Fludeoxyglucose (18F)

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Introduction to [18F]-fluorodeoxyglucose

Fluorodeoxyglucose or FDG is the most commonly used radiotracer in PET imaging, and it has a half life of 110 minutes. FDG is very similar to glucose in structure (an analog) with only difference being it has a radioactive 18F in place of a hydroxyl (OH) group in the 2' position of a glucose molecule, allowing it to share common metabolic pathways with glucose. In this section we outline its history, how it gets produced and the metabolic pathway by which it works, followed by clinical applications of this molecule in PET imaging.


Figure: A chair diagram structural comparison of Glucose and 2-deoxy-2[18F]fluoro-D- glucose. Each corner represents a carbon atom, O = Oxygen, H = Hydrogen, 18F = Radioisotope of Fluorine. Designed for this written chapter.


The following three events led to the synthesis of FDG and its applications in PET:

In 1968 Pacak and his group were the first to synthesize fluorinated glucose, but the isotope of fluorine they used was not radioactive . [1]. Then, in 1976 Wolf and his group synthesized FDG with the radioactive isotope 18F [2]. Then in the same year (1976), Alavi and colleagues administered FDG to two human volunteers for the first time to map metabolics of the brain through glucose consumption / FDG uptake.

Production of [18F]-fluorodeoxyglucose

18F is among the most common radionuclides used in PET imaging, used in roughly 85% of all procedures [3]. 18F can be incorporated into a multitude of biological molecules by replacing an oxygen molecule without changing the function of the molecule in the body [4].18F is most commonly added to glucose to form FDG [5]. There are two important steps in the synthesis of FDG, the first is synthesizing the radioactive 18 Flourine, and the second is adding it to the glucose molecule [6].

First, the radioactive 18F is synthesized in a cyclotron [6]. Cyclotrons are particle accelerators where a proton is plated in the middle of two vertical magnetic plates and two horizontal electrodes. The electrodes are given alternating charges so the proton in the middle accelerates towards one plate, and then when the charges change, towards the other plate. This accelerates the particle in a radial motion and eventually leads it to a chamber where it collides with the nucleusCenter of an atom consisting of protons, neutrons, and electrons. of an atom to produce a radioactive isotope. In our case, This proton collides with the nucleusCenter of an atom consisting of protons, neutrons, and electrons. of an 18O which produces a 19F neutronSubatomic particle in the nucleus of an atom with the same mass as a proton but no electrical charge. [6]. 19F is unstable and loses a neutronSubatomic particle in the nucleus of an atom with the same mass as a proton but no electrical charge. to produce our isotope of interest, 18F[6].


Figure 1. Synthesis of 18F in a cyclotron. A proton is radially accelerated using D-shaped plates with alternating charges, and then deflected towards an 18-Oxygen (18O) atom. This produces the 19-Fluorine atom (19F), which loses a neutronSubatomic particle in the nucleus of an atom with the same mass as a proton but no electrical charge. to become the 18- Fluorine atom (18F) of interest. Designed for this written chapter.

In the second part of the process which was discussed more at length in the PET radiotracer chapter, 18F is captured in K18F, dehydrated, and added to Kryptofix. However, before this step an FDG-precursor molecule is synthesized. The FDG-precursor is a mannose sugar with all hydroxides replaced with oxy-acetyl groups, except for the hydroxide at carbon position 2, which contains a triflat=e molecule (shown in Figure 1). The oxy-acetyl groups stop 18F from attaching to those carbons, while the triflate is a good leaving group and will easily be replaced by 18F. The first step of the FDG synthesis reaction is adding the FDG-precursor to the Kryptofix[K]18F solution to produce the intermediate 2-[18F]fluoro-1,3,4,6-tetra-O-acetyl-D-glucose. All excess Kryptofix[K]18F is removed from the reaction and the strong base NaOH is added, which removes the remaining acetyl groups and results in the final FDG molecule. This method produces roughly 18.5-22.2 GBq of FDG. After FDG is added to an alkaline solution suitable for physiological conditions, it is ready to be used in a clinical PET scan. The process of adding 18F to glucose is called nucleophilic or electrophilic flourination (depending on the method used)[6].

There are several quality control steps in the production of FDG. Due to the short half life of the molecule (110 minutes), most of these steps are performed after the product is shipped[6]. . A few of the quality control measures used are character, radiochemical identity, pH, chemical purity and sterility[6].

Figure 2. Synthesis of [18F]-fluorodeoxyglucose. A tetraacetyl mannosyl-2-triflate FDG precursor is added to potassium carbonate and Kyrptofix[K]18F in methylcyanide at 28°C and 18F nucleophilically substitutes the triflate molecule at Carbon-2. A base work up removes acetyl groups from the remaining oxygen’s resulting in [18F]-fluorodeoxyglucose. Figure adapted from [5].

FDG Metabolism

The intensity of the PET signal is indicative of glucose metabolism efficacy FDG is a glucose analog and is indiscriminately taken up by cells that express specific glucose transporter (GluT) proteins [6]. Cells that uptake FDG at a faster rate accumulate more FDG that undergo annihilation events. FDG is useful in medical imaging because different cell types uptake more glucose than others, creating contrast in the image [6]. Tissues take up glucose at different rates because of their different metabolic needs. For instance, the brain requires a constant influx or glucose to meet the energy demands of nerve transmission. However, the rate of glucose uptake can change depending on the cells metabolic needs. For instance, muscle cells increase their uptake of glucose during exercise to sustain the increase in muscle contractions. These underlying changes in glucose metabolism increase the intensity of the image. PET is sensitive to detecting changes in metabolism [6]. Diseased or cancerous cells often exhibit differences in their glucose metabolism, which is the primary reason why the glucose molecule is used to create the most commonly used radioisotope.

Figure: Diagram demonstrating the path of FDG and glucose into the cell and their different processes inside the cell.

Since FDG is an analog of glucose it competes with glucose for entering the cells. An important functional difference between glucose FDG is that only glucose in broken down and used by the cell for energy. On the other hand, FDG accumulates in the cell until the radioisotope (Fluorine 18) decays into the more stable oxygen 18 isotope where it can be broken down for energy or released from the cell through a glucose membrane transporter [6]. Both glucose and FDG become trapped in the cell after being phosphorylated by the enzyme hexokinase. Glucose-6-phosphate enters glycolysis by being converted into fructose-6-phosphate by the enzyme phosphoglucose isomerase, however FDG-6-phosphate does not fit into the active site of the phosphoglucose isomerase causing it to remain trapped inside the cell. This allows 18F positron emission decay to occur providing anatomical information about glucose uptake on a PET image [6]. 18F decays into 18O, which converts FDG-6-phosphate into [18O]-glucose-6-phosphate thus allowing its entry into glycolysis to be metabolized. FDG is normally used to identify malignant tumors because cancer cells overexpress GluT which increases glucose uptake (Figure 5). FDG is also used to identify metabolism patterns in the brain to identify different forms of dementia (Figure 6) [6].

Typical FDG-PET Patient Protocol

Before the radiotracers can be administered to the patient, there are specific preparative steps that need to be taken to optimize radiotracer uptake to produce the most useful image. PET imaging protocols vary depending on the type of image and the type of radiotracer being used, so explained here is the standard protocol for FDG PET preparation [7]. Prior to coming into the hospital, patients are usually asked to fast for 4-6 hours before their procedure. This is so the patient will be in a glucose deficient state when FDG is administered, priming the body for glucose uptake. Patients who are pregnant or have diabetes must follow a separate protocol that is tailored to each condition. Prior to injection, the blood glucose level is measured to ensure that serum glucose levels are not too high or too low. In both hyper and hypoglycemic states, there is a decreased FDG uptake in tumors. If the patient is receiving a brain scan, they must sit in a quiet, dimly lit room both before and after FDG injection to normalize neuronal uptake of FDG. Any excessive visual, auditory, or other sensory stimulation could affect neuronal FDG uptake. If the patient is receiving a full body scan, they must remain stationary following FDG uptake to limit muscular FDG uptake. The amount of FDG that is administered is dependent upon the weight of the patient and the amount of activity required to produce a diagnostically interpretable image [8]. The recommended FDG activity per weight is 8 MBq/kg. The average effective dose of an adult during an FDG PET procedure is 0.019 mSv/MBq, and the bladder receives the largest radiation dose (0.16 mGy/MBq) of any other tissue [7]. When the radiotracer is administered to the body it will have to interact with the organ or cellular process of interest before any information can be gathered from the PET image.

Clinical Applications

2-18F-Fluoro-2-deoxy-D-glucose (FDG) has a wide range of clinical applications in neurology, immunology, cardiology, nephrology, and oncology. Although there are a wide range of clinical applications, over 90% of clinical cases using PET are for oncology purposes [9].

For oncology, FDG can be used for diagnosing patients with metastatic cancers, staging disease, predicting treatment effectiveness, and monitoring treatment response. Certain cancers, such as malignant melanoma, colorectal cancers, lymphomas, and gastroesophageal cancers, are more often detected and staged using PET because of their high metabolic activities and the particular challenges of evaluating these cancers using more standard anatomical imaging methods [9]. Not all cancer cells have an avid uptake of glucose; for instance, prostate or thyroid cancers give a little or no visible signal. Benign tumours and inflammation can also increase the rate of FDG uptake, possibly causing a misdiagnosis[9]. Recently, FDG has been found to be useful in detecting changes in metabolic activity of a tumour before size differences can be visualized. Finally, PET is a useful imaging modality used in oncology because PET scans are fairly easy to interpret.

In cardiology, FDG PET is used to evaluate cardiac viability in diseased tissue. There are many different reasons for reduced ventricular wall motion, such as infarction, stunted myocardium, or hibernating myocardium. This reduced inefficient cardiac tissue can be revitalized though revascularization for stunted myocardium or hibernating myocardium where infarction results in a permanent loss of function. The other imaging modalities are often unable to differentiate the underlying cause of this cardiac dysfunction without identifying the differences in metabolic changes [9]. FDG PET is a useful imaging modality for differentiating between these different diseases because infarcted cardiac cells do not uptake FDG where stunted myocardium or hibernating myocardium main their metabolic efficiency. This information is useful for diagnosis and treatment planning. Patients with infarction will need to be added to the transplant list and patients with stunted myocardium or hibernating myocardium will get their needed treatment with recovery expectations [9].

FDG PET is also useful in functional brain imaging. FDG PET indirectly examines the brain’s neural activity by detecting the neural cell metabolic activities[9]. The greater the activity of the neural cells, the more glucose is required for the brain to operate effectively. Certain brain diseases, such as epilepsy and Alzheimer’s disease can be detected by their altered metabolic rates. For instance in complex partial epilepsy, the focal point of the seizure has reduced glucose uptake so FDG PET can be used to identify the location for surgical planning. Furthermore, Alzheimer’s dementia displays a typical pattern of reduced metabolic activity in the parietal and temporal lobes [9]. This diagnosis can be helpful for evaluating a patient with mild cognitive impairment to determine the long-term outcome.

Although the clinical applications of FDG PET are useful in diagnosis, staging, treatment predictions, and follow ups for many different diseases FDG is limited because glucose does not discriminate between healthy and diseased tissues. Therefore, other imaging techniques and biopsies are often necessary to make an accurate diagnosis [9]. Current research is focusing on creating radiotracers that are more specific to the molecule, cell, or tissue in question.

References

  1. Pacák, Josef, Zdeněk Točík, and Miloslav Černý. "Synthesis of 2-deoxy-2-fluoro-D-glucose." Journal of the Chemical Society D: Chemical Communications 2 (1969): 77-77
  2. Ido, T_, et al. "Fluorination with molecular fluorine. A convenient synthesis of 2-deoxy-2-fluoro-D-glucose." The Journal of Organic Chemistry 42.13 (1977): 2341-2342.
  3. Bushburg J. The Essential Physics of Medical Imaging: Lippincott Williams & Wilkins; 2002
  4. Wadsak W, Mitterhauser M. Basics and principles of radiopharmaceuticals for PET/CT. European Journal of Radiology. 2010;73(3):461-9.
  5. 5.05.1 Richards M, Scott P. Synthesis of [18F]-fluorodeoxyglucose ([18F]-FDG). In: Scott P, editor. Radiochemical Syntheses. Hoboken, NJ: Wiley; 2011. p. 3-14.
  6. 6.006.016.026.036.046.056.066.076.086.096.106.116.12 Yu, S. "Review of 18F-FDG synthesis and quality control." Biomedical imaging and intervention journal 2.4 (2006)
  7. 7.07.1 Delbeke D, Coleman RE, Guiberteau MJ, Brown ML, Royal HD, Siegel BA, et al. Procedure Guideline for Tumor Imaging with 18F-FDG PET/CT 1.0. Journal of Nuclear Medicine. 2006;47(5):885-95.
  8. Everaert H, Vanhove C, Lahoutte T, Muylle K, Caveliers V, Bossuyt A, et al. Optimal dose of 18F-FDG required for whole-body PET using an LSO PET camera. European Journal of Nuclear Medicine and Molecular Imaging. 2003 2003/12/01;30(12):1615-9.
  9. 9.09.19.29.39.49.59.69.7 Hoh, C, K. (2007).Clinical use of FDG PET. Nuclear Medicine and Biology, 34(1), 737-742.