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[ 11 C] precursor production possibilities: Consequences for the synthesis of radiopharmaceuticals

[ 11 C] precursor production possibilities: Consequences for the synthesis of radiopharmaceuticals Group 1 Sevinc Ugurlu Domin i ka Wozniczko Jochen Schmitz Postgraduate Diploma Course Radiopharmaceutical Chemistry / Radiopharmacy

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[ 11 C] precursor production possibilities: Consequences for the synthesis of radiopharmaceuticals

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  1. [11C] precursor production possibilities: Consequences for the synthesis of radiopharmaceuticals Group 1 Sevinc Ugurlu Dominika Wozniczko Jochen Schmitz Postgraduate Diploma Course Radiopharmaceutical Chemistry / Radiopharmacy Radiopharmaceutical Chemistry in Zurich, February 4-15, 2008

  2. [11C] – When? • [11C] is a suitable isotope when the study window for the study process is within 20-90 min. When we aim to study the metabolism and uptake of an endogenous molecule [11C] is the only suitable PET isotope. • When the protocol includes repeated PET studies on the same day in the same subject with different tracer or the same (pharmacological intervention) tracer • When effect of multiple labelling positions on the metabolism and uptake of PET radiopharmaceuticals is studied in order to optimize target specificity and minimize background. • [11C] radiopharmaceuticals can succesfully be used in drug development, research and clinical practice.

  3. [11C] – Why ? • [11C] can be routinely produced by small cyclotrones (10 MeV) • Targets for production of methane and carbon dioxide are commercially available • Labelled precursors and labelling reaction have been developed enabling vast production of [11C] radiopharmaceuticals • Carbon is an endogenous element and it forms the backbone of all organic molecules, thus [11C] gives the possiblity of labelling (in different position of the same molecule ) the endogenous and exogenous compounds without changing their physical properties • [11C] enables repeated PET studies on the same subject in the same day with different multitracers or the same pharmacological intervention tracer

  4. Decay Characteristics of [11C] • Half-life = 20.3 min ! • Decay modes: 99.8% by positron emission 0.2 % by electron capture • Decay product: 11B • Maximal positron energy = 0.96 MeV

  5. General considerations in radiochemistry with [11C] • Cyclotron at place of synthesis is mandatory • Reaction times should be as short as possible • Therefore 11C-labeling agents should be highly reactive • High starting activities require automated syntheses for radiation protection reasons

  6. The Time Factor

  7. Production Methods for [11C] Currently, the 14N(p,α) [11C] reaction is nearly always used

  8. Typical Production Parameters • Varies greatly according to production system (target etc). • Values up to 100 Ci/μmol (3.7 TBq/μmol) are possible for • [11C]methane.

  9. [11C]Labeling Agents Derivedfrom Irradiation Products • Use of Cyclotron-produced [11C] Carbon Dioxide to Prepare Labeling Agents • Use of Cyclotron-produced [11C] Methane to Prepare Labeling Agents

  10. Production of [11C]

  11. Examples of [11C]-labeled precursors

  12. Preparation of [11C]methyl iodide • [11C]methyl iodide is the classic methylation agent, which is usually synthesised by two common ways : • The „wet” method • The „gas phase” method

  13. The „wet“ method

  14. Preparation of Methyl Iodide from triphenyl-phosphine diiodide

  15. The „gas phase“ method

  16. Preparation of [11C]methyl triflate [11C] Methyl triflate is more reactive than methyl iodide and therefore provides a reasonable method to methylate sensitive compounds in good yields Preparation time : ~10 – 15 min Production efficiency: 70 % [11C] methyl nonaflate is even more reactive !!

  17. [11C]methy triflate vs. [11C]methyl iodid • Higher radiochemical yield • Shorter synthesis time • Higher specific activity • Less precursor needed

  18. Other precursors There is a variety of other [11C] precursors available like: • [11C] Ethyl iodide • [11C] Formaldehyde • [11C] Hydrogen cyanide • These offer a wide range of labelling possibilities.

  19. Summary • [11C] radiochemistry has to be performed in lead shelded environment (hot boxes) in order to protect the chemist from radiation • Time is a very important constraint, production must be performed within 60 min (usulally 20-45min) including purification,evaporation, formulation. • The amounts of reagents are small and transformations are performed in closed systems, mainly on-line according to GMP regulations

  20. Summary – cont. • The use of [11C] enables labelling of large number of endo and exogenous compounds often in different positions of the same molecule without changing their physical properties • A vast number of [11C] radiopharmaceuticals can be produced from [11C] methyl iodate and [11C] methyl triflate. Commercial devices for the production of these precursors are available. The gas phase method from [11C] methane gives high specific radioactivity • [11C] radiopharmaceuticals can succesfully be used in drug development, research and clinical practice

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