A Transmetalation Reaction Enables the Synthesis of [F]5-Fluorouracil from [F]Fluoride for Human PET Imaging

Overview

Journal Organometallics

Publisher American Chemical Society

Date 2016 Apr 19

PMID 27087736

Citations 25

Authors

Andrew J Hoover

Mark Lazari

Hong Ren

Maruthi Kumar Narayanam

Jennifer M Murphy

R Michael van Dam

Jacob M Hooker

Tobias Ritter

Affiliations

Soon will be listed here.

Abstract

Translation of new F-fluorination reactions to produce radiotracers for human positron emission tomography (PET) imaging is rare because the chemistry must have useful scope and the process for F-labeled tracer production must be robust and simple to execute. The application of transition metal mediators has enabled impactful F-fluorination methods, but to date none of these reactions have been applied to produce a human-injectable PET tracer. In this article we present chemistry and process innovations that culminate in the first production from [F]fluoride of human doses of [F]5-fluorouracil, a PET tracer for cancer imaging in humans. The first preparation of nickel σ-aryl complexes by transmetalation from arylboronic acids or esters was developed and enabled the synthesis of the [F]5-fluorouracil precursor. Routine production of >10 mCi doses of [F]5-fluorouracil was accomplished with a new instrument for azeotrope-free [F]fluoride concentration in a process that leverages the tolerance of water in nickel-mediated F-fluorination.

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References

Bergman J, Solin O . Fluorine-18-labeled fluorine gas for synthesis of tracer molecules. Nucl Med Biol. 1997; 24(7):677-83. DOI: 10.1016/s0969-8051(97)00078-4. View

Park N, Teverovskiy G, Buchwald S . Development of an air-stable nickel precatalyst for the amination of aryl chlorides, sulfamates, mesylates, and triflates. Org Lett. 2013; 16(1):220-3. PMC: 3926134. DOI: 10.1021/ol403209k. View

Gonzalez-Bobes F, Fu G . Amino alcohols as ligands for nickel-catalyzed suzuki reactions of unactivated alkyl halides, including secondary alkyl chlorides, with arylboronic acids. J Am Chem Soc. 2006; 128(16):5360-1. DOI: 10.1021/ja0613761. View

Kissel J, Brix G, Bellemann M, Strauss L, Dimitrakopoulou-Strauss A, Port R . Pharmacokinetic analysis of 5-[18F]fluorouracil tissue concentrations measured with positron emission tomography in patients with liver metastases from colorectal adenocarcinoma. Cancer Res. 1997; 57(16):3415-23. View

Huang X, Liu W, Hooker J, Groves J . Targeted fluorination with the fluoride ion by manganese-catalyzed decarboxylation. Angew Chem Int Ed Engl. 2015; 54(17):5241-5. DOI: 10.1002/anie.201500399. View

Tredwell M, Preshlock S, Taylor N, Gruber S, Huiban M, Passchier J . A general copper-mediated nucleophilic 18F fluorination of arenes. Angew Chem Int Ed Engl. 2014; 53(30):7751-5. DOI: 10.1002/anie.201404436. View

Saleem A, Yap J, Osman S, Brady F, Suttle B, Lucas S . Modulation of fluorouracil tissue pharmacokinetics by eniluracil: in-vivo imaging of drug action. Lancet. 2000; 355(9221):2125-31. DOI: 10.1016/s0140-6736(00)02380-1. View

Harte R, Matthews J, OReilly S, Price P . Sources of error in tissue and tumor measurements of 5-[18F]fluorouracil. J Nucl Med. 1998; 39(8):1370-6. View

Standley E, Jamison T . Simplifying nickel(0) catalysis: an air-stable nickel precatalyst for the internally selective benzylation of terminal alkenes. J Am Chem Soc. 2013; 135(4):1585-92. PMC: 3564234. DOI: 10.1021/ja3116718. View

10.

Teare H, Robins E, Kirjavainen A, Forsback S, Sandford G, Solin O . Radiosynthesis and evaluation of [18F]Selectfluor bis(triflate). Angew Chem Int Ed Engl. 2010; 49(38):6821-4. DOI: 10.1002/anie.201002310. View

11.

Dimitrakopoulou-Strauss A, Strauss L, Schlag P, Hohenberger P, Irngartinger G, Oberdorfer F . Intravenous and intra-arterial oxygen-15-labeled water and fluorine-18-labeled fluorouracil in patients with liver metastases from colorectal carcinoma. J Nucl Med. 1998; 39(3):465-73. View

12.

Shields J, Gray E, Doyle A . A modular, air-stable nickel precatalyst. Org Lett. 2015; 17(9):2166-9. PMC: 4719147. DOI: 10.1021/acs.orglett.5b00766. View

13.

Ren H, Wey H, Strebl M, Neelamegam R, Ritter T, Hooker J . Synthesis and imaging validation of [¹⁸F]MDL100907 enabled by Ni-mediated fluorination. ACS Chem Neurosci. 2014; 5(7):611-5. PMC: 4102961. DOI: 10.1021/cn500078e. View

14.

Schley N, Fu G . Nickel-catalyzed Negishi arylations of propargylic bromides: a mechanistic investigation. J Am Chem Soc. 2014; 136(47):16588-93. PMC: 4277758. DOI: 10.1021/ja508718m. View

15.

Keen A, Doster M, Johnson S . 1,4-shifts in a dinuclear Ni(I) biarylyl complex: a mechanistic study of C-H bond activation by monovalent nickel. J Am Chem Soc. 2007; 129(4):810-9. DOI: 10.1021/ja067112w. View

16.

Dimitrakopoulou A, Strauss L, Clorius J, Ostertag H, Schlag P, Heim M . Studies with positron emission tomography after systemic administration of fluorine-18-uracil in patients with liver metastases from colorectal carcinoma. J Nucl Med. 1993; 34(7):1075-81. View

17.

Camasso N, Sanford M . Design, synthesis, and carbon-heteroatom coupling reactions of organometallic nickel(IV) complexes. Science. 2015; 347(6227):1218-20. DOI: 10.1126/science.aaa4526. View

18.

Ichiishi N, Brooks A, Topczewski J, Rodnick M, Sanford M, Scott P . Copper-catalyzed [18F]fluorination of (mesityl)(aryl)iodonium salts. Org Lett. 2014; 16(12):3224-7. PMC: 4076000. DOI: 10.1021/ol501243g. View

19.

Graham T, Lambert R, Ploessl K, Kung H, Doyle A . Enantioselective radiosynthesis of positron emission tomography (PET) tracers containing [¹⁸F]fluorohydrins. J Am Chem Soc. 2014; 136(14):5291-4. DOI: 10.1021/ja5025645. View

20.

Moehler M, Dimitrakopoulou-Strauss A, Gutzler F, Raeth U, Strauss L, Stremmel W . 18F-labeled fluorouracil positron emission tomography and the prognoses of colorectal carcinoma patients with metastases to the liver treated with 5-fluorouracil. Cancer. 1998; 83(2):245-53. View