|
 
 |
| REVIEW ARTICLE |
|
| Year : 2022 | Volume
: 8
| Issue : 2 | Page : 82-93 |
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Synthesis of 18fluoride-fluorodeoxyglucose and its clinical applications in positron emission tomography/computed tomography
Rajeev Kumar1, Madhavi Tripathi2, Aditi Khurana2, Arunav Kumar1, Shubha G Ravindra2, Sumit Garg2, Manish Kumar1, Sanjay Kumar Suman3
1 Department of Nuclear Medicine, Indira Gandhi Institute of Medical Sciences, Patna, Bihar, India
2 Department of Nuclear Medicine, AIIMS, New Delhi, India
3 Department of Radio Diagnosis, Indira Gandhi Institute of Medical Sciences, Patna, Bihar, India
| Date of Submission | 23-Jun-2022 |
| Date of Acceptance | 04-Jul-2022 |
| Date of Web Publication | 2-Sep-2022 |
Correspondence Address:
Rajeev Kumar
Department of Nuclear Medicine, Indira Gandhi Institute of Medical Sciences, Patna - 800 014, Bihar
India
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/jigims.jigims_29_22
This review article covers a brief explanation on synthesis of Flourodeoxyglucose (18F–FDG) and its clinical uses with emphasis on practical uses. In present scenario, 18F–FDG is the most successful PET radiopharmaceutical because of its half-life and mode of uptake. 18F–FDG synthesised by electrophilic fluorination and Nucleophilic fluorination reaction (preferable Nucleophilic fluorination reaction). The simplicity in synthesis and clinical utility of 18F–FDG, together with its approval by the US FDA and the availability of PET radiopharmaceuticals are probably the main reasons for the flourish of clinical PET. Positron Emission Tomography (PET) has increased the accuracy of metabolic mapping of numerous malignancies, with significant impact on the management of cancer patients for initial staging, restaging and therapy monitoring. PET can provide functional information in addition to morphology from conventional imaging modalities. 18F–FDG is the most commonly used PET tracer and FDG PET can demonstrate the activity of glucose metabolism throughout the entire body in a single session. We describe the clinical utility of FDG in PET and display images of normal distribution and of patients.
Keywords: 18fluoride-fluorodeoxyglucose, clinical utility, oncology, positron emission tomography tracer, positron emission tomography/computed tomography, synthesis
How to cite this article:
Kumar R, Tripathi M, Khurana A, Kumar A, Ravindra SG, Garg S, Kumar M, Suman SK. Synthesis of 18fluoride-fluorodeoxyglucose and its clinical applications in positron emission tomography/computed tomography. J Indira Gandhi Inst Med Sci 2022;8:82-93 |
How to cite this URL:
Kumar R, Tripathi M, Khurana A, Kumar A, Ravindra SG, Garg S, Kumar M, Suman SK. Synthesis of 18fluoride-fluorodeoxyglucose and its clinical applications in positron emission tomography/computed tomography. J Indira Gandhi Inst Med Sci [serial online] 2022 [cited 2023 Mar 27];8:82-93. Available from: http://www.jigims.co.in/text.asp?2022/8/2/82/355318 |
| Introduction | |  |
In carbohydrates, most sugars end with sound oes, for example, glucose, fructose, sucrose, mannose, maltose, and arabinose. Chemically carbohydrate contains mainly two functional groups: carbonyl group (aldehyde or ketone) and hydroxyl group. Carbohydrates such as glucose, mannose, and fructose have the same structure and stereochemistry at carbon 3, 4, and 5 and all three have a primary alcoholic group at carbon number 6. They differ in functionality or stereochemistry only at carbon number 2. Their molecular structures are given below respectively, i.e., in [Figure 1]. Glucose and mannose have the same molecular formula, i.e., C6H12O6. They show a specific type of stereo-isomerism (i.e., epimerism) having multiple stereocenters but differ in one of the stereogenic centers, i.e., differ from each other by configuration at the C-2 atom in [Figure 2].[1]
The 18fluoride-fluorodeoxyglucose (18F-FDG) is a special type of glucose in which the hydroxyl group is replaced by a Fluorine atom due to its higher value of electronegativity by the process of nucleophilic substitution reaction, [Figure 3].
| Materials and Methods | | |
The synthesis of 18F-FDG is mainly described by two methods: electrophilic fluorination and nucleophilic fluorination. Electrophilic fluorination is outdated and nobody using this, so nucleophilic fluorination is the option nowadays.[2]
Nucleophilic fluorination
Nucleophilic substitution is a chemical reaction involving the addition of a nucleophile (highly negatively charged molecule) onto a molecule with a leaving group (electron drawing group attached to the parent molecule through an unstable chemical bond). [Figure 4] is a general scheme for an SN2 nucleophilic substitution reaction. The nucleophile has a high affinity toward the relatively electron-deficient center in the parent molecule created by the electron pulling the leaving group. As a result, the nucleophilic molecule forms a covalent bond with the parent molecule and displaces the leaving group. The stereoconfiguration of the parent molecule is also changed.[3],[4],[5],[6] | Figure 4: Nucleophilic substitution: Nu: Nucleophilic molecule, X: leaving group
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Many attempts have been made to develop a nucleophilic substitution method for the synthesis of 18F-FDG using 18F-CsF, 18F-Et4NF, and 18F-KHF[3],[7],[8],[9],[10],[11],[12] as a reagent. However, the breakthrough was reported in 1986 using Kryptofix 222TM catalyst by Hamacher et al., and also reaction had a consistent yield of over 50% with shortened reaction time to 50 min.[13]
In the synthesis of 18F-FDG, the 18F ion acts as the nucleophile. The precursor is mannose triflate, in which the 1, 3, 4, and 6 position carbons of a mannose molecule are protected with an acetyl group and triflate is the leaving group at the 2-carbon. In the presence of Kryptofix 222TM as catalyst and acetonitrile as a solvent, the 18F ion approaches the mannose triflate at the 2-carbon, while the triflate group leaves the protected mannose molecule to form 18F-FDG [Figure 4].[7] Synthesis of 18F-FDG is carried out in computer-controlled automatic synthesizers; the nucleophilic process proceeds in roughly having the same stages in all radiochemistry modules as mentioned in [Figure 5]. | Figure 5: Synthesis of 18F-FDG by Nucleophilic substitution. 18F-FDG: 18fluoride-fluorodeoxyglucose
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Removal of 18fluoride from the 18O-water coming out from the cyclotron target
Since 18F is produced by an 18O (p, n) 18F-reaction, it is necessary to isolate the 18F ion from its aqueous environment. The most convenient way to isolate is to use a light quaternary methyl ammonium anion exchange (QMA) Sep-Pak column (Accell plus QMA Sep-PakTM). Fluorine has high hydration energy, so water is not a suitable choice of solvent. Hence, polar aprotic solvent such as acetonitrile is used. When using the column, the 18F-is retained by or via an ion-exchange reaction and allowed the 18O-water to flow through.[8] The retained 18F- is then eluted with an acetonitrile solution of Kryptofix and potassium carbonate [Figure 6]. | Figure 6: (a) Retention of 18F-FDG in light QMA ion exchange column; (b) elution of 18F from light QMA ion exchange column. 18F-FDG: 18fluoride-fluorodeoxyglucose, QMA: Quaternary methyl ammonium
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In an aqueous environment, any negatively charged ions must be accompanied by positively charged counterparts. Usually, the 18F– washed out from the cyclotron target is accompanied by traces of metal ions from the surface of the target body. When passing through the light QMA anion exchange ion, the 18F– is retained and the metal ions will be lost in the 18O-water. Hence, it is necessary to introduce a positively charged counter ion to restore the 18F– reactivity before evaporation of residual 18O-enriched water.[9] Several types of positively charged counter ions may be used, including large metal ions such as rubidium or cesium; however, potassium ion complexes having a large ring structure such as Kryptofix 222TM and tetrabutylammonium salts are preferred. Kryptofix 222TM is cyclic crown ether [Figure 7], which binds the potassium ion, preventing the formation of 18F-KF. Thus, potassium acts as the counter ion of 18F-to enhance its reactivity, but does not interfere with the synthesis.
Since Kryptofix 222TM [Figure 7] causes apnea and convulsion, all automatic synthesis modules have multiple removal steps, so that there is only a negligible amount of Kryptofix in the final 18F-FDG products.[10]
Logically, the addition of a counter cation also includes the addition of another anion. The carbonate anion is most widely used because it is less likely to interfere with the synthesis.[11]
Evaporation of residual 18O-water from the 18fluoride with acetonitrile
After 18F- is eluted into a reaction vessel, it is necessary to evaporate any residual water from the solution. The advantage of using acetonitrile as the eluting solvent is that it forms an azeotropic mixture with water. Evaporation of the acetonitrile in a nitrogen atmosphere will at the same time remove any residual 18O-water escaped into the reaction vessel together with the 18F. Most of the 18F-FDG automatic synthesizers perform the acetonitrile evaporation step several times to ensure all the residual 18O-water is removed. All components of the synthesis system are also rinsed with acetonitrile to remove moisture.
Addition of mannose triflate into the 18F- with acetonitrile
The nucleophilic substitution takes place in this stage. After the evaporation of residual water, the precursor is added to the 18F. The choice of precursor depends on the ease of preparation, ease of producing the final product, consistency, yields, and so on. The most commonly used precursor molecule in the synthesis of 18F-FDG is 1, 3, 4, 6-O-Acetyl-2-O-trifluoro-methanesulfonyl-beta-D-mannopyranose (mannose triflate). Its structure [Figure 8] is similar to that of FDG, except with a triflate group at the 2 carbon position and acetyl groups at 1, 3, 4, 6 position carbons via ester bonds, which can be readily broken at a higher or lower pH. The use of acetyl groups is to protect the hydroxyl groups, so that fluorination would not occur at these positions. The 18F ion approaches the mannose triflate at the 2-position carbon, while the triflate group leaves the protected mannose molecule to form 18F-FDG [Figure 4]. After the nucleophilic replacement of the triflate group by 18F-, the acetyl groups can be easily removed by hydrolysis to give rise to 18F-FDG. | Figure 8: Structures of mannose triflate and 18F-FDG. 18F-FDG: 18fluoride-fluorodeoxyglucose
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Hydrolysis to remove the protective acetyl groups to form 18fluoride-fluorodeoxyglucose
The final step of the synthesis is to remove the protective acetyl groups on the 1, 3, 4, 6 position carbons. This can be accomplished by either using hydrochloric acid (acid hydrolysis) or sodium hydroxide (base hydrolysis). Acid hydrolysis requires a longer time and higher temperature. Base hydrolysis, which is more commonly used currently, is faster and takes place at room temperature. One of the improved base hydrolysis is to adsorb the 1, 3, 4, 6 acetyl protected 18F-labeled-2-deoxyglucoses onto a C-18 reverse phase column. All other impurities can be removed by rinsing heavily with water. Sodium hydro de is added to the column, so that the base hydrolysis occurs on the column surface. All steps are occurs inside the radiochemistry module [Figure 9]. The final 18F-FDG product can be eluted with water while the un-hydrolyzed or partially hydrolyzed 1, 3, 4, 6 acetyl protected 18F-labeled-2-deoxyglucose remains on the column.[12] | Figure 9: Figure of explora and steps of synthesis of 18F-FDG showing in the Monitor. 18F-FDG: 18fluoride-fluorodeoxyglucose
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Purification of the final 18fluoride-fluorodeoxyglucose product
Purification of the final 18F-FDG can be performed with a series of anion exchange columns, C-18 reverse phase column, and alumina column as shown in [Table 1]. | Table 1: Parts of purification column which absorb impurities during synthesis of 18fluoride-fluorodeoxyglucose in an acidic hydrolysis radiochemistry module
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| Clinical Applications of Fluorodeoxyglucose - Positron Emission Tomography | | |
Fluorodeoxyglucose positron emission tomography in oncology
In 2000, the Food and Drug Administration approved the use of 18F-FDG to assist in the evaluation of malignancy in patients with known or suspected abnormalities found by other testing methods or in patients with an existing diagnosis of cancer. Our knowledge about the increased glycolysis of cancer cells makes FDG positron emission tomography/computed tomography (PET/CT) the metabolic signature of most malignancies. It can assess the fundamental alterations in the cellular metabolism of glucose which is common to all neoplasms.[14]
18F-FDG PET has become an established modality in the management of many cancers. It can be used for initial treatment strategy planning, like baseline staging-in lymphomas, and lung cancers, or for subsequent treatment strategy, as a follow-up of treatment in Head and neck tumors, pancreatic tumors, esophageal cancers, etc. PETCT images of some of these clinical indication are shown from [Figure 10], [Figure 11], [Figure 12], [Figure 13], [Figure 14], [Figure 15] It is one-stop-shop imaging to look for any distant metastasis and can upstage or downstage the tumors with high sensitivity and negative predictive value.[15] Radiotherapy planning is also assisted by FDG-PET/CT which ensures targeted therapy and protects the normal tissues from its harmful effects. Where appropriate to support qualitative findings, specific measures including standardized uptake values, metabolic tumor volume, and lesion dimensions should be included. Various criteria have been developed by various committees around the world like the PERSIST, EORTC criteria, and Deauville's Criteria (based on Lugano's classification) for response evaluation of treatment.[16] | Figure 10: MIP image of 18F-FDG PET showing case of osteosarcoma of left distal femur with skip metastasis to left proximal femur and left tibia and bilateral pulmonary metastasis. 18F-FDG: 18fluoride-fluorodeoxyglucose, PET: Positron emission tomography, MIP: Maximum intensity projection
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 | Figure 11: Figure showing a case of left breast carcinoma. 18F-FDG PET images (a-c) Prechemotherapy PET image and axial fused PET-CT shows increased FDG uptake in left breast upper outer quadrant with left axillary lymph node (b) and left internal mammary node (c) metastasis. (d-f) images are postchemotherapy and shows significant decrease in size and metabolic activity of primary lesion, axillary and left internal mammary node in (d and e) favouring partial response to treatment. 18F-FDG: 18fluoride-fluorodeoxyglucose, PET: Positron emission tomography, CT: Computed tomography
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 | Figure 12: Figure showing of a case of DLBCL. 18F-FDG PET images (a and b) prechemotherapy PET MIP images and coronal fused PET CT images shows metabolically active lymph nodes on both sides of the diaphragm (c and d) MIP and coronal fused PET CT images are postchemotherapy and shows complete metabolic resolution, favouring complete metabolic response treatment. Arrow on image c shows 18F-FDG avid lesion in right lung on infective etiology Deauville X. MIP: Maximum intensity projection, 18F-FDG: 18fluoride-fluorodeoxyglucose, PET: Positron emission tomography, CT: Computed tomography
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 | Figure 13: Case of metastatic lung carcinoma. 18F-FDG PET MIP images. (a) Prechemotherapy PET MIP images shows primary lesion with metastatic foci and axial fused PET-CT, (b) shows increased 18F-FDGuptakein right lung middle lobe with mediastinal lymphadenopathy, (c) images are postchemotherapy and MIP images shows significant decrease in size and metabolic activity of primary lesion and metastatic lesion, (d) fused axial PET-CT shows decrease in metabolic activity and extent ofd primary lesion, favouring partial response to the treatment. MIP: Maximum intensity projection, 18F-FDG: 18fluoride-fluorodeoxyglucose, PET: Positron emission tomography, CT: Computed tomography
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 | Figure 14: Case of nasopharyngeal carcinoma. 18F-FDG PET MIP images (a and b) prechemotherapy PET MIP images and axial fused PET-CT images shows increased 18F-FDG uptake in right nasopharynx with extensions to contralateral sides. (c and d) Images are postchemotherapy and shows significant decrease in size and metabolic activity of primary lesion, favouring partial response to the treatment. MIP: Maximum intensity projection, 18F-FDG: 18fluoride-fluorodeoxyglucose, PET: Positron emission tomography, CT: Computed tomography
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 | Figure 15: 18F-FDG PET and corresponding CT images showing high-grade butterfly gliomas showing heterogeneous contrast enhancement extending in to bilateral cerebral hemisphere involving splenium. Top row axial section of (a) PET and (b) CECT, Bottom row coronal section of (c) PET and (d) CECT. 18F-FDG: 18fluoride-fluorodeoxyglucose, PET: Positron emission tomography, CT: Computed tomography, CECT: Contrast-enhanced CT
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The limitations of FDG-PET should also be kept in mind, which include limited spatial resolution (4–10 mm), tumors with poor FDG avidity, and low uptake, and it is generally considered not useful in the assessment of possible cerebral metastases from known primary neoplasms.[14] Below is a [Table 2] that summarizes the indications of FDG-PET/CT in various malignancies individually as per the latest National Cancer Comprehensive Network (NCCN) guidelines, which are followed worldwide by oncologists for cancer managemen. | Table 2: Indication of FDG-PET CT as per the latest NCCN guidelines in various malignancies
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| Fluorodeoxyglucose Positron Emission Tomography in Cardiology | | |
PET is a noninvasive technique that employs radionuclides labeled with biological molecules to capture metabolic and functional information related to the molecular behavior of the radiopharmaceutical itself. F-18 FDG PET/CT is one such PET tracer that is the gold standard for imaging myocardial viability.[17] Myocardial viability is defined as myocardium in acute or chronic coronary artery disease and other conditions with contractile dysfunction but maintained metabolic and electrical function, having the potential to improve dysfunction upon revascularization or other therapy.[18]
Myocardial ischemia can have three predictable outcomes. Either there is intermittent ischemia with reperfusion before necrosis sets in which leads to a Stunned myocardium. In a stunning myocardium, the coronary flow reserve is mildly impaired with preserved contractile function, perfusion, and metabolism. Histopathology shows no significant changes and this is a reversible stage usually spontaneously recovering over days to weeks. Severe and prolonged ischemia results in necrosis and would eventually be labeled as a myocardial scar with virtually no contractility, perfusion, and metabolic activity. Here microscopically the myocytes are replaced by fibrosis and no recovery is possible. A small subset of patients is hypothesized to have chronic low flow or have had multiple episodes of stunning and the heart metabolically adapts to an impaired coronary flow reserve, perfusion, and contractile function. The metabolism, however, is preserved; the cardiomyocytes have dedifferentiated and we label it as Hibernating myocardium. This condition does not spontaneously recover and revascularization is the key.[19]
The two key advantages that-myocardial perfusion-metabolic imaging (FDG) holds over SPECT perfusion imaging are a higher spatial resolution, and the ability to differentiate between dead irreversibly scarred myocardium and hibernating myocardium that may yet recover function following revascularization. 18F-FDG is normally administered after an oral glucose load or an insulin clamp or after injecting unfractionated heparin. A combination of the three has also been tried.[20] A matched pattern with reduced perfusion and metabolism is suggestive of a scar, whereas a mismatched pattern with reduced perfusion and preserved metabolism is the hallmark of hibernating myocardium.[21] Schinkel et al. published a review of 24 studies and calculated the weighted mean sensitivity of 92% (much higher than any other available modality) and a specificity of 63%.[22]
Another indication for FDG-PET/CT in cardiology is staging and treatment follow-up of cardiac sarcoidosis. Sarcoidosis is a multisystem disorder that is characterized by noncaseating, nonnecrotic granulomas. However, it is more common in the lungs and lymph nodes, it may involve any organ.[23] Cardiac sarcoidosis is an important cause of mortality in cases of sarcoidosis. Thus, its diagnosis, progression monitoring, and treatment follow-up are important concerns.
Traditionally, the diagnosis has been based on the guidelines of the Japanese Ministry of Health and Welfare,[24] which consider histological, clinical, biological, and diagnostic procedures, and on those published in 2014 by the Heart Rhythm Society.[25] Areas of active cardiac inflammation demonstrate increased glucose metabolism and therefore increased 18F-FDG uptake on PET. On the contrary, SPECT or PET MPI perfusion studies can show areas of hypoperfusion due to inflammation and vascular compression, due to edema or myocardial fibrosis and scarring. The disease can be staged depending on the degree of active inflammation on FDG-PET/CT and defects in the resting perfusion study. No evidence of active disease (if no inflammation and no scar), early disease stage when there is FDG uptake due to inflammation and mild or no scarring, progressive disease when there is active inflammation and moderate scarring, or fibrous disease with no inflammation and severe scar.[26]
| Fluorodeoxyglucose-Positron Emission Tomography in Neurology | | |
Cognitive impairment
Major cognitive impairment (dementia) refers to a decline in one or more cognitive domains severe enough to interfere with daily functioning.[27] The common underlying etiologies include Alzheimer's dementia (AD), followed by vascular dementia, dementia with Lewy bodies (DLB), and frontotemporal dementia.[28] Diagnostic dilemma in dementia may stem from the significant overlap between various dementia syndromes in terms of symptomatology and clinical manifestations. Structural imaging like magnetic resonance imaging (MRI) and CT can rule out reversible causes of cognitive decline but may fail to detect subtle changes that may be seen in early dementia. FDG PET, when performed, adds diagnostic value in such cases, with an overlap of symptoms and unclear diagnosis. Neurodegeneration resulting from various etiologies of dementia results in characteristic metabolic signatures on FDG PET imaging. For instance, the classical pattern of neurodegeneration noted on FDG PET in AD includes hypometabolism in the posterior cingulate, precuneus, parietal, and posterior temporal cortices. The metabolic activity is typically preserved in sensorimotor and visual cortices, thalami, basal ganglia, and cerebellar hemispheres.[29]
Mild cognitive impairment (MCI), is considered a transitional stage between normal aging and dementia. It is characterized by a cognitive decline that is not normal for a given age. However, there is the preservation of normal functional activities and the criteria for dementia are not met. FDG PET helps in the early identification of those individuals, who present with MCI, and are likely to progress to dementia (AD or other types). Hypometabolism in temporoparietal and posterior cingulate cortices has been reported in MCI subjects who progress rapidly to dementia, and are on an AD trajectory.[30]
Movement disorders
The commonly encountered movement disorders in clinical practice include idiopathic Parkinson's disease (PD) and atypical parkinsonian syndromes (APS) like DLB, multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration. Differentiation of PD from APS subgroups is important because treatment of APS remains unsatisfactory both in terms of symptom control and disease progression and the prognosis is grim. Disease-specific patterns seen on FDG PET aids in the differential diagnosis of PD and APS subgroups particularly when clinical evaluation and structural imaging fails to identify the underlying etiology.[31]
Seizure localization in epilepsy
Drug refractory epilepsy (DRE) is defined as the occurrence of disabling seizures despite appropriate trials of two well-tolerated antiepileptic drug schedules (either as monotherapies or in combination).[32] FDG PET imaging proves beneficial in evaluating DRE patients before surgical interventions, particularly when the clinical, electroencephalographic, and MRI findings are discordant or MRI is nonlesional. It has been observed that patients with temporal lobe epilepsy who are MRI negative, but PET-positive, have good surgical outcomes, and are therefore suitable candidates for surgery.[33],[34]
Autoimmune encephalitis
Autoimmune encephalitis (AIE) constitutes a group of disorders associated with antibodies against neuronal cell-surface proteins, ion channels, or receptors. The clinical features are predominantly neuropsychiatric with rapid onset and progression.[35] FDG PET imaging has a promising role to play in the diagnosis of AIE, particularly in MRI negative/equivocal cases or antibody-negative AIE.[36] Striatal hypermetabolism on FDG PET serves as an imaging biomarker of AIE. Further antibody subcategorization can be performed by characteristic metabolic patterns seen on PET.[37]
| Miscellaneous Applications | | |
The common etiologies of pyrexia of unknown origin (PUO) include infections, malignancies, systemic rheumatic diseases, and miscellaneous causes. FDG PET, when performed, may help in determining the underlying cause of PUO and guide further management. This is particularly important when potentially diagnostic clues toward the likely etiology of PUO cannot be determined in spite of repeated history-taking, physical examination, and essential investigations.[38] FDG PET can also be used as a potential infection imaging agent, particularly in suspected chronic osteomyelitis, diabetic foot, infected orthopedic implant, and vascular prosthesis. FDG PET has also been used in large-vessel vasculitis (giant cell arteritis and Takayasu arteritis), sarcoidosis, inflammatory bowel disease, and IgG4 disease for diagnosis, assessment of the extent of inflammation, and monitoring treatment response.[39]
Acknowledgments
The authors would link to thank the Director, Medical Superintendent, Dean Academic, and the staffs and faculties of the Department of Radiodiagnosis, IGIMS, Patna, Bihar.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11], [Figure 12], [Figure 13], [Figure 14], [Figure 15]
[Table 1], [Table 2]
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