[ C]Fluoroform, a Breakthrough for Versatile Labeling of PET Radiotracer Trifluoromethyl Groups in High Molar Activity

Overview

Journal Chemistry

Specialty Chemistry

Date 2017 May 18

PMID 28514059

Citations 16

Authors

Mohammad B Haskali

Victor W Pike

Affiliations

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Abstract

Positron-emission tomography (PET) is an immensely important imaging modality in biomedical research and drug development but must use selective radiotracers to achieve biochemical specificity. Such radiotracers are usually labeled with carbon-11 (t =20 min) or fluorine-18 (t =110 min), but these are only available from cyclotrons in a few simple chemical forms. [ F]Fluoroform has emerged for labeling tracers in trifluoromethyl groups but is severely limited in utility by low radioactivity per mass (low molar activity). Here, the synthesis of [ C]fluoroform is described, based on CoF -mediated fluorination of cyclotron-produced [ C]methane. This process is efficient and repetitively reliable. [ C]Fluoroform shows versatility for labeling small molecules in very high molar activity (>200 GBq μmol ), far exceeding that possible by using [ F]fluoroform. Therefore, [ C]fluoroform represents a major breakthrough for labeling prospective PET tracers in trifluoromethyl groups at high molar activity.

Citing Articles

Isotopologues of potassium 2,2,2-trifluoroethoxide for applications in positron emission tomography and beyond.

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Copper(I)-free syntheses of [C/F]trifluoromethyl ketones from alkyl or aryl esters and [C/F]fluoroform.

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References

Ruhl T, Rafique W, Lien V, Riss P . Cu(I)-mediated (18)F-trifluoromethylation of arenes: rapid synthesis of (18)F-labeled trifluoromethyl arenes. Chem Commun (Camb). 2014; 50(45):6056-9. DOI: 10.1039/c4cc01641f. View

Lien V, Riss P . Radiosynthesis of [18)F]trifluoroalkyl groups: scope and limitations. Biomed Res Int. 2014; 2014:380124. PMC: 4119740. DOI: 10.1155/2014/380124. View

van der Born D, Herscheid J, Orru R, Vugts D . Efficient synthesis of [18F]trifluoromethane and its application in the synthesis of PET tracers. Chem Commun (Camb). 2013; 49(38):4018-20. DOI: 10.1039/c3cc37833k. View

Prakash G, Jog P, Batamack P, Olah G . Taming of fluoroform: direct nucleophilic trifluoromethylation of Si, B, S, and C centers. Science. 2012; 338(6112):1324-7. DOI: 10.1126/science.1227859. View

Pike V . PET radiotracers: crossing the blood-brain barrier and surviving metabolism. Trends Pharmacol Sci. 2009; 30(8):431-40. PMC: 2805092. DOI: 10.1016/j.tips.2009.05.005. View

Huiban M, Tredwell M, Mizuta S, Wan Z, Zhang X, Collier T . A broadly applicable [18F]trifluoromethylation of aryl and heteroaryl iodides for PET imaging. Nat Chem. 2013; 5(11):941-4. DOI: 10.1038/nchem.1756. View

Pike V . Considerations in the Development of Reversibly Binding PET Radioligands for Brain Imaging. Curr Med Chem. 2016; 23(18):1818-69. PMC: 5579844. DOI: 10.2174/0929867323666160418114826. View

Kawai H, Yuan Z, Tokunaga E, Shibata N . A sterically demanding organo-superbase avoids decomposition of a naked trifluoromethyl carbanion directly generated from fluoroform. Org Biomol Chem. 2013; 11(9):1446-50. DOI: 10.1039/c3ob27368g. View

Bassetto M, Ferla S, Pertusati F . Polyfluorinated groups in medicinal chemistry. Future Med Chem. 2015; 7(4):527-46. DOI: 10.4155/fmc.15.5. View

10.

Hume S, Gunn R, Jones T . Pharmacological constraints associated with positron emission tomographic scanning of small laboratory animals. Eur J Nucl Med. 1998; 25(2):173-6. DOI: 10.1007/s002590050211. View

11.

Jagoda E, Vaquero J, Seidel J, Green M, Eckelman W . Experiment assessment of mass effects in the rat: implications for small animal PET imaging. Nucl Med Biol. 2004; 31(6):771-9. DOI: 10.1016/j.nucmedbio.2004.04.003. View

12.

Ivashkin P, Lemonnier G, Cousin J, Gregoire V, Labar D, Jubault P . [(18) F]CuCF3 : a [(18) F]trifluoromethylating agent for arylboronic acids and aryl iodides. Chemistry. 2014; 20(31):9514-8. DOI: 10.1002/chem.201403630. View

13.

Madsen K, Marner L, Haahr M, Gillings N, Knudsen G . Mass dose effects and in vivo affinity in brain PET receptor studies--a study of cerebral 5-HT4 receptor binding with [11C]SB207145. Nucl Med Biol. 2011; 38(8):1085-91. DOI: 10.1016/j.nucmedbio.2011.04.006. View

14.

Lapi S, Welch M . A historical perspective on the specific activity of radiopharmaceuticals: what have we learned in the 35 years of the ISRC?. Nucl Med Biol. 2012; 39(5):601-8. DOI: 10.1016/j.nucmedbio.2011.11.005. View

15.

Lishchynskyi A, Berthon G, Grushin V . Trifluoromethylation of arenediazonium salts with fluoroform-derived CuCF3 in aqueous media. Chem Commun (Camb). 2014; 50(71):10237-40. DOI: 10.1039/c4cc04930f. View

16.

Andersson J, Truong P, Halldin C . In-target produced [11C]methane: Increased specific radioactivity. Appl Radiat Isot. 2008; 67(1):106-10. DOI: 10.1016/j.apradiso.2008.09.010. View

17.

van der Born D, Sewing C, Herscheid J, Windhorst A, Orru R, Vugts D . A universal procedure for the [¹⁸F]trifluoromethylation of aryl iodides and aryl boronic acids with highly improved specific activity. Angew Chem Int Ed Engl. 2014; 53(41):11046-50. DOI: 10.1002/anie.201406221. View