Synthesis of 18FDG
  1. USP <823> is the regulatory aspect when compounding of PET radio-tracers
    1. Issue - testing for endotoxins and pathogens on radiopharmaceuticals that have very short lived agents
      1. LAL - https://pubmed.ncbi.nlm.nih.gov/8441042/
      2. Systematic review of bacteria testing for PET radiopharmaceuticals - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6406348/
      3. How might the testing of bacteria and radiopharmaceutical half-life be an issue?
    2. All cyclotrons now require a manufacturer license. This includes hospital base units
  2. Nuclear medicine has been reclassified to include the the words molecular imaging. Why?
    1. Basic agents used in PET are elements related to human life at the cellular level:  C, N, O, F
    2. Relates to its concept of molecular imaging
  3. Application of Nucleophilic Substitution (important) to the production of 18FDG
    1. Is a reaction where there is an electron-rich group exchanging with positively charged group of atoms by replacing that group of atoms.
    2. Consider OSO2F3 (has many electron available in its shell) leaving and the 18F (has one electron shell empty) replacing as seen below

      3.  

       

      Nucleophilic substitution leads to hydrolysis that produces FDG

      1. Mannose Triflate (1) is the initial component needed to develop FDG
      2. Trimethly sulfate (OSO2CF3) is the leaving group within the carbon ring that is (2) replaced by 18F via nucleophilic substitution
      3. Acetal groups (H3COCO and OCOCH3) are removed and replaced with OH via hydrolysis, resulting in FDG (3)
        1. This is accomplished by adding an acid or a base
        2. Hydrolysis is then applied with heat and HCl
      4. Note the above reactions are color coded

      5. Once FDG has be produced
        1. Acetone and acetanitriles helps clean/remove contaminates from the tracer solution
        2. Usually occurs in columns
        3. Micropore filter is used to assist in sterilization and filtering of the final product 18FDG
      6. The details of compounding via Wikipedia

        1. Separate 18F from solution by trapping it on an ion-exchange column which is then mixed with acetonitrile solution of 2,2,2-cryptand and potassium carbonate
        2. Evaporation yields [(crypt-222)K+]18F- - This generates #2
        3. Mannose triflate is then added where 18F reacts with triflate (OSO2CF4) via nucleophilic substitution #3
        4. HCl causes hydrolysis removing the acetly group #4
        5. Yields 50-80% FDG
    3. This is how SNMMI-TS study guide explains the production of FDG (there is some differences)
      1. 18F is extracted from the targeted solution via a tube and placed into a hot cell for FDG synthesis and place into an ionic exchange cartridge
      2. 18F is then eluted from the cartridge with potassium carbonate (Kryptofix 222) and acetonitrile and placed into a reactor vessel
      3. Heating evaporates and removes solvents and the mannose triflate is added
      4. Heating replaces the triflate group with 18F via nucleophilic substitution
      5. Results is 18F -FTAg
      6. Alkaline hydrolysis then removes OCOCH and replaces it with OH producing 18F-FDG
      7. Sterile water and neutralizing solution is applied which removes the free 18F atoms and any other contaminants
      8. Finally the solution is passed through a 0.22 μ
    4. Everything is now done on cassettes that contains all the necessary compounds to label 18F
      1. Very efficient
      2. Has all the components needed to tag
      3. Hook up the lap top to monitor and control the reaction
      4. Compounding of FDG takes about 30 minutes
      5. Other types of nucleophilic substitution may have other problems (ex)
        1. 18Fluorothymidine (FLT) gives a 6 - 12% yield
        2. Cleanup becomes more difficult:  requires pressure device, separations, and then capturing the labeled compound
        3. Cost $50k to $250k
    5. QC on FDG (prior to patient use)
      1. Visual - is it clear and colorless and lacks particles
      2. Filter member integrity - air pressure test to make sure that the filter isn't broken
      3. Radiochemical purity - <4% free
      4. Radionuclide purity - Where are the peaks 511 and 1024 keV are acceptable (why is 1024 keV acceptable?)
      5. Radionuclide identity - measure decay to make sure that T1/2 is 109 minutes
      6. pH - must be between 5.5 to 7.5
      7. Pyrogens/endotoxins - LAL test
      8. Chemical purity - other impurities are missing when applying gas and thin layer chromatography using Kryptofix 222
        1. Different products appear at different times on the graph
        2. Radiolysis
        3. HPLC - High Pressure Liquid Chromatography
      9. Sterility - Soy broth to see what might grow (takes 2 weeks) - what's the problem with this testing?
      10. 2-chloro-2-Deoxy-Dglucose - this can occur when HCl hydrolysis occurs instead of NaOH
    6. Must be made in a clean room where the compounding room is a class 100 room and the person enters the room from a class 1000 room - sterile environment

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