Fluorodeoxyglucose (18F): Difference between revisions

{{DISPLAYTITLE:Fluorodeoxyglucose (¹⁸F)}}

{{Use dmy dates|date=January 2020}}

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 459523586

| Name = Fluorodeoxyglucose (¹⁸F)

| ImageFile = Fluorodeoxyglucose 18-F skeletal.svg

| ImageFile_Ref = {{chemboximage|correct|??}}

| ImageSize =

| ImageName = Stereo skeletal formula of fluorodeoxyglucose (18F) ((2''S'',6''R'')-6-meth,-2-ol)

|Section1={{Chembox Identifiers

| Abbreviations = [¹⁸F]FDG

| CASNo_Ref = {{cascite|correct|CAS}}

| CASNo = 63503-12-8

| CASNo_Comment = <small>(2''S'',6''R'')-6-meth,-2-ol</small>

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 0Z5B2CJX4D

| PubChem4 = 25173432

| PubChem4_Comment = <small>(2''S'')-2-ol</small>

| PubChem1 = 11469444

| PubChem1_Comment = <small>(6''R'')-6-meth</small>

| PubChem2 = 9920539

| PubChem2_Comment = <small>(2''R'',6''R'')-6-meth,-2-ol</small>

| PubChem3 = 450503

| PubChem3_Comment = <small>(2''S'',6''R'')-6-meth,-2-ol</small>

| ChemSpiderID2 = 9644274

| ChemSpiderID2_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID2_Comment = <small>(6''R'')-6-meth</small>

| ChemSpiderID1 = 8096174

| ChemSpiderID1_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID1_Comment = <small>(2''R'',6''R'')-6-meth,-2-ol</small>

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| KEGG = D01843

| KEGG_Ref = {{keggcite|changed|kegg}}

| ChEBI_Ref = {{ebicite|changed|EBI}}

| ChEBI = 49130

| ChEMBL = 497613

| ChEMBL_Ref = {{ebicite|changed|EBI}}

| Beilstein = 2047723

| SMILES = OCC1OC(O)[C@H]([18F])[C@@H](O)[C@@H]1O

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

|Section2={{Chembox Properties

| Formula = C₆H₁₁¹⁸FO₅

| MolarMass = 181.1495 g mol⁻¹

| MeltingPtC = 170 to 176<ref name="JCS_1969">{{cite journal | vauthors = Pacák J, Točík Z, Černý M | year = 1969| title = Synthesis of 2-Deoxy-2-fluoro-D-glucose | journal = [[Journal of the Chemical Society D: Chemical Communications]] | volume = 1969 | issue = 2| pages = 77 | doi = 10.1039/C29690000077 }}</ref>

|Section6={{Chembox Pharmacology

| ATCCode_prefix = V09

| ATCCode_suffix = IX04

| AdminRoutes = Intravenous

| Metabolism = 6-[[Phosphorylation]]<br />

| HalfLife = 110 min (at 70%)<br />

| Excretion = 20% Radioactivity renally excreted in two hours

| Pregnancy_AU = X

'''[¹⁸F]Fluorodeoxyglucose''' ([[International Nonproprietary Name|INN]]), or '''fluorodeoxyglucose F 18''' ([[United States Adopted Name|USAN]] and [[United States Pharmacopeia|USP]]), also commonly called '''fluorodeoxyglucose''' and abbreviated '''[¹⁸F]FDG, 2-[¹⁸F]FDG''' or '''FDG''', is a [[radiopharmaceutical]], specifically a [[radiotracer]], used in the [[medical imaging]] modality [[positron emission tomography]] (PET). Chemically, it is '''2-deoxy-2-[¹⁸F]fluoro-<small>D</small>-glucose''', a [[glucose]] [[analog (chemistry)|analog]], with the [[positron]]-emitting [[radionuclide]] [[fluorine-18]] substituted for the normal hydroxyl group at the C-2 position in the glucose molecule.

The uptake of [¹⁸F]FDG by tissues is a marker for the tissue [[Glucose uptake|uptake of glucose]], which in turn is closely correlated with certain types of tissue [[metabolism]]. After [¹⁸F]FDG is injected into a patient, a PET scanner can form two-dimensional or three-dimensional images of the distribution of [¹⁸F]FDG within the body.

Since its development in 1976, [¹⁸F]FDG had a profound influence on research in the [[neurosciences]].<ref>{{cite journal | vauthors = Newberg A, Alavi A, Reivich M | title = Determination of regional cerebral function with FDG-PET imaging in neuropsychiatric disorders | journal = Seminars in Nuclear Medicine | volume = 32 | issue = 1 | pages = 13–34 | date = January 2002 | pmid = 11839066 | doi = 10.1053/snuc.2002.29276 }}</ref> The subsequent discovery in 1980 that [¹⁸F]FDG accumulates in tumors underpins the evolution of PET as a major clinical tool in cancer diagnosis.<ref>{{cite journal | vauthors = Som P, Atkins HL, Bandoypadhyay D, Fowler JS, MacGregor RR, Matsui K, Oster ZH, Sacker DF, Shiue CY, Turner H, Wan CN, Wolf AP, Zabinski SV | display-authors = 6 | title = A fluorinated glucose analog, 2-fluoro-2-deoxy-D-glucose (F-18): nontoxic tracer for rapid tumor detection | journal = Journal of Nuclear Medicine | volume = 21 | issue = 7 | pages = 670–5 | date = July 1980 | pmid = 7391842 }}</ref> [¹⁸F]FDG is now the standard radiotracer used for PET neuroimaging and cancer patient management.<ref>{{cite journal | vauthors = Kelloff GJ, Hoffman JM, Johnson B, Scher HI, Siegel BA, Cheng EY, Cheson BD, O'shaughnessy J, Guyton KZ, Mankoff DA, Shankar L, Larson SM, Sigman CC, Schilsky RL, Sullivan DC | display-authors = 6 | title = Progress and promise of FDG-PET imaging for cancer patient management and oncologic drug development | journal = Clinical Cancer Research | volume = 11 | issue = 8 | pages = 2785–808 | date = April 2005 | pmid = 15837727 | doi = 10.1158/1078-0432.CCR-04-2626 | doi-access = free }}</ref>

The images can be assessed by a [[nuclear medicine]] physician or [[radiologist]] to provide diagnoses of various medical conditions.

==History==

In 1968, Dr. Josef Pacák, Zdeněk Točík and Miloslav Černý at the Department of Organic Chemistry, [[Charles University]], Czechoslovakia were the first to describe the synthesis of FDG.<ref>{{cite journal |vauthors=Pacák J, Točík Z, Černý M | title=Synthesis of 2-Deoxy-2-fluoro-D-glucose| journal=Journal of the Chemical Society D: Chemical Communications| issue=2| year=1969 | pages=77 | doi = 10.1039/C29690000077}}</ref> Later, in the 1970s, Tatsuo Ido and Al Wolf at the [[Brookhaven National Laboratory]] were the first to describe the synthesis of FDG labeled with fluorine-18.<ref name=Ido>{{cite journal |doi=10.1002/jlcr.2580140204|vauthors=Ido T, Wan CN, Casella V, Fowler JS, Wolf AP, Reivich M, Kuhl DE | title=Labeled 2-deoxy-D-glucose analogs: ¹⁸F-labeled 2-deoxy-2-fluoro-D-glucose, 2-deoxy-2-fluoro-D-mannose and ¹⁴C-2-deoxy-2-fluoro-D-glucose| journal=J Labeled Compounds Radiopharm | year=1978 | volume=24 |issue=2 | pages=174–183 }}</ref> The compound was first administered to two normal human volunteers by [[Abass Alavi]] in August, 1976 at the University of Pennsylvania. Brain images obtained with an ordinary (non-PET) nuclear scanner demonstrated the concentration of [¹⁸F]FDG in that organ (see history reference below).

Please see the comparative figure below for further history of the FDG molecule.

[[File:FDG Total Body Scan and First X-ray.png|thumb|400x400px|Comparative images of the first X-ray (left) and the first total body FDG-PET scan (right), the latter pioneered by Abass Alavi. These diagnostic tools have revolutionized modern medicine, with the FDG-PET scan having an impact akin to that of the first X-ray.]]

==Synthesis==

[¹⁸F]FDG was first synthesized via [[electrophilic fluorination]] with [¹⁸F]F₂.<ref name=Ido/> Subsequently, a "nucleophilic synthesis" was devised with the same radioisotope.

As with all [[radioactive]] ¹⁸F-labeled [[radioligand]]s, the fluorine-18 must be made initially as the fluoride anion in a [[cyclotron]]. Synthesis of complete [¹⁸F]FDG [[radioactive tracer]] begins with synthesis of the unattached fluoride radiotracer, since cyclotron bombardment destroys organic molecules of the type usually used for [[ligand (biochemistry)|ligand]]s, and in particular, would destroy glucose.

Cyclotron production of fluorine-18 may be accomplished by bombardment of [[neon-20]] with [[deuterons]], but usually is done by [[proton]] bombardment of ¹⁸O-enriched water, causing a [[(n-p) reaction|(p-n) reaction]] (sometimes called a "knockout reaction"{{snd}}a common type of [[nuclear reaction]] with high probability where an incoming proton "knocks out" a neutron) in the ¹⁸O. This produces "carrier-free" dissolved [¹⁸F]fluoride ([¹⁸F]F⁻) ions in the water. The 109.8-minute [[half-life]] of fluorine-18 makes rapid and automated chemistry necessary after this point.

Anhydrous fluoride salts, which are easier to handle than fluorine gas, can be produced in a cyclotron.<ref>{{citation |url=http://www2.massgeneral.org/imagingintranet/pdf/news/miller_janet_4_17_09.pdf |title=Radiopharmaceutical development at the Massachusetts General hospital |access-date=June 12, 2013 |author=Janet Miller |url-status=dead |archive-url=https://web.archive.org/web/20150211233851/http://www2.massgeneral.org/imagingintranet/pdf/news/miller_janet_4_17_09.pdf |archive-date=February 11, 2015 }}</ref> To achieve this chemistry, the [¹⁸F]F⁻ is separated from the aqueous solvent by trapping it on an [[ion-exchange]] column, and eluted with an [[acetonitrile]] solution of [[2,2,2-cryptand]] and potassium carbonate. Evaporation of the eluate gives [(crypt-222)K]⁺&nbsp;[¹⁸F]F^&minus; ('''2''') .

The fluoride anion is [[Nucleophile|nucleophilic]] but its anhydrous conditions are required to avoid competing reactions involving hydroxide, which is also a good nucleophile. The use of the [[cryptand]] to sequester the potassium ions avoids [[ion-pairing]] between free potassium and fluoride ions, rendering the fluoride anion more reactive.

Intermediate '''2''' is treated with the protected [[mannose]] [[Trifluoromethanesulfonate|triflate]] ('''1'''); the fluoride anion displaces the triflate [[leaving group]] in an [[SN2|S_N2 reaction]], giving the protected fluorinated deoxyglucose ('''3'''). [[Base hydrolysis]] removes the acetyl protecting groups, giving the desired product ('''4''') after removing the cryptand via ion-exchange:<ref>{{cite journal | vauthors = Fowler JS, Ido T | title = Initial and subsequent approach for the synthesis of 18FDG | journal = Seminars in Nuclear Medicine | volume = 32 | issue = 1 | pages = 6–12 | date = January 2002 | pmid = 11839070 | doi = 10.1053/snuc.2002.29270 | url = https://zenodo.org/record/1235998 }}</ref><ref>{{cite journal | vauthors = Yu S | title = Review of F-FDG Synthesis and Quality Control | journal = Biomedical Imaging and Intervention Journal | volume = 2 | issue = 4 | pages = e57 | date = October 2006 | pmid = 21614337 | pmc = 3097819 | doi = 10.2349/biij.2.4.e57 }}</ref>

:[[File:Synthesis of 18FDG.png|450px]]

==Mechanism of action, metabolic end-products, and metabolic rate==

[¹⁸F]FDG, as a glucose analog, is taken up by high-glucose-using cells such as brain, [[brown adipose tissue|brown adipocytes]], kidney, and cancer cells, where [[phosphorylation]] prevents the glucose from being released again from the cell, once it has been absorbed. The 2-hydroxyl group (–OH) in normal glucose is needed for further [[glycolysis]] (metabolism of glucose by splitting it), but [¹⁸F]FDG is missing this 2-hydroxyl. Thus, in common with its sister molecule [[2-Deoxy-D-glucose|2-deoxy-<small>D</small>-glucose]], FDG cannot be further metabolized in cells. The [¹⁸F]FDG-6-phosphate formed when [¹⁸F]FDG enters the cell cannot exit the cell before [[radioactive decay]]. As a result, the distribution of [¹⁸F]FDG is a good reflection of the distribution of glucose uptake and phosphorylation by cells in the body.

The fluorine in [¹⁸F]FDG decays radioactively via beta-decay to [[oxygen-18|¹⁸O]]⁻. After picking up a [[proton]] H⁺ from a [[hydronium ion]] in its aqueous environment, the molecule becomes glucose-6-phosphate labeled with harmless nonradioactive "heavy oxygen" in the hydroxyl at the C-2 position. The new presence of a 2-hydroxyl now allows it to be metabolized normally in the same way as ordinary glucose, producing non-radioactive end-products.

Although in theory all [¹⁸F]FDG is metabolized as above with a radioactivity elimination half-life of 110 minutes (the same as that of fluorine-18), clinical studies have shown that the radioactivity of [¹⁸F]FDG partitions into two major fractions. About 75% of the fluorine-18 activity remains in tissues and is eliminated with a half-life of 110 minutes, presumably{{Citation needed|date=April 2021}} by decaying in place to O-18 to form [¹⁸O]O-glucose-6-phosphate, which is non-radioactive (this molecule can soon be metabolized to carbon dioxide and water, after [[nuclear transmutation]] of the fluorine to oxygen ceases to prevent metabolism). Another fraction of [¹⁸F]FDG, representing about 20% of the total fluorine-18 activity of an injection, is [[Renal excretion|excreted renally]] by two hours after a dose of [¹⁸F]FDG, with a rapid half-life of about 16 minutes (this portion makes the renal-collecting system and bladder prominent in a normal PET scan). This short biological half-life indicates that this 20% portion of the total fluorine-18 tracer activity is eliminated renally much more quickly than the isotope itself can decay. Unlike normal glucose, FDG is not fully reabsorbed by the kidney.<ref>Moran, J. K., Lee, H. B., & Blaufox, M. D. (1999). Optimization of urinary FDG excretion during PET imaging. The Journal of Nuclear Medicine, 40(8), 1352.</ref> Because of this rapidly excreted urine ¹⁸F, the urine of a patient undergoing a PET scan may therefore be especially radioactive for several hours after administration of the isotope.<ref>{{cite web|url=https://www.drugs.com/cons/fludeoxyglucose-f-18.html|title=Fludeoxyglucose drug information|access-date=19 April 2024}}</ref>

All radioactivity of [¹⁸F]FDG, both the 20% which is rapidly excreted in the first several hours of urine which is made after the exam, and the 80% which remains in the patient, decays with a half-life of 110 minutes (just under two hours). Thus, within 24 hours (13 half-lives after the injection), the radioactivity in the patient and in any initially voided urine which may have contaminated bedding or objects after the PET exam will have decayed to 2⁻¹³ = {{Frac|1|8192|}} of the initial radioactivity of the dose. In practice, patients who have been injected with [¹⁸F]FDG are told to avoid the close vicinity of especially radiation-sensitive persons, such as infants, children and pregnant women, for at least 12 hours (7 half-lives, or decay to {{frac|1|128}} the initial radioactive dose).

==Production==

[[Alliance Medical]] and [[Siemens Healthcare]] are{{when|date=February 2020}} the only producers in the United Kingdom.{{citation needed|date=February 2020}} A dose of FDG in England costs{{when|date=February 2020}} about £130. In Northern Ireland, where there is a single supplier, doses cost up to £450.<ref>{{cite news|title='Monopoly' fears over £350m scans contract|url=http://www.lgcplus.com/news/health/social-care/monopoly-fears-over-350m-scans-contract/5082106.article|access-date=22 February 2015|publisher=Local Government Chronicle|date=12 February 2015}}</ref> IBA Molecular North America and Zevacor Molecular, both of which are owned by Illinois Health and Science (IBAM having been purchased as of 1 August 2015), Siemens' PETNET Solutions (a subsidiary of Siemens Healthcare), and [[Cardinal Health]]<ref>{{cite web | title = What is the impact of 21 C.F.R. Part 212? | date = 2021 | work = Cardinal Health | url = http://www.cardinalhealth.com/en/product-solutions/pharmaceutical-products/nuclear-medicine/safety-and-compliance/pet-biomarker-manufacturing.html }}</ref> are producers in the U.S.<ref name="label">{{cite web | title=Fludeoxyglucose F 18- fludeoxyglucose f-18 injection | website=DailyMed | date=8 May 2018 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2028be0c-333c-4e0c-be57-099276c725d7 | access-date=29 January 2020}}</ref><ref>{{Cite web |url=http://ibamolecular.com/fluorodeoxyglucose-f-18-fdg |title=Fluorodeoxyglucose (F-18 FDG) |access-date=2015-07-24 |archive-url=https://web.archive.org/web/20150725012402/http://ibamolecular.com/fluorodeoxyglucose-f-18-fdg |archive-date=2015-07-25 |url-status=dead }}</ref><ref>[http://www.accessdata.fda.gov/scripts/cder/ndc/dsp_searchresult.cfm "National Drug Code Directory"], ''U.S. Food and Drug Administration'', Retrieved 5 February 2016.{{dead link|date=January 2020}}</ref><ref>{{cite web | vauthors = Matthews M | title=Siemens' PETNET Solutions to Aid The US Oncology Network | website=Axis Imaging News | date=19 September 2013 | url=https://www.axisimagingnews.com/imaging-news/company-news/siemens-petnet-solutions-to-aid-the-us-oncology-network | access-date=5 February 2016}}</ref>

The labeled [¹⁸F]FDG compound has a relatively short shelf life which is dominated by the physical decay of fluorine-18 with a half-life of 109.8 minutes, or slightly less than two hours. Still, this half life is sufficiently long to allow shipping the compound to remote PET scanning facilities, in contrast to other medical radioisotopes like carbon-11. Due to transport regulations for radioactive compounds, delivery is normally done by specially licensed road transport, but means of transport may also include dedicated small commercial jet services. Transport by air allows to expand the distribution area around a [¹⁸F]FDG production site to deliver the compound to PET scanning centres even hundreds of miles away.

Recently, on-site cyclotrons with integral shielding and portable chemistry stations for making [¹⁸F]FDG have accompanied PET scanners to remote hospitals. This technology holds some promise in the future, for replacing some of the scramble to transport [¹⁸F]FDG from site of manufacture to site of use.<ref>{{cite web|url=http://www.medicalimagingmag.com/issues/articles/2003-07_05.asp |year=2003 |publisher=Medical Imaging |author=Lisa Fratt |title=Radiation Testing and PET Minding the Radiopharmaceutical Store |url-status=dead |archive-url=https://web.archive.org/web/20081120152623/http://www.medicalimagingmag.com/issues/articles/2003-07_05.asp |archive-date=2008-11-20 }}</ref>

==Applications==

[[File:PET-MIPS-anim.gif|thumb|Whole-body PET scan using ¹⁸F-FDG to show liver metastases of a colorectal tumor]]

In PET imaging, [¹⁸F]FDG is primarily used for imaging tumors in [[oncology]], where a static [¹⁸F]FDG PET scan is performed and the tumor [¹⁸F]FDG uptake is analyzed in terms of [[Standardized Uptake Value]] (SUV). FDG PET/CT can be used for the assessment of glucose metabolism in the [[heart]] and the [[brain]]. [¹⁸F]FDG is taken up by cells, and subsequently phosphorylated by [[hexokinase]] (whose [[mitochondrial]] form is greatly elevated in rapidly growing malignant tumours).<ref>{{cite journal | vauthors = Bustamante E, Pedersen PL | title = High aerobic glycolysis of rat hepatoma cells in culture: role of mitochondrial hexokinase | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 74 | issue = 9 | pages = 3735–9 | date = September 1977 | pmid = 198801 | pmc = 431708 | doi = 10.1073/pnas.74.9.3735 | bibcode = 1977PNAS...74.3735B | doi-access = free }}</ref> Phosphorylated [¹⁸F]FDG cannot be further metabolised and is thus retained by tissues with high metabolic activity, such as most types of malignant tumours. As a result, FDG-PET can be used for diagnosis, staging, and monitoring treatment of cancers,<ref>{{cite journal | vauthors = Hofman MS, Hicks RJ | title = How We Read Oncologic FDG PET/CT | journal = Cancer Imaging | volume = 16 | issue = 1 | pages = 35 | date = October 2016 | pmid = 27756360 | pmc = 5067887 | doi = 10.1186/s40644-016-0091-3 | doi-access = free }}</ref> particularly in [[Hodgkin's disease]], [[non-Hodgkin lymphoma]], [[colorectal cancer]], [[breast cancer]], [[melanoma]], and [[lung cancer]]. It has also been approved for use in diagnosing [[Alzheimer's disease]].

In body-scanning applications in searching for tumor or metastatic disease, a dose of [¹⁸F]-FDG in solution (typically 5 to 10 [[Curie (unit)|millicuries]] or 200 to 400 [[Becquerel|MBq]]) is typically injected rapidly into a saline drip running into a vein, in a patient who has been fasting for at least six hours, and who has a suitably low blood sugar. (This is a problem for some diabetics; usually PET scanning centers will not administer the isotope to patients with blood glucose levels over about 180&nbsp;mg/dL = 10&nbsp;mmol/L, and such patients must be rescheduled). The patient must then wait about an hour for the sugar to distribute and be taken up into organs which use glucose – a time during which physical activity must be kept to a minimum, in order to minimize uptake of the radioactive sugar into muscles (this causes unwanted artifacts in the scan, interfering with reading especially when the organs of interest are inside the body vs. inside the skull). Then, the patient is placed in the PET scanner for a series of one or more scans which may take from 20 minutes to as long as an hour (often, only about one-quarter of the body length may be imaged at a time).

== See also ==

* [[Fluorodopa]]

== References ==

{{reflist}}

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