Radiofluorination

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Radiofluorination is the process by which a radioactive isotope of fluorine is attached to a molecule and is preferably performed by nucleophilic substitution using nitro or halogens as leaving groups. Fluorine-18 is the most common isotope used for this procedure. This is due to its 97% positron emission and relatively long 109.8 min half-life. The half-life allows for a long enough time to be incorporated into the molecule and be used without causing exceedingly harmful effects. This process has many applications especially with the use of positron emission tomography (PET) as the aforementioned low positron energy is able to yield a high resolution in PET imaging.

Contents

History

The first notable radiofluorination synthesis was performed in 1976 for the synthesis of Fluorine-18 labeled fludeoxyglucose. [1] In the 1980s this molecule was discovered to accumulate in tumors of cancer patients. Since this time, this molecule has become a standard in PET imaging of cancer, and currently the only FDA-approved substance to do so. In recent years, research is being performed to find alternatives to the fludeoxyglucose molecule. These new molecules are bifunctional labeling agents that can attach to proteins or peptides to label not only cancer, but also amyloid plaques and inflammatory processes. [1]

Procedure

Due to the ongoing research involving radiofluorinated molecules and their various uses, the demand for suitable syntheses has increased over the years. In order for synthetic methods to be considered viable, the process must be rapid and efficient as well as compatible with the forms of 18F with are available. [2] In many cases, the synthesis must also be capable of regio- and stereo-specificity. [2]

Positron Emission of Fluorine-18. Positron Emission of Fluorine-18.png
Positron Emission of Fluorine-18.

[3]

Typically, radiofluorinated products are synthesized using nucleophilic or electrophilic substitution processes. One classical method for radiofluorination is the Balz-Schiemann reaction, or a modified Balz-Schiemann reaction with [18F] F−. [4] Electrophilic substitution reactions typically make use of [18F] F2 as a precursor which can then be added to an array of molecules such as alkenes, aromatic rings, and carbanions [21]. However, methods utilizing [18F] F2 are at a disadvantage due to the loss 50% of the input activity in the form of [18F] F−. [4] To facilitate these procedures the reaction may also be carried out within a microfluidic chamber. [1]

Uses

One of the most popular uses of radiofluorination is its application in PET scans. Positron emission tomography (PET) is a widely used imaging technique in the field of nuclear medicine. [1] [5] With applications in research and in diagnosis, a PET scan can be used to image tumors, diagnose brain disease, and monitor brain or heart function [8,9,12]. These images are created with the aid of radiotracers that emit positrons which decay via an annihilation reaction to generate two 510 KeV photons that are then detected and used to reconstruct images using the same software utilized in X-Ray CT units. The gamma rays are then emitted nearly 180 degrees from each other and their detection allows the ability to pinpoint the source, thus creating an image. [1] [5] One of the most popular isotopes used as a positron emitting radiotracer is fluorine-18. This isotope is particularly advantageous due to its short half-life of approximately 109.8 min, its decay being 97% positron emission, its ease of production, and its  energy being low (0.64 MeV). [1]  Therefore, the radiofluorination procedure is incorporates the radioactive isotope of choice in order to create the images.

Another application in the field of radiofluorination chemistry lies in the field of biofuels. Recent interest has been given to the exploration of lignocellulostic material as a biofuel source. [6] [7] [8] Given that it is the most plentiful renewable carbon source in the biosphere, it is a natural choice for this purpose. The composition consists of three elements—hemicellulose, cellulose, and lignin. [8] It is the last of these three, lignin, that presents the greatest obstacle to the efficient use of such material as a feasible biofuel source. The recalcitrant chemical nature of the lignin molecule currently requires an extensive and expensive process to degrade for bioethanol. [8] [7] Current research is being conducted to find more economical ways to breakdown this lignin barrier. This research will explore the use of radiofluorination with the fluorine-18 isotope to search for places in nature that lignin is being degraded. The radioactive fluorine will be attached to lignin-degradation products in order to search for enzymes in nature that breakdown lignin. This will help to make the process more efficient for use in biofuel production.

Applications with radiopharmaceuticals

Fluorine-18 is typically produced by proton bombardment of oxygen-18 enriched water in a particle accelerator. [1] Due to the relatively short half-life, the isotope must be quickly incorporated into a tracer molecule designed for the desired target. These radiotracers generally fall into two main categories—labeled molecules normally used in the body such as water or glucose or labeled molecules that react with or bind to receptors within the body. [1] [9] [10] One important application in the latter class is the attachment of the  molecule to a biologically active proteins and peptides, including antibodies and antibody fragments. [9] [11] This class of radiotracers is of particular interest due to their role in imaging the regulation of cellular growth and function. Consequently, radiolabeling these labeled biologically active proteins and peptides with fluorine-18 to image various aspects of nuclear medicinal purposes such as tumors and inflammatory processes is important in nuclear medicine. [1] [9]

Thesis fbam rat LDL.png

[1]

However, due to the chemically sensitive nature of proteins, the synthesis of radiofluorine-labeled proteins and peptides presents some formidable challenges. The harsh conditions needed for the addition of the  into the biomacromolecule can easily hinder its use in radiolabeling reactions. [1] In order to overcome these obstacles, protein or peptide labeling can be performed through a prosthetic group or bifunctional labeling agent to which the radiofluorine has been attached. [1] [11] This molecule can then be conjugated to the protein or peptide under milder conditions. [1] [12]

Thesis FBAM rat tumor PET.png

[9]

The three main categories of prosthetic groups are carboxyl-reactive, amino-reactive, and thiol-reactive. [13] Of these three, the carboxyl-reactive group is the least utilized, and the amino-reactive is the most utilized. The thiol-reactive prosthetic groups are the newest class of the three. [13] The choice of method by which the protein is labeled is dependent upon the structure. Thiol-reactive molecules can be used in cases where the amino-reactive prosthetic groups would not work. Below can be seen the structures and names of various prosthetic groups currently being used for protein and peptide labeling.

Related Research Articles

<span class="mw-page-title-main">Positron emission tomography</span> Medical imaging technique

Positron emission tomography (PET) is a functional imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in metabolic processes, and in other physiological activities including blood flow, regional chemical composition, and absorption. Different tracers are used for various imaging purposes, depending on the target process within the body.

A radioactive tracer, radiotracer, or radioactive label is a chemical compound in which one or more atoms have been replaced by a radionuclide so by virtue of its radioactive decay it can be used to explore the mechanism of chemical reactions by tracing the path that the radioisotope follows from reactants to products. Radiolabeling or radiotracing is thus the radioactive form of isotopic labeling. In biological contexts, use of radioisotope tracers are sometimes called radioisotope feeding experiments.

A radioligand is a radioactive biochemical substance, in particular, a ligand that is radiolabeled. Radioligands are used for diagnosis or for research-oriented study of the receptor systems of the body, and for anti-cancer radioligand therapy.

Fluorodeoxyglucose (<sup>18</sup>F) Chemical compound

[18F]Fluorodeoxyglucose (INN), or fluorodeoxyglucose F 18, 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-D-glucose, a glucose analog, with the positron-emitting radionuclide fluorine-18 substituted for the normal hydroxyl group at the C-2 position in the glucose molecule.

<span class="mw-page-title-main">Molecular imaging</span> Imaging molecules within living patients

Molecular imaging is a field of medical imaging that focuses on imaging molecules of medical interest within living patients. This is in contrast to conventional methods for obtaining molecular information from preserved tissue samples, such as histology. Molecules of interest may be either ones produced naturally by the body, or synthetic molecules produced in a laboratory and injected into a patient by a doctor. The most common example of molecular imaging used clinically today is to inject a contrast agent into a patient's bloodstream and to use an imaging modality to track its movement in the body. Molecular imaging originated from the field of radiology from a need to better understand fundamental molecular processes inside organisms in a noninvasive manner.

<span class="mw-page-title-main">Fluorine-18</span> Isotope of fluorine emitting a positron

Fluorine-18 (18F) is a fluorine radioisotope which is an important source of positrons. It has a mass of 18.0009380(6) u and its half-life is 109.771(20) minutes. It decays by positron emission 96% of the time and electron capture 4% of the time. Both modes of decay yield stable oxygen-18.

<span class="mw-page-title-main">Radioactivity in the life sciences</span>

Radioactivity is generally used in life sciences for highly sensitive and direct measurements of biological phenomena, and for visualizing the location of biomolecules radiolabelled with a radioisotope.

Copper-64 (64Cu) is a positron and beta emitting isotope of copper, with applications for molecular radiotherapy and positron emission tomography. Its unusually long half-life (12.7-hours) for a positron-emitting isotope makes it increasingly useful when attached to various ligands, for PET and PET-CT scanning.

<span class="mw-page-title-main">Altanserin</span> Chemical compound

Altanserin is a compound that binds to the 5-HT2A receptor. Labeled with the isotope fluorine-18 it is used as a radioligand in positron emission tomography (PET) studies of the brain, i.e., studies of the 5-HT2A neuroreceptors. Besides human neuroimaging studies altanserin has also been used in the study of rats.

<span class="mw-page-title-main">Setoperone</span> Chemical compound

Setoperone is a compound that is a ligand to the 5-HT2A receptor. It can be radiolabeled with the radioisotope fluorine-18 and used as a radioligand with positron emission tomography (PET). Several research studies have used the radiolabeled setoperone in neuroimaging for the studying neuropsychiatric disorders, such as depression or schizophrenia.

Cardiac PET is a form of diagnostic imaging in which the presence of heart disease is evaluated using a PET scanner. Intravenous injection of a radiotracer is performed as part of the scan. Commonly used radiotracers are Rubidium-82, Nitrogen-13 ammonia and Oxygen-15 water.

Emission computed tomography (ECT) is a type of tomography involving radioactive or emissions. Types include positron emission tomography (PET) and Single-photon emission computed tomography (SPECT).

<span class="mw-page-title-main">Brain positron emission tomography</span> Form of positron emission tomography

Brain positron emission tomography is a form of positron emission tomography (PET) that is used to measure brain metabolism and the distribution of exogenous radiolabeled chemical agents throughout the brain. PET measures emissions from radioactively labeled metabolically active chemicals that have been injected into the bloodstream. The emission data from brain PET are computer-processed to produce multi-dimensional images of the distribution of the chemicals throughout the brain.

<span class="mw-page-title-main">Desmethoxyfallypride</span> Chemical compound

Desmethoxyfallypride is a moderate affinity dopamine D2 receptor/D3 receptor antagonist used in medical research, usually in the form of the radiopharmaceuticals desmethoxyfallypride or DMFP(18F) and has been used in human studies as a positron emission tomography (PET) radiotracer.

Metabolic trapping refers to a localization mechanism of synthesized radiocompounds in the human body. It can be defined as the intracellular accumulation of a radioactive tracer based on the relative metabolic activity of the body's tissues. It is a basic principle of the design of radiopharmaceuticals as metabolic probes for functional studies or tumor location.

Fluorodeoxyglycosylamine is a product of fluorodeoxyglucose and biological amines. The Maillard reaction of sugars and amines results in the formation of glycosylamines and Amadori products that are of biological significance, for drug delivery, role in central nervous system, and other potential applications.

<span class="mw-page-title-main">Dihydrotetrabenazine</span> Chemical compound

Dihydrotetrabenazine or DTBZ is an organic compound with the chemical formula C19H29NO3. It is a close analog of tetrabenazine. DTBZ and its derivatives, when labeled with positron emitting isotopes such as carbon-11 and fluorine-18, are used as PET radioligands for examining VMAT2.

<span class="mw-page-title-main">Jacob Hooker</span>

Jacob M. Hooker is an American chemist and expert in molecular imaging, particularly in the development and application of simultaneous MRI and PET. He has contributed major advances on the entire spectrum of research from fundamental chemistry methodology with radioisotopes to human neuroimaging.

<span class="mw-page-title-main">Peter J. H. Scott</span>

Peter J. H. Scott FRSC CChem is a British and American chemist and radiochemist who is a professor of radiology, professor of pharmacology and professor of medicinal chemistry, as well as a core member of the Rogel Cancer Center at the University of Michigan in the United States. He is Chief of Nuclear Medicine and director of the University of Michigan Positron Emission Tomography (PET) Center, and runs a research group developing new radiochemistry methodology and novel PET radiotracers.

Neil Vasdev is a Canadian and American radiochemist and expert in nuclear medicine and molecular imaging, particularly in the application of PET. Radiotracers developed by the Vasdev Lab are in preclinical use worldwide, and many have been translated for first-in-human neuroimaging studies. He is the director and chief radiochemist of the Brain Health Imaging Centre and director of the Azrieli Centre for Neuro-Radiochemistry at the Centre for Addiction and Mental Health (CAMH). He is the Tier 1 Canada Research Chair in Radiochemistry and Nuclear Medicine, the endowed Azrieli Chair in Brain and Behaviour and Professor of Psychiatry at the University of Toronto. Vasdev has been featured on Global News, CTV, CNN, New York Times, Toronto Star and the Globe and Mail for his innovative research program.

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 13 Berndt, M.; Pietzsch, J.; Wuest, F. (2007). "Labeling of low-density lipoproteins using the18F-labeled thio-reactive reagent N-[6-(4-[18F]fluorobenzylidene)aminooxyhexyl]maleimide". Nuclear Medicine and Biology. 34 (1): 5–15. doi:10.1016/j.nucmedbio.2006.09.009. PMID   17210457.
  2. 1 2 Speranza, M. (1985). "Electrophilic radiofluorination of arytrimethylsilanes as a general route to 18F-labeled aryl fluoride". Journal of Fluorine Chemistry. 30: 97–107. doi:10.1016/S0022-1139(00)80525-4.
  3. ↑ "Positron Emission Tomography".
  4. 1 2 Knochel, A., Zwernemann, O. (1991). "Aromatic n.c.a. labelling with 18F- by modified Balz-Schiemann-decomposition. International Journal of Radiation Applications and Instrumentation". Applied Radiation and Isotopes. 42: 1077–1080. doi:10.1016/0883-2889(91)90014-R.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. 1 2 Rennen, HJ.; Coasters, FH.; Oyen, WJ.; Berman, OC. (2001). "New concepts in infection/inflammation imaging". Q J Nucl Med. 45 (2): 167–173. PMID   11476166.
  6. ↑ US 4687741,Farrell, Roberta L.; Kirk, Thomas K.& Tien, Ming,"Novel enzymes which catalyze the degradation and modification of lignin",published 1987-08-18, assigned to Repligen Corp. and U.S. Secretary of Agriculture
  7. 1 2 Geib, S. M.; Filley, T. R.; Hatcher, P. G.; Hoover, K.; Carlson, J. E.; Jimenez-Gasco, M. d. M.; Nakagawa-Izumi, A.; Sleighter, R. L.; Tien, M. (2008). "Lignin degradation in wood-feeding insects". Proceedings of the National Academy of Sciences. 105 (35): 12932–12937. Bibcode:2008PNAS..10512932G. doi: 10.1073/pnas.0805257105 . PMC   2529026 . PMID   18725643.
  8. 1 2 3 Tien, Ming (2019). "Imaging Lignin Degradation: Bio-prospecting for New Enzymes for Use in Biofuel Production". Penn State University Project Summary. doi:10.2172/1506469. OSTI   1506469. S2CID   214542436.
  9. 1 2 3 4 Namavari, M.; Padilla De Jesus, O.; Cheng, Z.; De, A.; Kovacs, E.; Levi, J.; Gambhir, S. (2008). "Direct Site-Specific Radiolabeling of an Affibody Protein with 4-[18F]Fluorobenzaldehyde via Oxime Chemistry". Molecular Imaging and Biology. 10 (4): 177–181. doi:10.1007/s11307-008-0142-7. PMC   4155982 . PMID   18481153.
  10. ↑ Sosabowski, J.; Melendez-Alafort, L.; Mather, S. (2003). "Radiolabeling of peptides for diagnosis and treatment of human cancer". In Vivo. 19 (1): 9–29. PMID   15796153.
  11. 1 2 Dolle, F.; Hinnen, F.; Lagnel, B.; Boisgard, R.; Sanson, A.; Russo-Marie, F.; et al. (2003). "Radiosynthesis of a [18F]fluoropyridine-based maleimide reagent for protein labeling". J Label Compd Radiopharm. 46: S15.
  12. ↑ US 2910454,Clark, Gerald A.; Havens, Carl B.& Brookens, Ronald G.,"Hydrocarbon polymers stabilized with B-resorcylic acid diesters",published 1959-10-27, assigned to The Dow Chemical Company
  13. 1 2 Banister, S.; Roeda, D.; Dolle, F.; Kassiou, M. (2010). "Fluorine-18 Chemistry for PET: A Concise Introduction". Current Radiopharmaceuticals. 3 (2): 68–80. doi:10.2174/1874471011003020068.
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