The Cyclotron and Radiochemical Procedures

Positron-emitting radionuclides are generated in a cyclotron. In this machine, charged particles (protons, deuterons, or negative hydrogen ions) are accelerated in a circular path to achieve sufficient kinetic energy. The particles are then directed to bombard a stable isotope and the resultant interaction creates a new, unstable, proton-rich isotope. This isotope becomes a more stable atom by a nuclear process in which a proton is converted to a neutron, a positron (the antiparticle of the electron with the same mass but positively charged), and a neutrino. The positron and neutrino are emitted from the nucleus of the radioactive species at a characteristic decay rate, depending on the particular isotope. The positron-emitting isotopes most often produced for PET studies are radioactive forms of oxygen (¹⁵O), nitrogen (¹³N), carbon (¹¹C), and fluorine (¹⁸F). These isotopes have decay rates in the range of minutes to hours (e.g., half-lives of 2 minutes for ¹⁵O and 109 minutes for ¹⁸F) and are ideally suited for biologic imaging because there is sufficient time to image their presence in the body without producing long-term radiation exposure (see Table 20-1 for the physical characteristics of radioisotopes). These radioisotopes can be readily incorporated into a wide variety of molecules, including the labeling of physiologic substrates (e.g., glucose, amino acids), neuroreceptor ligands, and substrates and inhibitors of enzymes. The injectable end product is then introduced into the body, usually by intravenous injection. Because these compounds are injected in minute quantities (subnanomolar concentrations) and do not produce pharmacologic effects, they are referred to as biologic tracers or probes. The tracer is then distributed throughout the body in accordance with its delivery, uptake, and metabolism characteristics. Throughout this time, the tracer continues to decay and emit positrons and neutrinos. The neutrinos pass through the body and are not detected. Wherever the tracer is trapped in tissues, the positrons travel only a short distance (≈1 mm) and lose energy in collisions with electrons in the tissue, until they collide with nearby electrons, which results in annihilation of the two particles and conversion of their masses into two gamma-ray photons, referred to as annihilation photons. These photons each have an energy of 511 keV and are projected linearly at approximately 180 degrees to each other. They have a high probability of escaping the body without attenuation, which allows their detection. A pair of detectors set at 180 degrees to each other can register the arrival of these photons and localize the positron emitter along that line of travel, referred to as a coincidence line, or line of response. For a given localized concentration of positron emitters, the resultant photon pairs are emitted in all directions and can be detected by a circumferential ring of scintillation detectors (Fig. 20-1). On combining the lines of response from many different angles, the data are reconstructed with a mathematical algorithm (special coincidence technique called a reconstruction algorithm) to establish their distribution pattern, a pattern that corresponds to regional concentrations of the radionuclide. These profiles are then used to produce tomographic brain images, which can then be coregistered with computed tomography (CT) or magnetic resonance imaging (MRI) to obtain precise anatomic localization.⁶

TABLE 20-1 Physical Properties of Selected Positron-Emitting Radionuclides

FIGURE 20-1 The positron-electron interaction results in their annihilation and the coincident emission of two 511-keV photons at 180 degrees to each other. Detection of the essentially simultaneous arrival of these annihilation photons at the positron emission tomography camera detectors establishes a coincidence line (line of response). In an actual tomogram that registers the photons emitted from regions of accumulated radioactivity, there are about 1 to 2 million detector pair combinations that can record these events simultaneously. For a subject injected with [¹⁸F]fluoro-2-deoxy-D-glucose (FDG), the distribution and accumulation of radioactivity throughout the entire body can be imaged by sequentially moving the subject through the ring of detectors. The darker areas represent regions of higher glucose metabolic rates.

(Adapted from Phelps ME. PET: The merging of biology and imaging into molecular imaging. J Nucl Med. 2000;41:661-681.)

For a PET brain study, the tracer, on injection, is distributed and accumulated in tissues as a function of time. Accordingly, different time intervals of data acquisition (frames) are used to discriminate these time-dependent changes in regional concentrations of activity. Immediately after injection of the tracer, short time frames of 1 minute or less are acquired to image the rapid changes in radioactivity, whereas at later times, longer time frames of 5 to 10 minutes suffice. These temporal and spatial distributions of radioactivity are then fitted to a kinetic model that has been designed to quantify the biologic process being investigated.

Camera and Brain Imaging

The PET camera is a sophisticated imaging instrument that is used to measure the photons generated from positron-electron annihilation. The PET camera can acquire data in intervals that range from seconds to minutes, thereby allowing monitoring of many biologic processes. The quality and quantity of the acquired data from a particular PET camera are a function of technical parameters, some of which are described later. These parameters are often listed in the methods sections of PET studies because they provide critical information on the quality of the data acquisition.

Sensitivity refers to the fraction of positron emission events within a field of view that is detected by the camera. As the relative sensitivity of a camera increases, more counts from the same amount of radioactivity are detected, which results in an increase in the signal-to-noise ratio and therefore better image quality.

Spatial resolution, or the ability to accurately locate events, refers to the smallest distance between two points that can be distinguished by the PET scanner. This parameter defines the ability of the camera to differentiate spatial activity and is based primarily on the camera detector elements, with smaller elements providing better detail. A typical clinical PET camera has a spatial resolution of 5 to 8 mm; small animal scanners have a resolution as low as 2 mm.⁷ With recent advances in detector and scanner design technology, the sensitivity and spatial resolution of PET have dramatically improved, especially as data collection has evolved from a two- to a three-dimensional mode of acquisition (which increases the number of gamma rays being collected). State-of-the-art PET cameras can now image subregional cortical and subcortical structures throughout the brain (Fig. 20-2).

FIGURE 20-2 [¹⁸F]Fluoro-2-deoxy-D-glucose (FDG) and positron emission tomography (PET)–computed tomography (CT) imaging. Left, The two columns show the tomographic planes of sagittal (column 1) and transaxial (column 2) CT data (top row) and the PET data overlaid on the CT images (bottom). Right, Transaxial planes of FDG-PET images covering the superior to inferior extent of the brain. The darker areas represent regions of higher glucose metabolic rates and clearly delineate cortical and subcortical structures.

(Courtesy of D. H. Silverman, M.D., Ph.D., Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles.)

Full width at half-maximum (FWHM) is a technical term that refers to the width of a gaussian-shaped curve at half its maximal peak value. When activity is acquired from a single point source, the PET camera has a limited ability to accurately locate that activity, which results in a spatial distribution of that activity that resembles a bell-shaped curve. The corresponding FWHM for that distribution is used to define the spatial resolution of the PET camera (i.e., objects that are closer together than one FWHM cannot be distinguished).

Partial volume correction describes methods for removing errors in the regional quantification of activity caused by analysis of regions that are smaller in width than twice the spatial resolution of the camera (i.e., regions with a diameter less than two times the FWHM). For example, if the FWHM is expressed as 4 to 5 mm, any structure less than 10 mm will be affected by concentrations of radioactivity in the surrounding areas. If the structure of interest has a higher concentration than adjacent structures, its concentration of radioactivity will be underestimated. In contrast, if the structure of interest has a lower concentration than adjacent structures, its radioactivity will be overestimated. In general, a region of interest should be quantified only when its size is twice that of the FWHM. Therefore, whenever a small region of interest is quantified, its dimensions should be stated relative to the spatial resolution of the camera. However, further processing of the data can correct for this partial volume effect, provided that the spatial resolution of the PET camera, the exact size and shape of the region, and the relative concentrations of radioactivity are all known. The methods of partial volume correction that have been developed require an MRI scan or other anatomic brain image of the individual.⁸

Image reconstruction refers to the mathematical process of creating an image from a series of detection events obtained from the PET camera. Radioactive decay events are detected as lines of response, and a reconstruction algorithm is used to determine the distribution of radioactivity from the summation of all observed lines of response. The most commonly used reconstruction algorithm initially was called filtered backprojection (FBP). With FBP, the counts from all detector pairs are projected back along the lines of response where they originated, which results in overlapping of backprojections and a corresponding two-dimensional distribution of emission origins. Before projection, these data are processed with a mathematical filter algorithm, relatively graded from sharp to smooth, to improve the signal characteristics. Sharp filters result in better spatial resolution and more statistical noise, whereas smooth filters result in less resolution and a reduction in statistical noise.⁹ The FBP method is increasingly being replaced by iterative reconstruction methods (e.g., maximal likelihood estimation) that essentially begin with an estimated image based on the intersection of lines of response followed by comparison of its calculated projection data with the actual projection data. With subsequent iterations, the image is revised until convergence is achieved, with limiting factors being the technical features of the detector system.

Tracer Kinetic Models

Hundreds of PET tracers have been synthesized for research in animal and human imaging studies. A representative list of positron-labeled compounds is presented in Table 20-2 to illustrate the wide range of imaging applications. It should be emphasized that the initial PET data acquisition reflects the total radioactivity in a region over the time that the data were acquired. Because only radioactivity is measured in the brain and not the relative concentrations of the tracer and its metabolites, optimal use of a particular PET tracer requires an appropriate tracer kinetic model to interpret the observed changes in radioactivity levels. Tracer kinetic models provide a mathematical framework by which the time course of tracer distribution and changes in regional concentrations of accumulated radioactivity are used to derive rates of biologic processes.

TABLE 20-2 Examples of Radiolabeled Compounds Used for Positron Emission Tomography

EDTA, ethylenediaminetetraacetic acid.

To construct kinetic models, the biologic process is categorized into compartments (e.g., plasma and a tissue region would represent a two-compartment model) and then formulated by differential equations that describe exchange of the isotope between compartments.¹⁰ In general, models contain parameters that are used to determine transport rates of the tracer into and out of the region of interest, the extent of tracer-receptor binding, and enzymatic activities. The images that are constructed from these parameters and subsequent model fitting are referred to as parametric images.

A typical three-compartment tracer kinetic model is presented in Figure 20-3. After intravenous injection of the tracer, the time course of the tracer concentration in plasma (obtained from arterial blood samples) is determined. This plasma-time activity curve is referred to as the input function and is used to provide a quantitative parameter on tracer availability to the brain as a function of time.

FIGURE 20-3 A, Three-compartment tracer kinetic model for [¹⁸F]fluoro-2-deoxy-D-glucose (FDG) that consists of plasma, tissue free FDG, and trapped FDG-6-phosphate (FDG-6-P) compartments. The FDG is transported from plasma to the tissue. The subsequent phosphorylation rate, k₃, is proportional to the use of glucose by the tissue. The K₁ rate coefficient (milliliters per minute per gram) accounts for blood flow and tracer extraction; the fractional rate constants (k₂, k₄) each represent the fraction of the tracer that leaves the respective compartment per unit time. B, On phosphorylation, glucose-6-P continues through the glycolysis pathway, but FDG-6-P is not a substrate for further metabolism and remains trapped within the tissue.

(From Phelps ME, Mazziotta JC, Heinrich R, et al. Positron Emission Tomography and Autoradiography: Principles and Applications for the Brain and Heart. New York: Raven Press; 1986.)

The time course of tracer activity in the brain is obtained from the PET measurements. A tracer kinetic model can then be used to calculate rate constants for exchange of the tracer between compartments. The following is a description of the model used for monitoring metabolic rates of glucose in the brain.

2-[¹⁸F]Fluoro-2-deoxy-D-glucose (FDG) is the most widely used tracer in PET studies. It was adapted from the 2-deoxyglucose (2-DG) method for imaging glycolysis by autoradiography as developed by Sokoloff.^11,12 The 2-DG method established that measurement of 2-DG accumulation could be used to quantify metabolic rates of glucose, which are closely coupled to functional activity of the brain (e.g., increased glucose consumption with focal seizures, decreased glucose consumption with anesthesia or blockade of visual input).

FDG is a fluorinated analogue of 2-DG, and its use in PET is a direct extension of Sokoloff’s model. In the brain, FDG is used to measure the cerebral metabolic rate of glucose (CMRGlu) in selected regions. FDG and glucose are transported by the same carrier across the blood-brain barrier into tissues (see Fig. 20-3). Both compounds then enter the glycolysis cycle and are phosphorylated by the enzyme hexokinase. However, after this step, FDG-6-phosphate, unlike glucose-6-phosphate, is not a substrate for further metabolism, and it remains trapped in the tissue for at least 1 hour before slowly leaving the tissue. Accordingly, FDG-6-phosphate accumulates in the tissue proportional to that tissue’s metabolic rate of glucose. To correct for small relative differences between FDG and glucose as substrates for hexokinase activity, an additional factor—the “lumped” constant—is used in calculating the metabolic rate of glucose.

The FDG compartmental model contains rate constants as the kinetic parameters used to assess the transport and phosphorylation of FDG. Based on this model using FDG, CMRGlu can be obtained from the following equation:

where Cp is the plasma glucose concentration and LC is the lumped constant. The parameter K₁ is a rate coefficient (mL/min/g) that represents the transport of FDG from plasma to tissue and accounts for blood flow and extraction of tracer. First-order rate constants (min⁻¹) represent the transport of FDG from tissue to plasma (k₂) and phosphorylation of FDG to FDG-6-phosphate by hexokinase (k₃); a correction factor (k₄) can be added to account for the small amount of dephosphorylation of FDG-6-phosphate that can occur at later times (60 to 90 minutes after injection).

Movement Disorders

A wide range of movement disorders associated with basal ganglia dysfunction have been imaged with PET. Neurochemical deficits have been identified that uniquely characterize Parkinson’s disease, Huntington’s disease, progressive supranuclear palsy, multiple system atrophy, essential tremor, and dystonia. In particular, striatal dopamine system abnormalities have been studied with tracers specifically designed to assess different components of presynaptic and postsynaptic function.¹³ For example, dopamine synthesis capacity is used as an index of presynaptic terminal functional integrity, whereas binding of tracer to the dopamine transporter (DAT) is used to estimate nerve terminal density. For the postsynaptic system, ligands that bind to dopamine receptors have provided measures of receptor number (B_max) and receptor affinity (K_d).^14,15 The opportunity to conduct longitudinal studies with these tracers provides a unique noninvasive methodology for monitoring the temporal progression of many disease processes.¹⁶ The use of PET to assess nigrostriatal deficits in Parkinson’s disease and the striatal degeneration associated with Huntington’s disease is discussed next.

Parkinson’s Disease

The progressive loss of nigrostriatal neurons eventually exceeds a nonsymptomatic threshold, at which point motor and cognitive symptoms appear.^17,18 However, even before symptoms begin, underlying deficits in the dopamine system can be detected with PET. The capability of detecting these biochemical deficits in the striatal dopamine system can provide insight into the differential diagnosis and therapeutic options.

The first approach to imaging presynaptic integrity of the dopamine system in patients with Parkinson’s disease was based on the assessment of striatal dopamine synthesis capacity.¹⁹ The clinical application of exogenous L-dopa as a substrate for brain dopamine synthesis provided the rationale to synthesize a fluorinated analogue of L-DOPA, [¹⁸F]6-fluoro-L-dopa (FDOPA), as a PET tracer. FDOPA is transported across the blood-brain barrier into the brain by the large neutral amino acid transporter, as is L-DOPA and other large neutral amino acids.²⁰ In dopaminergic presynaptic terminals, FDOPA is a substrate for aromatic amino acid decarboxylase and is converted to [¹⁸F]fluorodopamine (FDA), which is subsequently stored in vesicles. The extent of FDA accumulation in striatum during the imaging period is used to estimate dopamine synthesis rates.²¹ Thus, reductions in FDA accumulation in patients with Parkinson’s disease have been associated with decreases in dopaminergic terminal activity. Moreover, relative decreases in accumulation of FDA between the caudate and putamen, as well as between putaminal subregions, have been used to stage progression of Parkinson’s disease (Fig. 20-4).

FIGURE 20-4 Noninvasive imaging of early Parkinson’s disease. The magnetic resonance image (A) of the striatum does not indicate any significant anatomic abnormalities, but positron emission tomography (PET) reveals regional and selective alterations in neurochemical processes. The [¹⁸F]fluoro-2-deoxy-D-glucose–PET image (B) shows abnormal putamen hypermetabolism (≈10%) relative to the caudate. The [¹⁸F]fluoroethylspiperone–D₂ receptor binding image (C) shows regional densities in the putamen that are about 15% greater than those in the caudate. The dopamine synthesis–[¹⁸F]6-fluoro-L-DOPA uptake image (D) shows a significant reduction in dopamine synthetic capacity (80%) in the putamen but not in the caudate. Arrows in B, C, and D indicate putamen.

(From Phelps ME. PET: The merging of biology and imaging into molecular imaging. J Nucl Med. 2000;41:661-681.)

Additionally, FDG has been used in conjunction with FDOPA to provide a complementary assessment of compensatory regional alterations in glucose metabolism.²² These PET assessments have been used to differentiate idiopathic Parkinson’s disease from related movement disorders.

An alternative to FDOPA assessment of striatal dopamine system integrity is obtained with PET tracers that bind selectively to the presynaptic DAT and thereby may provide an index of its terminal density.²³ For example, the cocaine congener N-(3-¹⁸F-fluoropropyl)-2β-carbomethoxy-3β-(4-iodophenyl)nortropane ([¹⁸F]FPCIT), which has high binding affinity for the DAT (Fig. 20-5), has been used to show how the pathology in Parkinson’s disease progresses from unilateral to bilateral striatal dopamine deficits and that their magnitude correlates with the severity of behavioral symptoms.²⁴ Other [¹⁸F]FPCIT-PET studies have revealed 50% decreases in mean striatal DAT binding in patients with early-stage Parkinson’s disease who were imaged within 2 years of diagnosis, thus suggesting that significant nigrostriatal degeneration had occurred by the time that the first symptom appeared.²⁵

FIGURE 20-5 Progression of striatal dopamine system degeneration in Parkinson’s disease (PD). The dopamine transporter (DAT) is located at the presynaptic terminal, and its density in the striatum can be used as an index of dopamine system integrity. The positron emission tomographic images show the striatal uptake of N-(3-¹⁸F-fluoropropyl)-2β-carbomethoxy-3β-(4-iodophenyl)nortropane ([¹⁸F]FPCIT), a ligand with high binding affinity for DAT, for a normal volunteer (top row) and two patients with PD (middle row: Hoehn & Yahr (H&Y) stage I; bottom row: H&Y stage III). [¹⁸F]FPCIT uptake is reduced predominantly in the putamen, unilaterally in early-stage PD (middle row) and more pronounced bilaterally (bottom row) with disease progression.

(From Kazumata K, Dhawan V, Chaly T, et al. Dopamine transporter imaging with fluorine-18-FPCIT and PET. J Nucl Med. 1998;39:1521-1530.)

For the postsynaptic striatal dopamine system, PET tracers have been synthesized for the dopamine D₁ and D₂ receptors.²⁶ These receptors subserve different functions based on their signal transduction mechanisms of stimulation and inhibition of adenylyl cyclase, respectively.²⁷ At present, PET studies of dopamine receptors have been limited to the assessment of receptor density and, in some instances, receptor affinity.

Nonetheless, changes in apparent ligand-receptor binding are indicative of dysfunctional neurotransmission at the synapse. For example, changes in D₂ receptor density in patients with Parkinson’s disease as a result of compensatory reactions to the ongoing disease process have been measured with PET.²⁸ Subregional striatal alterations that show larger increases in D₂

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