3Basisof F-FDGPositronEmissionTomographyImaging 18

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3 Basis of ¹⁸ F-FDG Positron Emission Tomography Imaging

Seham Mustafa, Abbas Alavi, Abdelhamid H. Elgazzar

3.1 Introduction 50 3.2 Uptake of Glucose 50 3.2.1 Facilitated Diffusion 50 3.2.2 Active Transport 51

3.2.2.1 Sodium-Dependent Glucose Transporter 52 3.3 Fates of Glucose in Normal Cells 52 3.3.1 Phosphorylation of Glucose 52 3.3.2 Glycolysis 52

3.3.3 Storage of Glycogen 52 3.4 FDG Localization 52

3.5 Basis of Specific Clinical Applications of FDG 53 3.5.1 Cancer: Diagnosis, Staging and Follow-up 53 3.5.1.1 Pathophysiology of FDG Cancer Uptake 53 3.5.1.2 Clinical Utilization in Cancer 54

3.5.2 Neuropsychiatric Disorders 57

3.5.2.1 Alzheimer’s Disease and Related Disorders 57 3.5.2.2 Movement Disorders 57

3.5.2.3 Epilepsy 57

3.5.2.4 Other Neuropsychiatric Disorders 57 3.5.3 Cardiovascular Disease 58

3.5.3.1 Myocardial Viability 58 3.5.3.2 Atherosclerosis 60 3.5.4 Skeletal Disorders 60 3.5.5 Inflammatory Disorders 60 3.6 Other PET Radiotracers 61 References 62

3.1 Introduction

During the past few decades the development of novel radiolabeled tracers and the improvement of instru- ments for imaging have enabled a functional approach to be taken based on metabolic alterations rather than physiological phenomena [1].

Positron emission tomography (PET) is a unique form of diagnostic imaging that observes in vivo biolog- ic changes using radiopharmaceuticals that closely mimic endogenous molecules. It produces images of the concentration of a radioactive tracer in the body, which has been selected to represent the specific metabolic process under study. PET studies consist of a series of consecutive PET images and contain information about the temporal evolution of the radiotracer concentration.

18-Fluorodeoxyglucose (¹⁸F-FDG) is considered the current ideal radiopharmaceutical for PET imaging owing to its low positron energy (0.64 MeV) of 18 F, which results in a low radiation dose rate to the patient and also allows high resolution images [2]. It is the most commonly used tracer because of the practical half-life of¹⁸F of 110 min, compared with other shorter- lived positron emitters.¹⁸F-FDG allows the evaluation of glucose metabolism in several disorders.

3.2 Uptake of Glucose

Glucose is an essential compound for living organ- isms. It is the most important carbon supplier for the synthesis of tissue ingredients and energy-producing metabolic processes that depend largely on glucose availability. Glucose cannot normally diffuse through the pores of the cell membrane because the maximum molecular weight of substrates for such a process is about 100, whereas glucose has a molecular weight of 180. The uptake of glucose by human cells can take place, however, through two mechanisms of transport. The first method involves facilitative glucose transport (GLUT) and the second method is active transport.

3.2.1

Facilitated Diffusion

Many cell membranes possess specialized transport mechanisms that regulate entry and exit of physiologi- cally important molecules, such as glucose. Facilitated diffusion is also called carrier-mediated diffusion because a substance transported in this manner usually cannot pass through the membrane without a specific carrier protein allowing one entry. That is, the carrier facilitates the diffusion of the substance to the other side. However, the carrier protein transports a specific molecule partly but not all the way through the membrane. The molecule to be transported enters the channel and then becomes bound. Then in a fraction of a second a conformational change occurs in the carrier

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Fig. 3.1. A postulated mechanism for facilitated diffusion

protein so that the channel now opens to the opposite side of the membrane. This mechanism allows the transported molecule to diffuse in either direction through the membrane as shown in Fig. 3.1. Insulin can increase the rate of facilitated diffusion of glucose as much as 10- to 20-fold. This is the principal mechanism by which insulin controls glucose use in the body [3].

Carrier-mediated transport, because it involves a binding step, shows the characteristic of saturation.

With simple diffusion, the rate of transport increases directly in proportion to the concentration gradient, whereas with carrier-mediated transport the carrier sites become saturated at high ligand concentrations and the rate of transport does not increase beyond this point. Furthermore, competitive inhibition of transport can occur in the presence of a second ligand that binds to the same carrier. Carrier-mediated transport is important for some drugs that are chemically related to endogenous substances.

Such systems may operate purely passively, without any energy source; in this case they merely facilitate the process of transmembrane equilibration of the transported species in the direction of its electrochemical gradient. If the concentration of glucose is greater on one side of the membrane than on the other side, more glucose will be transported from the high concentration area than in the opposite direction.

Six isoforms of facilitative glucose transporters have been identified so far: GLUT-1 to GLUT-5 and GLUT-7 (Table 3.1). These isoforms share the same transmembrane topology, but they differ in kinetic properties, tissue location, sugar specificities and regulation in states of imbalanced glucose homeostasis [1].

GLUT-1. This transporter is widely expressed at the membranes of many different cells in the human body.

The highest concentrations are found in fetal tissue and placenta. Insulin, insulin-like growth factor 1, growth

Table 3.1. Facilitative glucose transporters and their tissue locations

Trans- porter

Site of highest concentration

GLUT-1 Fetal tissue and placenta

GLUT-2 Intestine, kidney, liver and q cells of pancreas, brain GLUT-3 Neurons in the brain

GLUT-4 Brown and yellow adipose tissue and skeletal muscle GLUT-5 Small intestine

GLUT-7 Endoplasmic reticulum

hormone and thyroid hormone induce a higher expression of GLUT-1 [1]. It has been suggested that GLUT-1 belongs to the family of glucose-regulated proteins, which are expressed in situations of cellular stress [4].

GLUT-2. This low-affinity transporter can be found in the intestine, kidney, liver q cells of the pancreas and brain. Together with the glycolytic enzyme glucokinase, it constitutes a glucose-sensing system, which sig- nals the differences in glycemia to the liver and the

q cells of the pancreas [5].

GLUT-3. High affinity of this transporter for glucose ensures a constant glucose supply to neurons in the brain, even at low extracellular glucose concentrations [6]. In the brain, glucose is transported across the blood-brain barrier by GLUT-1 and, once it reaches the neurons, GLUT-3 is the most efficient transporter in the hypoglycemic conditions of the cerebral interstitial space.

GLUT-4. Expression of this transporter is high in brown and yellow adipose tissue and in skeletal and cardiac muscle. In hyperglycemic states, glucose transport can be increased up to 30 times in response to insulin. Insulin stimulates GLUT-4 transporter [7].

GLUT-5. This transporter is only 40% identical to the other isoforms [8]. It is the main transporter of fruc- tose, and expressed in the small intestine.

GLUT-7. The sequence of GLUT-7, cloned in rat liver, resembles that of GLUT-2. It has a role in the dephos- phorylation process of glucose-6-phosphate inside the endoplasmic reticulum [1].

3.2.2

Active Transport

Glucose may be coupled to the electrochemical gradient of Na⁺; in this case transport can occur against an electrochemical gradient and is called active transport, which occurs through the gastrointestinal membrane or through the epithelium of the renal tubules. Glucose is transported by the mechanism of active sodium cot-

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Blood Vessel 18FDG

Glucose Glucose-6-P

FDG-6-P Glucose

Cell FDG

Hexokinase Further Glycolysis

Aelgazzar

ransporter, in which active transport of sodium provides energy for absorbing glucose against a concentration difference. This sodium cotransport mechanism functions only in certain special epithelial cells that are specifically adapted for active absorption of glucose.

3.2.2.1

Sodium-Dependent Glucose Transporter

This process requires Na⁺as a co-factor for the active transport of glucose across intestinal and kidney epithelial cells by sodium/glucose transporters. This means that Na⁺enters the cell down its electrochemical gradient, accompanying glucose. The accumulated Na inside the cell is cleared by the Na⁺/K⁺ATPase. Two different isoforms are currently known for sodium/glucose transporter (SGLT-1 and SGLT-2). SGLT-1 has a high affinity for glucose and transports Na⁺and glucose in the ratio 2:1, whereas SGLT-2 has a low affinity and the Na⁺/glucose ratio is 1:1 [9].

3.3 Fates of Glucose in Normal Cells

3.3.1

Phosphorylation of Glucose

Immediately upon entry in the cells, glucose combines with a phosphate radical. This phosphorylation is pro- moted by the enzyme glucokinase in the liver or hexokinase in most other cells. Four different types of hexokinase are known. Type I is most abundant in brain and erythrocytes. Type II is predominant in insulin-sensitive tissue, such as skeletal muscle, heart, diaphragm and adipose tissue. Type III is predominant in any tissue and Type IV, also called glucokinase, is predominant in liver cells. The enzymatic activity of all hexoki- nases except glucokinase is inhibited by glucose-6- phosphate. When glucose is abundant, glucokinase becomes activated in the liver to produce glucose-6-phosphate for the synthesis of glycogen [1].

The phosphorylation of glucose is almost complete- ly irreversible except in the liver cells, the renal tubular epithelium, and the intestinal epithelial cells in which glucose phosphatase is available for reversing the reaction. Therefore, in most tissues of the body phosphorylation serves to capture the glucose in the cell (Fig. 3.2).

After absorption into the cells, glucose can either be used immediately for release of energy to the cells or can be stored in the form of glycogen.

3.3.2 Glycolysis

Energy is released from the glucose molecule by this process, which occurs by splitting of the glucose mole-

Fig. 3.2. Glucose and FDG are transported into the cell and phosphorylated, but FDG does not undergo further metabolism and accumulates in proportion to glucose utilization (increased in tumors, macrophages and ischemic myocytes)

cule to form two molecules of pyruvic acid. This occurs by ten successive steps of chemical reactions in the cytosol.

3.3.3

Storage of Glycogen

Glycogenesis is the process by which glycogen is formed in the cell. Several specific enzymes are required for this process. Glycogenolysis is the break- down of glycogen to re-form glucose in the cells. Glyco- genolysis does not occur by reversal of the same chemical reactions that serve to form glycogen; instead, each succeeding glucose molecule on each branch of the glycogen polymer is split away by a process of phosphorylation, catalyzed by the enzyme phosphorylase. Under resting conditions, the phosphorylase is in an inactive form so that glycogen can be stored but not reconver- ted into glucose. Two hormones, epinephrine and glucagon, can specifically activate phosphorylase and cause rapid glycogenolysis.

3.4 FDG Localization

The glucose analogue deoxyglucose, which has one oxygen atom less than the glucose molecule (Fig. 3.3), is transported into the cell in the same way as glucose.

Once it has reached the cytosol, it is phosphorylated to deoxyglucose-6-phosphate by the enzyme hexokinase,

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D–Glucose ^FDG O

CH₂OH

OH

OH OH HO

O CH₂OH

OH

18F OH HO

Fig. 3.3. [¹⁸F]2-deoxy-2-fluoro-D-glucose (FDG). In FDG the hydroxyl group in the 2-position of D-glucose is replaced by¹⁸F

just like normal glucose. The next reaction in glycolysis, producing deoxyfructose-6-phosphate, in effect a rearrangement of the carbonyl group from the C-1 to C-2 position in the ring structure, is not possible because this would require an oxygen atom at the C-2 position. When it is labeled with¹⁸F, this molecule can be revealed by PET at sites of uptake of this agent. Hence, a high uptake of¹⁸F-fluorodeoxyglucose reflects an increased glucose metabolism, for example in tumor cells [1]. As a result, the very polar FDG-6-phosphate is trapped in the cytoplasm. FDG-6-phosphate may be converted back to FDG, but the enzyme glucose-6- phosphatase, which is responsible for this reaction, is either present at very low levels or absent in cancer tissues [10].

The uptake and retention of FDG as radiopharmaceuticals (metabolic substrates) by different tissues and organs vary substantially depending on the levels of glycolysis at one site (Fig. 3.2). The injury to a cell or tissue significantly alters the morphology and molecular biology compared with that of normal tissue or organs. FDG PET is now being extensively used for an in- creasing number of clinical indications at different stages of cancer, e.g., diagnosis, staging, monitoring of response to therapy, and finally detection of recurrence. In addition, FDG accumulates in activated white cells and macrophages and as such may also play a role in detecting infection and inflammation.

Biodistribution of¹⁸F-FDG can be affected by various physiologic factors. Blood glucose levels have an impact on¹⁸F-FDG uptake through competition for the sites of high glycolysis. Patients should fast 4 – 6 h to reduce competition with plasma glucose and thus opti- mize and standardize¹⁸F-FDG uptake. These require- ments are especially important in diabetic patients, in whom high glucose levels can alter the distribution of FDG. When plasma glucose levels are greater than reference values, FDG uptake increases in muscles and af- fects the quality of the images [11]. Muscle relaxants may be used to reduce muscle uptake. Good hydration

is required before imaging to encourage urinary excre- tion. Patients should remain silent during and after injection to reduce laryngeal muscle uptake [12].

3.5 Basis of Specific Clinical Applications of FDG

3.5.1

Cancer: Diagnosis, Staging and Follow-up 3.5.1.1

Pathophysiology of FDG Cancer Uptake 3.5.1.1.1

Basis of Uptake by Cancer Cells

Cancer cells have an altered metabolism compared with normal cells. As a result, cancer cells use more glucose than normal cells. Due to the increased rate of cell proliferation, the protein and DNA synthesis is aug- mented and the cancer cells need to transport large amounts of precursors and nucleotides. In addition to overproduction of glycolytic enzymes, increased uptake of glucose is seen in tumor cells. The facilitative glucose transporters, the expression and activity of which are regulated by oncogenes and growth factors, are generally held responsible for this increase of glucose taken up. Therefore overexpression of GLUT-1, GLUT-3 and GLUT-5 plays a role in this enhanced transport [13].

The transport and phosphorylation of FDG to FDG- 6-phosphate occurs at a higher rate in cancer cells than in normal cells. FDG has become a tumor marker for assessing disease activity in current clinical practice [11].

The glycolytic capacity of a given tumor is generally assumed to be characteristic of its state of differentia- tion [14]. It was suggested that the promoting force for this increased glycolytic flux is the phosphorylation of glucose, the first reaction of the glycolytic pathway. This step is catalyzed by hexokinase and it is this enzyme that promotes an increased glycolytic activity of tumor cells [15]. At least two factors contribute to this increased activity of hexokinase [1]. One is the difference in binding to the outer membrane of the mitochondrion; the other is the overproduction of this enzyme in malignant cells compared to normal cells. Rempel et al. [15] found that the percentage of membrane-bound hexokinase activity increases with the grade of malignancy. Four different isoenzymes of hexokinase are known and there is a pronounced tissue-specific distribution. In malignant cells, type 11 hexokinase and to a lesser extent type 1 hexokinase are overexpressed [16]. Therefore, it is clear that accumulation of FDG in tumor cells is due to: (1) increased transporter expression and its activity, (2) increased production and activity of hexokinase, (3) absent or low levels of glucose-6-phosphatase.

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Tumor perfusion and delivery of¹⁸F-FDG is affected by necrosis and therapy-induced changes.¹⁸F-FDG is a highly sensitive and specific imaging modality in the evaluation of biochemical changes that occur in tumors during or after therapy. Uptake of FDG in tumor cells is influenced by a certain number of factors such as increased expression of glucose transporters and the presence of a highly active hexokinase isoform, hypoxia and the glucose levels in the blood.

3.5.1.1.2 Tumor Hypoxia

Clavo et al. [17] showed that FDG uptake was increased when cells were exposed to a hypoxic environment. The hypoxia was associated with an increased expression of the GLUT-1 glucose transporter and an increased membrane transport of glucose. Wang and Semenza [18] determined the presence of a specific region in- ducing hypoxia in the promoter of hexokinase. The hypoxic state of a solid tumor may cause upregulation of hexokinase, which enhances the rate of glycolysis, serving as a mechanism for the tumor cell to survive [1]. Many solid tumors develop areas of hypoxia during their evolution. This is primarily caused by unregulat- ed cellular growth, resulting in a great demand on oxygen for energy metabolism [19]. Hypoxia in tumor tissue is an important prognostic indicator of response to either chemotherapy or radiation therapy. Thus, detection of hypoxia in advance of such interventions is important for optimizing the use and outcome of different therapeutic modalities. Several hypoxia-imaging agents have been developed rather than FDG [20].

These compounds diffuse into normally oxygenated and hypoxic cells but are retained substantially in a higher concentration in the hypoxic tissues, which can be detected on images.

3.5.1.1.3 Fed/Fast State

In normal cells, insulin is active in the high glucose level states. Therefore opposing effects on gene expression have been found: insulin activates the transcription of hexokinase and glucagon inhibits this transcription.

Both insulin and glucagon activate the promoter of the hexokinase II gene in cancer cells. This can be seen as a strategy of the cancer cell to keep its glycolysis high, even with a limited supply of glucose. If the glucose level in the environment rises, the cancer cell can utilize the available glucose immediately, without a lag period.

This means that transcription of hexokinase in tumor cells is independent of the metabolic state of neighbor- ing healthy cells. Thus, cancer cells have an advantage over their cell of origin [19].

FDG uptake into human cancer cells is inhibited by

high glucose levels in the medium, because of the competition between FDG and glucose for uptake into malignant cells [21]. It has been demonstrated in vitro and in vivo that tumor uptake of FDG is markedly dimin- ished by acute hyperglycemia. It has also been shown that tumor targeting with FDG is impaired by insulin- induced hypoglycemia. Therefore to optimally evaluate tumor biology by PET, the fasting state seems necessary for FDG. Since glucose represents the preferred fuel for cancer cells, there is some debate about the potential stimulation of tumor metabolism induced by glucose- based total parenteral nutrition (TPN) in cancer patients. It was proven that despite glucose being the preferred fuel for cancer cells, its disproportionately high uptake even in fasting conditions makes the glucose consumption unable to be modulated by a further supply of glucose or lipid [22]. All diabetic patients should have their blood sugar level controlled with oral hypoglycemic or insulin, although some time after the time of FDG injection (8 2 h). Insulin injection close to the time of FDG administration induces diffusely increased uptake of FDG in the skeletal muscles [23].

When plasma glucose levels are greater than reference values, FDG uptake increases in muscles. This will lead to blurring of tumor margins [11].

3.5.1.1.4

Degree of Uptake

Intensity of radiopharmaceutical uptake relative to the normal tissue has been used to differentiate benign from malignant lesions. There have been multiple re- ports of varying degrees of uptake of¹⁸F-FDG in benign conditions demonstrating hypermetabolism on ¹⁸F- FDG PET scans, including granulomatous infection, benign tumors, and autoimmune diseases, also bronchiolitis obliterans organizing pneumonia [24]. Ac- cordingly, intensity is not a reliable parameter and dual acquisition and quantitation are helpful in this regard.

The intensity of the uptake reflects the viability of the cells in the involved lesion. ¹⁸F-FDG directly targets malignant cells anywhere in the body and, therefore, is able to visualize disease activity directly at all anatomic sites.

3.5.1.2

Clinical Utilization in Cancer

The introduction of ultrasonography, magnetic reso- nance imaging and computed tomography has improved the clinical management of patients with malignant tumors. However, these substantially structurally based techniques assess primary tumors and metastases by size and visual patterns. Furthermore, they lack specificity in characterizing many lesions. The introduction of PET has improved further the diagnosis and

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F-18 FDG

Fig. 3.4. An FDC study of a patient with known colon cancer. The study shows metastases to the liver and abdominal lymph nodes (arrows)

Fig. 3.5. FDG study of a patient with osteogenic sarcoma showing in- tense uptake by the tumor (arrow)

management of cancer patients.¹⁸F-FDG PET is useful in detecting, staging, restaging, and assessment of response to treatment of many tumors including lung, colorectal, breast carcinoma, melanoma, lymphoma, head and neck, thyroid, brain, cervical, prostate and ovarian cancers [11, 12, 20, 25 – 35].

3.5.1.2.1

Tumor Detection

FDG PET is valuable in the early detection of tumor (Figs. 3.4, 3.5) and can help in its diagnosis [36]. The indeterminate lung nodule is an important example illustrating this. It is estimated that solitary pulmonary nodules are detected in 52 per 100,000 people in the

United States. Thirty percent of these will be considered benign based on an initial examination for history of risk factors and standard radiographs. The remaining 70% are considered indeterminate, requiring further examination – often by X-ray computed tomography (CT). Of the cases sent to CT, 78% are diagnosed indeterminate or malignant, and 75% will be referred to surgery, resulting in approximately 68,000 thoracotomies annually. Twenty percent of these thoracotomies will yield a benign diagnosis. Based on published data, PET would reduce the number of unnecessary thoracotomies, resulting in only a 6% yield of benign diagnosis for resected solitary pulmonary nodules [37 – 40].

3.5.1.2.2 Tumor Staging

FDG-PET is particularly valuable in staging cancer and has proven cost effective in avoiding unnecessary costs for surgeries by adding PET FDG studies such as in cases with lung cancer (Fig. 3.6). Accuracy in staging permits selection of the most appropriate treatment.

Identification of metastases that are not seen with anatomic imaging (upstaging) avoids the high morbidity and cost of treatments that cannot benefit the patient and permits more effective choices of therapy. Like- wise, metabolic reclassification of malignant lesions to benign (downstaging) allows patients with false-posi-

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a b

c d

Fig. 3.7a–d. Young male pre- sents with right axillary ade- nopathy proven to be non- Hodgkin’s lymphoma. The CT scan (a) shows enlarged nodes (arrow). The FDG PET study (b) shows intense uptake by the tumor (arrows).

The postchemotherapy CT scan (c) shows a decrease in the size of the nodes while the post-therapy FDG study (d) shows no uptake, indicat- ing a definite good response to therapy

˜ Fig. 3.6.¹⁸F-FDG study for staging of a patient recently diagnosed with non-small-cell right lung cancer. CT showed increased sizes of lymph nodes ipsi- and contralaterally. The question was whether the patient had stage N2 or N3 to determine resectability. The FDG study shows only ipsilateral lymph node metastasis, indicating minimal N2, M0 stage.

(Courtesy of Professor Osama Sabri, Leipzig)

tive anatomic findings but limited disease to receive potentially curative treatment.

3.5.1.2.3

Evaluation of Therapy and Detecting Recurrence The most important application of PET in cancer is early and accurate evaluation of therapy (Fig. 3.7) and early detection of recurrence, which has a significant impact on cancer management. Evaluation of the response to therapy and follow-up of tumor patients de- termining the residual uptake and recurrence provide important prognostic information. For example, in the United States, there are approximately 110,000 new colon cancers and 45,000 new rectal cancers reported ev- ery year. Approximately 66% of these cases are cured by surgical resection, while cancer in the remaining 33%

recurs generally before 2 years postsurgery. Distin- guishing which of these recurrent cases can benefit from additional surgery is challenging, because only one in four of recurrent cases is curable. The incurable cases run the risk of unnecessary and expensive surgery [41] (see Chapter 12 for more details).

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3.5.2

Neuropsychiatric Disorders

Under resting conditions, the metabolism of the brain accounts for about 15% of the total metabolism in the body, even though the mass of the brain is only 2% of the total body mass. Therefore, brain metabolism is about 7.5 times the average metabolism in the rest of the body. Most of this excess metabolism of the brain occurs in the neurons. During excessive brain activity, neuronal metabolism can increase severalfold.

The brain cells are quite different from most other cells of the body in that they normally use essentially only glucose as the source of energy, utilizing other substrates, such as fat and ketone bodies, only as a last resort. The brain is also quite different from most other tissues of the body in that insulin has little or no effect on uptake or use of glucose. Instead, the brain cells are even normally permeable to glucose and can use glucose without the mediation of insulin. Therefore, even in patients who have serious diabetes with essentially zero secretion of insulin, glucose still diffuses readily into the neurons [3].

FDG PET is an excellent tool with which to evaluate brain function because the synthesis of over 95% of adenosine triphosphate that is hydrolyzed to fuel cerebral function originates from the catabolism of glucose [42]. For example, in patients with varying severity of dementia, the magnitude and extent of hypometabolism correlates with the severity of dementia [43].

3.5.2.1

Alzheimer’s Disease and Related Disorders

In its early stages, the identification and differential diagnosis of dementia is especially challenging, because of the difficulty of distinguishing it from the mild cognitive decline associated with normal aging, and from mild cognitive manifestations associated with neuropsychiatric conditions (i.e., depression).

It is well established that regional cerebral metabolic rates for glucose as assessed by FDG PET in patients in the resting state (eyes and ears covered) provide a sensitive, in vivo metabolic index for diagnosing Alzhei- mer’s disease. The brain hypometabolism revealed by FDG PET is a sensitive marker of disease progression in this disease. Therefore FDG PET can be used to investigate the progression of serious brain disorder [44, 45].

Patients with neurodegenerative disease gain the most from effective therapies that intervene as early as possible. Since several prescription medications for the treatment of mild to moderate Alzheimer’s disease are available, early and accurate diagnosis has become more urgent. The drugs which increase acetylcholine levels in the brain are considered efficacious if pre- scribed early during the course of the disease. Early

Alzheimer’s disease can be detectable only by metabolic imaging techniques [46 – 48]. As the disease progres- ses, metabolic changes may translate into significant cortical atrophy. FDG PET may become the critical test for selecting the appropriate patients for treatment when the disease process is at the molecular level and before structural alterations have taken place [49].

3.5.2.2

Movement Disorders

Kuhl et al. [50] found that in Parkinson’s disease, findings on FDG PET were nonspecific. Cerebral glucose metabolism was reduced uniformly throughout the brain (average 18% decrease). Bradykinesia severity was increased associated with mild to moderate dementia. In Parkinson’s disease the whole brain metabolism decreases further. Severe parietal cortex hypometabolism was found in one moderately demented patient with Parkinson’s disease, and also in Alzheimer’s disease. In contrast, mildly to moderately demented patients with Huntington’s disease had marked caudate hypometabolism, but cerebral glucose metabolism was normal elsewhere. It appears that some neurotransmit- ters are decreased or are lost in the nigrostriatal system in the parkinsonian brain, and it is now clear that there is an abnormal metabolic process involving neurons [50].

3.5.2.3 Epilepsy

The use of FDG PET in localizing seizure foci in the temporal lobe for surgical interventions is well established. It has been clearly shown that FDG PET is quite sensitive in detecting such sites, with 85% – 90% accuracy [51]. Hypometabolism at the seizure focus is not- ed when there is clinical evidence for epilepsy while anatomic images remain normal for an extended period [52 – 54]. It has been realized that longstanding seizure episodes eventually lead to significant atrophy, and also that longstanding metabolic and molecular abnormality eventually will result in significant atrophy in most chronic disorders of the brain [49]. Abnor- malities of glucose utilization and metabolic dysfunction will be related to persistent epilepsy ([55], Fig. 3.8, [56]).

3.5.2.4

Other Neuropsychiatric Disorders

There is growing evidence that PET is useful in several other neuropsychiatric disorders including evaluation of severe dysfunction in head injury [57, 58], Hunting- ton’s chorea [59, 60], schizophrenia [61, 62], migraine [63] and frontal lobe dementia [64, 65].

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a b

Fig. 3.8a,b. FDG PET (a) was performed in a 4-year-old boy with refractory frontal lobe seizures and developmental delay and with exten- sive left front parietal dys- plasia on MRI (b, arrow- heads, transaxial image).

The PET study shows increased metabolic activity (a, arrowheads) associated with virtually continuous epileptiform activity ema- nating from the left frontal lobe, and normal metabolic activity in the right cerebral hemisphere. On the basis of the PET findings, a decision was made to proceed to surgery, limiting the resection to the hypermetabolic cortex in the left frontal lobe. The child had a significant reduction in seizure frequency, with a marked improvement in cognitive and developmental milestones. (Reprinted with permission from [56])

Encephalitis during the acute phase of the disease manifests itself on¹⁸F-FDG PET as areas of hypermetabolism. However, there can also be large areas of hypometabolism associated with encephalitis. These areas can be the result of active inflammation or seizure activity. EEG monitoring during the PET scan would be essential for ruling out subclinical seizure activity as the cause of the hypermetabolism [66]

(see Chapter 18 for more on PET in neuropsychiatric disorders).

3.5.3

Cardiovascular Disease 3.5.3.1

Myocardial Viability

FDG PET has been used to study cardiovascular disorders ranging from hypertrophic and idiopathic dilated cardiomyopathy [67] to unstable angina [68], myocardial infarction [69] and chronic ischemic left ventricular dysfunction [70].

The use of FDG PET to determine myocardial viability remains a very important technique and is considered the gold standard for viability [49].

The myocardium derives energy from a variety of sources such as free fatty acids, glucose, lactate, pyru- vate, ketone bodies and amino acids [71]. Under normal resting conditions, metabolism is mainly oxidative, with free fatty acids being the major source of energy, while glycolysis contributes only about 30% to the overall metabolic activity of the heart. Dietary and hor- monal conditions markedly alter the selection of substrates. For example, in the fasting state, free fatty acids levels are high and glucose and insulin levels are low.

Consequently, the rate of myocardial free fatty acid oxi- dation is high and inhibits glycolysis. After ingestion of carbohydrates, plasma concentrations of glucose and insulin rise. Insulin reduces peripheral lipolysis, there- by further lowering plasma concentrations of free fatty acids and hence reducing their availability to the myocardial energy production [72].

Myocardial ischemia alters myocardial substrate metabolism, and also results in a dramatic and sus- tained switch to glucose uptake. Ischemia is also associated with increased glycolysis, with glucose transporters expressed in higher numbers as possible flux-gener- ating steps. Uptake of FDG may remain normal or may even increase in altered myocardial states, such as contractile dysfunction or reduced perfusion resulting from ischemia in patients with stable angina, unstable angina and chronic hibernation [73]. FDG accumulation in such altered myocardium indicates the persis- tence of metabolic activity and thus the potential for re- covery of contractile function (Fig. 3.9) [74].

Myocardial FDG uptake depends quantitatively on plasma concentrations of glucose and insulin. Glucose uptake in peripheral tissues is the most important mechanism of clearance of FDG from blood. Myocardi- al glucose uptake also depends on myocardial work, plasma level of free fatty acids, insulin, catecholamines and oxygen supply [71].

Under fasting conditions, the normal myocardium primarily utilizes free fatty acids, while glucose utilization, and thus FDG uptake, is minimal. In ischemic myocardium, when glucose becomes an important energy substrate, FDG uptake will be enhanced. Conse- quently, there will be a marked difference in FDG uptake between normal and ischemic myocardium, which is reflected on the image as a “hot spot”. Thus for the

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Fig. 3.9. Patterns of myocardial viability by use of myocardial perfusion and FDG PET. Patterns refer to post-glucose-loading FDG PET imaging. (Reprinted with permission from [74])

detection of ischemia, fasting may be preferable. How- ever, FDG distributes heterogeneously throughout the normal myocardium in the fasted state, limiting the specificity for the detection of myocardial ischemia. In addition, uptake of glucose and FDG in both myocardial and skeletal muscle is low, resulting in poor-quality images. Therefore it was proven that small doses of reg- ular, short-acting insulin might improve image quality.

It has been demonstrated that oral administration of a nicotinic acid or its derivatives may be such an alterna- tive approach. Nicotinic acid inhibits peripheral lipolysis and thus reduces plasma free fatty acid concentrations. Acipimox is a nicotinic acid derivative, which is 20 times more potent than nicotinic acid [75].

Recently, metabolic aspects, perfusion autoregula- tion, and receptor-mediated cardiac responses of the or- thotopic cardiac transplant have been a priority in re- search. In one study [76] increased myocardial uptake on FDG PET was explained by inefficient metabolic utilization of glucose by the transplanted myocardium or by the influence of circulating catecholamines, which may stimulate glucose uptake independently of cardiac workload.¹⁸F-FDG regional uptake was approximately threefold higher in the transplanted heart than in the native heart. This largely results from the difference in myocardial tissue viability, as well as probably reflect- ing functional-metabolic coupling of the transplanted heart as opposed to the native heart [76].

Injured myocardium frequently demonstrates impaired oxidative metabolism, an excess of glucose utili-

zation relative to flow. Stunned myocardium shows preserved flow, and either matched or excessive FDG accumulation [77]. At times, stunning results in impaired FDG accumulation have been obtained, producing an underestimation of viability [78]. Hibernation has been shown to demonstrate decreased perfusion, and relatively preserved or disproportionately increased FDG accumulation. Infarcted myocardium shows a matched decrease in both perfusion and FDG uptake.

Syndrome X has been recognized as a disease that is primarily reflected in the cardiac microvasculature. In syndrome X patients, myocardial FDG uptake is increased extensively, and is strongly associated with nar- rowed myocardial microvasculature [79].

Coronary artery disease is the most important cause of morbidity and mortality on a global scale. FDG can be used to evaluate accurately the exercise-induced myocardial ischemia [80]. Detection of myocardial viability is most important for patients diagnosed with congestive heart failure, compromised left ventricular function, and end-stage coronary artery disease. For these patients, the goals of therapy include reduction of cardiac mortality and relief of congestive heart failure symptoms (leading to a gain in quality of life years).

Options for therapeutic intervention are cardiac trans- plantation, surgical revascularization, and medical management.

Several approaches for identifying viable myocardium are available. A popular technique is dobutamine (i.e., pharmacologically induced) stress echocardiography, which can show preserved contractile reserve as a key feature of reversible dysfunctional myocardium. A study by Bax et al. [81] emphasized good specificity of stress echocardiography but a low sensitivity. An alter- native approach for assessing myocardial viability is the conventional nuclear medicine test: rest-redistribu- tion²⁰¹Tl-single photon emission computed tomography (SPECT). Although conceptually sound, ²⁰¹Tl- SPECT may lack diagnostic accuracy in patients with markedly enlarged left ventricles, and poor myocardial perfusion, and suffer from technique-related problems such as poor image quality (low signal-to-noise and at- tenuation artifacts) [82].

Compared with²⁰¹Tl-SPECT,¹⁸F-FDG PET has substantially better sensitivity, as many studies have reported uncovering substantial amounts of viable myocardium in patients with equivocal SPECT studies or with fixed defects on SPECT. For example, two investi- gations reported the presence of metabolic activity with FDG PET in 90% [83] and in 52% [84] of patients with ischemic cardiomyopathy and with fixed defects or equivocal findings on²⁰¹Tl-SPECT rest-distribution imaging.

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3.5.3.2 Atherosclerosis

FDG is taken up in the atherosclerotic vessel wall [85].

This process is quite noticeable in the aorta in its en- tirety and other major arteries. There is evidence that the uptake is mainly located in the intimae and likely represents high metabolic activity in macrophages, which are abundant in the atherosclerotic plaques [86].

It is also likely that the smooth muscles in the arterial wall are visualized due to high glucose use by this tissue. The uptake in the peripheral vessels, such as the popliteal and the lower femoral arteries, is mostly located in the smooth muscle rather than in the intimae, while FDG is mainly localized in the atherosclerotic plaques in the aorta, and its tributaries in the trunk, neck and upper thighs [49].

There is also evidence that thrombosis and atherosclerosis are associated with increased glucose use, which can be detected with FDG PET [85].

The cellular components of the atherosclerotic plaque, such as macrophages, exhibit high glucose metabolic activity. This vascular uptake might be due to smooth muscle metabolism in the media, subendothe- lial smooth muscle proliferation from senescence, and the presence of macrophages within the atherosclerotic plaque [86].

3.5.4

Skeletal Disorders

FDG directly targets malignant cells anywhere in the body, including the marrow space, and therefore is able to visualize disease activity directly at all anatomic sites. However, bone imaging displays indirect evidence for the presence of disease. Some aggressive malignancies such as lung cancers may not result in an ad- equate degree of new bone formation to be detectable by bone scanning. However, they can be visualized directly by FDG PET in the marrow space [49]. FDG-PET can be used for the detection and follow-up of bone tumors when^99mTc-MDP bone scintigraphy gives nega- tive findings [87].

Positron emission tomography also shows promise in the evaluation and treatment of inflammatory ar- thropathies. Psoriatic arthritis increases the level of FDG uptake in the joints of the hands. The areas of increased activity correlate well with the regions of symptoms reported by the patient [88]. FDG PET has also shown a potential in the diagnosis of chronic active osteomyelitis. A recent study has shown that FDG- PET has the highest diagnostic accuracy for confirming or excluding the diagnosis of chronic osteomyelitis, particularly in the axial skeleton compared to other modalities including leukocyte scintigraphy [89].

3.5.5

Inflammatory Disorders

FDG has proven to be an excellent tracer for detecting inflammation in the setting of either infectious or non- infectious processes [90]. Activated inflammatory cells appear to have increased rates of glycolysis and accumulate FDG with high concentration [91]. Therefore, FDG can be effectively used to detect sites of infection and inflammation [92].

Orthopedic infections, particularly those related to implanted prostheses [93], and osteomyelitis [91] can be detected successfully by FDG PET. Increasingly, this technique is being used for detecting infection in soft tissues anywhere in the body, including the source of fever of unknown origin [94]. The potential of FDG PET for detecting inflammatory processes in disorders such as regional ileitis [95], sarcoidosis [96], rheumato- logic disease [97, 98], and vasculitis [99] and any other disorder is also vast.

PET can be used in the diagnosis of giant cell arteritis. PET revealed diffuse abnormal¹⁸F-FDG arterial uptake in a patient with giant cell arteritis. The patient showed prompt resolution of symptoms after treatment with steroids. A repeat PET scan showed near- complete resolution of the abnormal FDG uptake [100].

Among the large number of positron imaging radiopharmaceuticals that have been synthesized to date, FDG stands out as the most effective preparation for re- search and clinical applications. This preparation will remain the agent of choice for many years to come.

More than 95% of PET procedures performed around the world use FDG as the imaging agent [49].

While uptake of FDG continues to increase at malignant sites for several hours, as can be shown by an in- cremental increase of the standardized uptake values (SUV), inflammatory lesions peak at approximately 60 min, and their SUV either stabilize or decline there- after. This difference in the behavior of FDG in malignant versus inflammatory cells can be explained best by the varying levels of enzymes that degrade deoxyglucose-6-phosphate in the respective cells (Fig. 3.10).

Glucose-6-phosphatase dephosphorylates intracellular FDG-6-phosphate, allowing it to leave the cell. It has been shown that most tumor cells have low levels of this enzyme, while its expression is high in the mononucle- ar cells [101, 102]. For this reason, imaging at two time points after administration of FDG may prove to be important in differentiating between these two common disorders.

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Time (min)

0 20 40 60 80 100 120 140

Malignancy Inflammation

Fig. 3.10. A plot of SUV change over time in malignancy and in- flammatory lesions illustrating the decline of SUV in inflammation

3.6 Other PET Radiotracers

More than 30 years after its inception, FDG is still the most widely used radiopharmaceutical for PET studies, but numerous radiotracers have been developed.

There are four positron-emitting radioisotopes that are well suited for standard production by modern cy- clotrons. These are fluorine-18 (¹⁸F), carbon-11 (¹¹C), nitrogen-13 (¹³N) and oxygen-15 (¹⁵O). The reason these are so commonly used is that they have many at- tractive properties, one of which is that they can be eas- ily substituted directly into biomolecules. Substitution of¹¹C for¹²C does not alter the biological behavior of one molecule. A similar situation exists for¹³N and¹⁵O.

18F can often be substituted for a hydroxyl group on a molecule or placed in a position where its presence does not significantly alter the in vivo biochemical ki-

Fig. 3.11. a Magnetic reso- nance imaging (MRI, a1) and 3’-[¹⁸F]fluoro-3’-deoxy- l-thymidine-positron emission tomography (FLT-PET, a2) images of a low-grade soft tissue sarcoma (STS).

b MRI (b1) and FLT-PET (b2) images of a high-grade STS. The MRI images of both patients demonstrate a heterogeneous tumor. How- ever, the FLT uptake in the high-grade STS is higher than in the low-grade STS.

(Reprinted with permission from [106])

netics of the compound. The half-lives of these tracers are: ¹¹C = 20.4 min; ¹³N = 9.98 min; ¹⁵O = 2.03 min and

18F = 109.8 min [103].

Several new more specific tracers will be approved and routinely used in the coming years. The tissue uptake of¹⁸F-FDG is nonspecific. Thus, radiopharmaceuticals that are more specific for tumor imaging are de- sirable, as well as development of new radiopharmaceuticals that target amino acid and protein synthesis, DNA synthesis and cell proliferation, lipid synthesis, receptor-mediated radioligands, hypoxia, angiogenesis, apoptosis and gene therapy.

Protein synthesis is essential for growth and development. Several amino acids have been labeled with¹⁸F for tumor imaging such as O-(2[¹⁸F]fluoroethyl)-l-tyrosine. The incorporation of¹⁴C or³H-labeled thymidine into cells has been standard for measuring tissue proliferation and growth kinetics. ¹⁸F-3-fluoro-3-de- oxythymidine ([¹⁸F]FLT) measures cell proliferation, [¹⁸F]FLT being taken up by cells and phosphorylated by thymidine kinase-1, leading to the 5’-phosphate, which is intracellularly trapped [104]. It is logical to assume that [¹⁸F]FLT uptake is specific for malignant lesions since benign tumors do not exhibit cell proliferation.

Furthermore, following a favorable response to treatment, an inflammatory reaction may confound the use of FDG but does not affect the use of [¹⁸F]FLT in this setting. Thus [¹⁸F]FLT may be a better tumor-imaging agent than FDG (Fig. 3.11), although the high uptake of [¹⁸F]FLT in liver decreases its usefulness in liver tumors [105, 106].

Choline is one of the components of phosphatidyl- choline, an essential element of phospholipids in cell membrane. The levels of choline and choline kinase are elevated in neoplasms [107]. Human studies have indi- cated that both¹¹C- and¹⁸F-labeled choline are superi- or to¹⁸F-FDG for the detection of brain tumors, prostate cancer, lung cancer, and head and neck cancer

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[108].¹⁸F-FDG imaging resulted in a broad accumulation of tracer in normal brain as well as the lesion, whereas the accumulation of methionine was more specific, as was the accumulation of choline. ¹¹C-labeled choline was reported to be useful in the detection of clin- ically localized prostate cancer, while¹⁸F-FDG was not particularly useful (most of the tumors of the prostate are not sufficiently malignant to accumulate FDG) [109].

Acetate also has a high uptake in tumors. Its accumulation in tumor cells seems to be caused by the low oxygen consumption and enhanced lipid synthesis of these cells. Both¹¹C- and¹⁸F-labeled acetate have been used as tumor imaging agents.

High levels of receptors have been found in certain tumors. For example, ¹⁸F-labeled steroid receptor radioligands have been used to image breast cancer and prostate cancer.

Agents that measure regional hypoxia in malignant tumors and possibly in some benign disorders will be frequently employed. Hypoxia in tumor tissue is an important indicator of response to both chemotherapy and radiation therapy. [^60/62Cu]ATSM is a promising imaging tumor hypoxic agent [110].

Tumor angiogenesis is essential for growth, inva- sion, and metastasis. These days there are specific radiopharmaceuticals available for imaging angiogenesis.

Detection of cell death (apoptosis) by imaging is an interesting area for assessing both malignant and benign disorders [111]. ^99mTc-labeled annexin V is the first agent used for this purpose. This compound binds to phosphatidylserine, which is externalized in the cell membrane following apoptosis. Because apoptosis me- diates regression of both tumor cells and angiogenic vascular endothelial cells, annexin V imaging may provide insight into the therapeutic response to cancer therapy. Labeling annexin V with¹⁸F may permit imaging by PET and substantially improve the quality of scans [41].

Nitrogen-13 ammonia is used as a blood flow tracer in a similar manner to²⁰¹Tl, which has been used for perfuse cardiac imaging for 3 decades.¹⁵O-labeled wa- ter has also been used for this purpose, although not as commonly as ammonia. The myocardial oxygen consumption is often measured with¹¹C-labeled acetate.

Fatty acid metabolism is often measured with ¹¹C-labeled palmitate.

A variety of PET radiotracers for application in neu- roscience have been introduced. These radiotracers are used for studying dopamine, serotonin, opioid, norepi- nephrine and the cholinergic system and for imaging q -amyloid.¹⁸F-labeled dopa is expected to be used for the diagnosis of Parkinson’s disease and will be widely adopted for this purpose. There are several amyloid imaging agents that may become the test of choice in the early diagnosis of Alzheimer’s disease [112].

Dopamine plays an important role in regulating movement, cognition, motivation, addiction and rein- forcement. Dopamine does not pass the blood-brain barrier. Thus to study brain dopamine metabolism, the labeled derivative of L-dopa or tyrosine that can transport into the brain then converted to dopamine can be used. These radiotracers are 6-[¹⁸F]fluoro-dopa, 6-[¹⁸F]fluoro-L-m-tyrosine and [¹¹C]-L-dopa. There are also dopamine receptor radioligands, dopamine transporter and vesicular monoamine transporter radioligands [105].

Abnormalities in the brain serotonin system have been implicated in various neuropsychiatry disorders including anxiety, depression, eating disorders, sleep disorders and suicide. 5-HT_1Aand 5-HT_1Breceptor radioligands and serotonin transporter radioligands have been developed for PET. Abnormalities in norepi- nephrine have been implicated in cardiac failure, in major depression and in Alzheimer’s disease. [¹¹C]me- thylreboxetine([¹¹C]MeNER) and [¹⁸F]MeNER have shown promise as agents in animals. Opioid receptors (µ, · , κ) mediate the effects of endogenous and exoge- nous opioids, including respiratory depression, analge- sia, sedation, and reward. Radiotracers for the brain opioid system such as [¹¹C]carfentanil, [¹¹C]diprenor- phine, [¹¹C]buprenorphine, 6-O-[¹⁸F]fluoroethyldipre- norphine, [¹¹C]GR89696, and [¹¹C]naltrindole have been used in humans. Benzodiazepine drugs have potent anxiolytic, anticonvulsant, and hypnotic properties. Several benzodiazepine receptor radioligands have been developed such as [¹¹C]RO15 – 1788 ([¹¹C]flumazenil) and [¹¹C]PK11195.

Acetylcholine has been implicated in learning, memory, and Alzheimer’s disease. Many PET radiotracers are being used to investigate acetylcholine.

These include muscarine-cholinergic receptor radioligands such as [¹¹C]scopolamine and nicotinic-cholinergic receptor radioligands such as [¹⁸F]NIDA52189.

Acetylcholinesterases include ([¹¹C]physostigmine,

11C-PHY), and vesicular acetylcholine transporter radiotracers include [¹⁸F]fluorobenzyltrozamicol ([¹⁸F]FBT) [105].

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3Basisof F-FDGPositronEmissionTomographyImaging 18

3 Basis of 18 F-FDG Positron Emission Tomography Imaging

3.1

Introduction

3.2

Uptake of Glucose

3.3

Fates of Glucose in Normal Cells

3.4

FDG Localization

3.5

Basis of Specific Clinical Applications of FDG

F-18 FDG

3.6

Other PET Radiotracers

References

3 Basis of ¹⁸ F-FDG Positron Emission Tomography Imaging