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MedChemComm View Article Online REVIEW View Journal | View Issue 2-[18F]Fluoroethyl tosylate – a versatile tool for building 18F-based radiotracers for positron Cite this: Med. Chem. Commun., 2015, 6,1714 emission tomography Torsten Kniess,* Markus Laube, Peter Brust and Jörg Steinbach Positron emission tomography (PET) is a modern in vivo imaging technique and an important diagnostic modality for clinical and pre-clinical research. The incorporation of a radionuclide like fluorine-18 into a target molecule to form PET radiopharmaceuticals is a repeated challenge for radiochemists. [18F]Fluoro- ethylation is a well-acknowledged method for 18F-radiolabeling and 2-[18F]fluoroethyl tosylate ([18F]FETs) is Received 17th July 2015, a preferred reagent because of its high reactivity to phenolic, thiophenolic, carboxylic and amide function- Accepted 1st September 2015 alities. This review will highlight the role of [18F]FETs in PET chemistry and summarize its applicability in radiotracer design. The radiolabeling conditions and the pros and cons of direct and indirect radiolabeling DOI: 10.1039/c5md00303b as well the aspects of the reactivity of [18F]FETs compared with other [18F]fluoroalkylating reagents will be Creative Commons Attribution 3.0 Unported Licence. www.rsc.org/medchemcomm discussed comprehensively. Introduction into a target molecule, PET radiopharmaceuticals are formed, enabling the non-invasive visualization of bio- Positron emission tomography (PET) is a modern in vivo chemical processes and the imaging and quantification of imaging technique and has become an important diagnostic pathological situations in vivo. The most prominent example, 18 18 modality for clinical and pre-clinical research. By incorpora- 2-[ F]fluoro-2-deoxy-D-glucose ([ F]FDG), a radiopharmaceuti- β+ tion of a radionuclide like fluorine-18 (t1/2 = 109.8 min, = 97%) cal for glucose metabolism, has been widely used for more 1,2 This article is licensed under a than 25 years as a diagnostic tool for neuropsychiatric and 2,3 Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer cardiovascular disorders and is the working horse for the 4 Research, Dresden, Germany. E-mail: [email protected] diagnosis, monitoring and staging of cancerous diseases. Open Access Article. Published on 03 September 2015. Downloaded 9/24/2021 4:23:34 AM. Torsten Kniess graduated from Markus Laube studied food Technical University Dresden chemistry, graduated in 2009 at and received his Ph.D. in Technical University Dresden Organic Chemistry in 1993. His and received his Ph.D. in 2014 career in radiopharmacy started at Helmholtz-Zentrum Dresden- in 1994 at Research Center Rossendorf (HZDR) under the Rossendorf (now Helmholtz- supervision of Professor Jörg Zentrum Dresden-Rossendorf, Steinbach. His diploma and Ph.D. HZDR) as a post-doc under the work dealt with the synthesis and supervision of Prof. Bernd radiolabeling of cyclooxygenase-2 Johannsen and continued in inhibitors for imaging purposes 2001 at Instituto Tecnologico é with PET – his ongoing research Torsten Kniess Nuclear (ITN, Sacavém, Portu- Markus Laube interest. This and the develop- gal) with Prof. Isabel Rego Dos ment of novel carbon-11 labeled Santos. He moved to the PET-Center in Dresden-Rossendorf with radiotracers are part of his continuing post-doc work at HZDR. Prof. Frank Wüst in 2002 and dealt with palladium-mediated Besides these, working in the project ForMaT HypoFood/ cross-coupling reactions in PET chemistry. Since 2008, he has HypoFeed (2009, Prof. T. Henle, TU Dresden) and a research been the head of the Organic and Radiochemistry group at HZDR. stay at the Turku PET Centre, Finland (2014, Prof. O. Solin) His actual research interests are radiolabeled inhibitors of tyro- enriched his academic career. sine kinases (TKIs) and cyclooxygenase-2 (COX-2). 1714 | Med. Chem. Commun.,2015,6,1714–1754 This journal is © The Royal Society of Chemistry 2015 View Article Online MedChemComm Review Radiochemists have developed a number of methods of stronger than that when a methyl substituent is used (Δlog [18F]radiofluorination via electrophilic and nucleophilic path- P = 0.54).11 However, the increased lipophilicity originating ways for the incorporation of fluorine-18 into molecules of from the fluoroethyl group may be beneficial for addressing interest. Due to its ease of handling, direct nucleophilic specific targets or organs, e.g. the brain. From a radiochem- substitution using [18F]fluoride has been established as the ist's point of view, the [18F]fluoroethyl group may act as a preferred approach so far. However, the weak nucleophilic surrogate for a [11C]methyl radiolabel because it can be character of the fluoride ion often displays a major hin- coupled to the same functional groups. Precursors already drance. Aprotic conditions, highly reactive leaving groups, available for methylation with [11C]methyl iodide may be and in the case of aromatic nucleophilic substitution, an used without modification for [18F]fluoroethylation. This is electron-deficient aromatic system are the basic require- advantageous for the transfer of a promising 11C-labeled ments for successful incorporation of [18F]fluoride into an radiotracer into its 18F-labeled counterpart by exploita- organic molecule.5 Alternative labeling strategies have been tion of the longer half-life of fluorine-18. Besides that, developed, making use of so-called prosthetic groups [18F]fluoroethylation can be performed with unprotected by first attaching the radionuclide to a small bifunctional compounds and the reaction conditions are less reactive unit and their subsequent coupling to the target restricting in comparison to those for direct nucleophilic compound. An overview on prosthetic groups for substitution. 18F-radiolabeling comprising activated esters, aldehydes and [18F]FETs is one of the mostly used reagents for amines as well as halogenides, azide- and alkyne-based [18F]fluoroethylation due to its beneficial properties; it is easy small molecules can be found in a number of excellent to prepare, possesses low volatility, is almost stable and – reviews.6 8 Beyond this, [18F]fluoroalkylating agents like shows high reactivity in correspondence with some [18F]fluoromethyl bromide, 2-[18F]fluoroethyl bromide chemoselectivity. On the other hand, some disadvantages are ([18F]FEBr), 2-[18F]fluoroethyl triflate or 2-[18F]fluoroethyl known: (1) [18F]FETs may be sensitive to distinct solvents, 18 18 9 18 Creative Commons Attribution 3.0 Unported Licence. tosylate ([ F]FETs) or even [ F]fluorocyclobutyl tosylate bases and high temperatures, (2) [ F]FETs may react unselec- have gained increased interest because they provide high tively, e.g. if multiple hydroxyl and amino groups are present reactivity to phenolic, thiophenolic, carboxylic and amide in the target molecule, and (3) often, it shows inadequate functionalities.10 In general, the fluoroethyl group holds chemical purity. To circumvent the latter drawback, interme- similar steric properties like ethyl and methyl groups and is diate purification steps for [18F]FETs have been developed expected to maintain the pharmacological properties of a comprising solid phase extraction (SPE) as well as HPLC- lead compound. Compared to the methyl group, the fluoro- based procedures, partly remote-controlled, which as a conse- ethyl moiety is more lipophilic, so the shift in lipophilicity quence, afford the implementation of a two-pot radiolabeling by introduction of a fluoroethyl moiety (Δlog P = 0.70) is procedure.12,13 This article is licensed under a Peter Brust received his M.S. in Jörg Steinbach is the Director of Immunology in 1981 and his Ph. the Institute of Radiopharmaceu- Open Access Article. Published on 03 September 2015. Downloaded 9/24/2021 4:23:34 AM. D. in Neuroscience from Leipzig tical Cancer Research, University in 1986. He worked Helmholtz-Zentrum Dresden- as a postdoctoral fellow at Mon- Rossendorf and has been a Pro- treal Neurological Institute and fessor of Bioinorganic and Johns Hopkins University Balti- Radiopharmaceutical Chemistry more from 1990 to 1991. He at Technische Universität Dres- joined the Research Center den, Germany since 2005. • Rossendorf (now known as 2001–2009: Full Professor of Iso- Helmholtz-Zentrum Dresden- tope Research, Universität Leip- Rossendorf, HZDR) in 1992 and zig, Germany, Director, Institute Peter Brust headed the Department of Bio- Jörg Steinbach of Interdisciplinary Isotope chemistry. Since 2002, he has Research • 1992–2001:Head of worked in Leipzig first at the Institute of Interdisciplinary Isotope the PET Department, Institute of Bioinorganic and Radiopharma- Research and since 2010, after operational transfer, again at ceutical Chemistry, Forschungszentrum Dresden-Rossendorf • HZDR where he leads the Department of Radiopharmaceutical 1982–1991: Scientist, Central Institute of Nuclear Research Cancer Research. Since 2010, he has been an adjunct professor of Rossendorf, Department of Radioactive Isotopes • 1982: Ph.D. Radiopharmacy at Leipzig University. Inorganic Chemistry, Technical University Dresden • Research stays at Åbo Akademi, Turku, Finland (1986–1988), Research Fields • Radiochemistry and Radiopharmacy • Radiotracers and targeted radionuclide therapy • Radionuclide production and targetry. This journal is © The Royal Society of Chemistry 2015 Med. Chem. Commun.,2015,6,1714–1754 | 1715 View Article Online Review MedChemComm This review will summarize the role of [18F]FETs as a with phenol, [18F]FETs gave