has the capability to image metabolism, receptor systems, and pathologies, there are innumerable potential tracers and neurological processes/conditions that could be investigated using these techniques. Frequently, optimizing the information content of these images requires the creation of parametric images or extensive pharmacokinetic modeling to derive the parameters of interest (e.g., Bmaxand KDfor a particular receptor system). The widespread use of many of these agents is limited not only by the availability of the radiotracer, but also by the technical, image analysis, and pharmacokinetic expertise required. Therefore, the emphasis of this review will be on PET radiopharmaceuticals that have proven clinical utility and/or widespread availability. Spe- cifically, the review will focus on cerebral blood flow imaging, glucose metabolic imaging, and amyloid imaging with emphasis on the use of these techniques in epilepsy and dementia.