Advertisement

The Radiopharmaceutical Chemistry of Carbon-11: Tracers and Applications

  • Verena Pichler
  • Neydher Berroterán-Infante
  • Marius Ozenil
  • Sarah Pfaff
  • Cécile Philippe
  • Wolfgang WadsakEmail author
Chapter

Abstract

In this chapter, several different aspects of carbon-11 radiochemistry are discussed, including general and technical considerations surrounding the setup for 11C-radiosyntheses and specific radiolabeling routes for the preparation of 11C-labeled radiotracers. Both equipment and procedures have to be thoroughly optimized for the radiosynthesis and quality control testing of radiopharmaceuticals labeled with the short-lived radionuclide carbon-11. In particular, special attention has to be paid to time reduction in all processes while concomitantly maintaining accuracy and reproducibility. The synthetic possibilities for 11C-labeled radiotracers resemble a multicolored bouquet of flowers, with methods ranging from gas-phase reactions to in-loop syntheses and from rather simple 11C-methylations to more complex 11C-carbonylations or even tricky multistep Grignard reactions. A variety of synthons—including [11C]CH3I, [11C]HCN, [11C]CS2, and [11C]CO—can be used to prepare a plethora of radiotracers containing 11C-labels at desired positions in the target molecule without altering its physicochemical and biological properties. This may seem to be a heaven for radiochemists where only the sky is the limit. However, the reality is unfortunately quite different, as several critical limitations are placed upon 11C-radiochemists, including time constraints as well as the need for sufficient yields and molar activities. Nevertheless, you will find plenty of examples within this chapter in which scientists have overcome these obstacles and were able to set up feasible synthetic routes that demonstrate the beauty of 11C-radiochemistry.

Keywords

Synthesizer Post-target production In-loop reactions Molar activity 

References

  1. 1.
    Shao X, Hoareau R, Runkle AC, Tluczek LJM, Hockley BG, Henderson BD, et al. Highlighting the versatility of the Tracerlab synthesis modules. Part 2: fully automated production of [11C]-labeled radiopharmaceuticals using a Tracerlab FX C-pro. J Label Compd Radiopharm. 2011;54(14):819–38.Google Scholar
  2. 2.
    European Directorate for the Quality of Medicines (EDQM). Parenteral Preparations. In: European Pharmacopoeia, 9th Edition. Strasbourg: Council of Europe; 2015. pp. 871–3.Google Scholar
  3. 3.
    Gómez-Vallejo V, Llop J. Specific activity of [11C]CH3I synthesized by the “wet” method: main sources of non-radioactive carbon. Appl Radiat Isotop. 2009;67(1):111–4.CrossRefGoogle Scholar
  4. 4.
    Långström B, Lundqvist H. The preparation of 11C-methyl iodide and its use in the synthesis of 11C-methyl-L-methionine. Int J Appl Radiat Isot. 1976;27(7):357–63.CrossRefGoogle Scholar
  5. 5.
    Larsen P, Ulin J, Dahlstrom K, Jensen M. Synthesis of [11C]iodomethane by iodination of [11C]methane. Appl Radiat Isotop. 1997;48(2):153–7.CrossRefGoogle Scholar
  6. 6.
    Jewett DM. A simple synthesis of [11C]methyl triflate. Int J Radiat Appl Instrum A. 1992;43(11):1383–5.CrossRefGoogle Scholar
  7. 7.
    Ermert J, Coenen HH. Methods for 11C- and 18F-labelling of amino acids and derivatives for positron emission tomography imaging. J Label Compd Radiopharm. 2013;56(3–4):225–36.CrossRefGoogle Scholar
  8. 8.
    Crippa F, Alessi A, Serafini GL. PET with radiolabeled aminoacid. Q J Nucl Med Mol Imaging. 2012;56(2):151–62.PubMedGoogle Scholar
  9. 9.
    Visser AKD, van Waarde A, Willemsen ATM, Bosker FJ, Luiten PGM, den Boer JA, et al. Measuring serotonin synthesis: from conventional methods to PET tracers and their (pre)clinical implications. Eur J Nucl Med Mol Imaging. 2011;38(3):576–91.CrossRefGoogle Scholar
  10. 10.
    Diksic M, Nagahiro S, Sourkes TL, Yamamoto YL. A new method to measure brain serotonin synthesis in vivo. I. Theory and basic data for a biological model. J Cereb Blood Flow Metab. 1990;10(1):1–12.CrossRefGoogle Scholar
  11. 11.
    Huang X, Xiao X, Gillies RJ, Tian H. Design and automated production of 11C-alpha-methyl-l-tryptophan (11C-AMT). Nucl Med Biol. 2016;43(5):303–8.CrossRefGoogle Scholar
  12. 12.
    Chakraborty PK, Mangner TJ, Chugani DC, Muzik O, Chugani HT. A high-yield and simplified procedure for the synthesis of α-[11C]methyl-l-tryptophan. Nucl Med Biol. 1996;23(8):1005–8.CrossRefGoogle Scholar
  13. 13.
    Reske SN, Blumstein NM, Neumaier B, Gottfried H-W, Finsterbusch F, Kocot D, et al. Imaging prostate cancer with 11C-choline PET/CT. J Nucl Med. 2006;47(8):1249–54.PubMedGoogle Scholar
  14. 14.
    Engkvist O, Wrede P, Rester U. Prediction of CNS activity of compound libraries using substructure analysis. J Chem Inf Comput Sci. 2003 Jan 1;43(1):155–60.CrossRefGoogle Scholar
  15. 15.
    Cohen AD, Klunk WE. Early detection of Alzheimer’s disease using PiB and FDG PET. Neurobiol Dis. 2014;72(Pt A):117–22.CrossRefGoogle Scholar
  16. 16.
    Philippe C, Haeusler D, Mitterhauser M, Ungersboeck J, Viernstein H, Dudczak R, et al. Optimization of the radiosynthesis of the Alzheimer tracer 2-(4-N[11C]methylaminophenyl)-6-hydroxybenzothiazole ([11C]PIB). Appl Radiat Isot. 2011;69(9):1212–7.CrossRefGoogle Scholar
  17. 17.
    Haeusler D, Mien L-K, Nics L, Ungersboeck J, Philippe C, Lanzenberger RR, et al. Simple and rapid preparation of [11C]DASB with high quality and reliability for routine applications. Appl Radiat Isot. 2009;67(9):1654–60.CrossRefGoogle Scholar
  18. 18.
    Philippe C, Zeilinger M, Mitterhauser M, Dumanic M, Lanzenberger R, Hacker M, et al. Parameter evaluation and fully-automated radiosynthesis of [11C]harmine for imaging of MAO-A for clinical trials. Appl Radiat Isot. 2015;97:182–7.CrossRefGoogle Scholar
  19. 19.
    Rotstein BH, Liang SH, Holland JP, Collier TL, Hooker JM, Wilson AA, Vasdev N. 11CO2 fixation: a renaissance in PET radiochemistry. Chem Commun (Camb). 2013;49(59):5621–9.CrossRefGoogle Scholar
  20. 20.
    Mossine AV, Brooks AF, Jackson IM, Quesada CA, Sherman P, Cole EL, et al. Synthesis of diverse 11C-labelled PET radiotracers via direct incorporation of [11C]CO2. Bioconjug Chem. 2016;27(5):1382–9.CrossRefGoogle Scholar
  21. 21.
    Pike VW, Eakins MN, Allan RM, Selwyn AP. Preparation of [1−11C]acetate—an agent for the study of myocardial metabolism by positron emission tomography. Int J Appl Radiat Isot. 1982;33(7):505–12.CrossRefGoogle Scholar
  22. 22.
    Rami-Mark C, Unbergsboek J, Haeusler D, Nics L, Philippe C, Mitterhauser M, et al. Reliable set-up for in-loop 11C-carboxylations using Grignard reactions for the preparation of [carbonyl-11C]WAY-100635 and [11C]-(+)-PHNO. Appl Radiat Isot. 2013;82:75–80.CrossRefGoogle Scholar
  23. 23.
    Mitterhauser M, Wadsak W, Krcal A, Schmaljohann J, Bartosch E, Eidherr H, et al. New aspects on the preparation of [11C]acetate—a simple and fast approach via distillation. Appl Radiat Isot. 2004;61(6):1147–50.CrossRefGoogle Scholar
  24. 24.
    Soloviev D, Tamburella C. Captive solvent [11C]acetate synthesis in GMP conditions. Appl Radiat Isot. 2006;64(9):995–1000.CrossRefGoogle Scholar
  25. 25.
    Plisson C, Huiban M, Pampols-Maso S, Singleton G, Hill SP, Passchier J. Automated preparation of the dopamine D2/3 receptor agonist ligand [11C]-(+)-PHNO for human PET imaging studies. Appl Radiat Isot. 2012;70(2):380–7.CrossRefGoogle Scholar
  26. 26.
    Wilson AA, McCormick P, Kapur S, Willeit M, Garcia A, Hussey D, et al. Radiosynthesis and evaluation of [ 11 C]-(+)-4-Propyl-3,4,4a,5,6,10b-hexahydro-2 H -naphtho[1,2- b ][1,4]oxazin-9-ol as a potential radiotracer for in vivo imaging of the dopamine D2 high-affinity state with positron emission tomography. J Med Chem. 2005;48(12):4153–60.CrossRefGoogle Scholar
  27. 27.
    Oya S, Joseph SK, Carberry P, Divgi CR, Koren AO. Preparation of [11C]-(+)-PHNO using an automated synthesizer coupled with a stand-alone system for making [11C]propionyl chloride. J Label Compd Radiopharm. 2013;56:466.Google Scholar
  28. 28.
    Dahl K, Halldin C, Schou M. New methodologies for the preparation of carbon-11 labeled radiopharmaceuticals. Clin Transl Imaging. 2017;5(3):275–89.CrossRefGoogle Scholar
  29. 29.
    Kealey S, Gee A, Miller PW. Transition metal mediated [11C]carbonylation reactions: recent advances and applications. J Label Compd Radiopharm. 2014;57(4):195–201.CrossRefGoogle Scholar
  30. 30.
    Hooker JM, Schönberger M, Schieferstein H, Fowler JS. A simple, rapid method for the preparation of [11C]formaldehyde. Angew Chem Int Ed Engl. 2008;47(32):5989–92.CrossRefGoogle Scholar
  31. 31.
    Wu C, Li R, Dearborn D, Wang Y. Reductive amination with [11C]formaldehyde: a versatile approach to radiomethylation of amines. Int J Org Chem. 2012;2(3):202–23.CrossRefGoogle Scholar
  32. 32.
    Ogawa M, Takada Y, Suzuki H, Nemoto K, Fukumura T. Simple and effective method for producing [11C]phosgene using an environmental CCl4 gas detection tube. Nucl Med Biol. 2010;37(1):73–6.CrossRefGoogle Scholar
  33. 33.
    Roger G, Dollé F, de Bruin B, Liu X, Besret L, Bramoullé Y, et al. Radiosynthesis and pharmacological evaluation of [11C]EMD-95885: a high affinity ligand for NR2B-containing NMDA receptors. Bioorg Med Chem. 2004;12(12):3229–37.CrossRefGoogle Scholar
  34. 34.
    Scott PJH. Radiochemical syntheses. Volume 2: further radiopharmaceuticals for positron emission tomography and new strategies for their production. Hoboken: John Wiley & Sons; 2015.CrossRefGoogle Scholar
  35. 35.
    Ma L, Placzek MS, Hooker JM, Vasdev N, Liang SH. [11C]Cyanation of arylboronic acids in aqueous solutions. Chem Commun (Camb). 2017;53(49):6597–600.CrossRefGoogle Scholar
  36. 36.
    Haywood T, Kealey S, Sánchez-Cabezas S, Hall JJ, Allott L, Smith G, et al. Carbon-11 radiolabelling of organosulfur compounds: 11C synthesis of the progesterone receptor agonist tanaproget. Chem Eur J. 2015;21:9034–8.CrossRefGoogle Scholar
  37. 37.
    Pascali C, Bogni A, Iwata R, Cambiè M, Bombardieri E. [11C]Methylation on a C18 Sep-Pak cartridge: a convenient way to produce [N-methyl-11C]choline. J Labelled Comp Radiopharm. 2000;43:195–203.Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Verena Pichler
    • 1
  • Neydher Berroterán-Infante
    • 1
  • Marius Ozenil
    • 1
  • Sarah Pfaff
    • 1
  • Cécile Philippe
    • 1
  • Wolfgang Wadsak
    • 1
    Email author
  1. 1.Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear MedicineMedical University of ViennaViennaAustria

Personalised recommendations