• Production of PET Radionuclides

    The energy of the particle and the density of the beam particle as well as the cross section of the nuclear reaction itself, determine the quantity of radionuclide that can be produced in any time period. Experiments have shown that appropriate amounts of the four positron emitters commonly used in PET (15O, 13N, 11C and 18F) can be obtained with 10 MeV protons and 5 MeV deuterons to satisfy the clinical needs of most PET centres.
    Open Cyclotron.

    Radionuclides Nuclear reaction Production yield

    Oxygen-15 14N(d,n)15O 300mCi (12GBq)
    Nitrogen-13 16O(p,a)13N 100mCi (4GBq)
    Carbon-11 14N(p,a)11C 800mCi (32GBq)
    Fluorine-18 18O(p,n)18F 1000mCi (37GBq)

    These positron emitters are explained in more detail below:

    • Oxygen-15

      Oxygen-15 is produced by deuteron bombardment of natural nitrogen through the 14N(d,n)15O nuclear reaction. Oxygen-15 can be produced as molecular oxygen (15O2), or directly as carbon dioxide (C15O2) by mixing the target gas with 5% of natural carbon dioxide as a carrier. Carbon monoxide (C15O) can also be easily produced by reduction of C15O2 on activated charcoal at 900°C.

    • Carbon-11

      Carbon-11 is produced by proton bombardment of natural nitrogen through the 14N(p,a)11C nuclear reaction. A target gas mixture of 2% oxygen in nitrogen will produce radioactive carbon dioxide (11CO2) and 5% hydrogen in nitrogen will produce methane (11CH4). Carbon monoxide (11CO) can also be made by reduction of 11CO2 on activated charcoal at 900°C.

    • Nitrogen-13

      Nitrogen-13 is produced by proton bombardment of distilled water through the 16O(p,a)13N nuclear reaction. Even with the relatively low energy proton beam delivered by our cyclotron (10 MeV) a useful production yield of 100 mCi can be achieved with 20 minutes irradiation. The use of a scavenger for oxidising radicals, such as ethanol (5 mM), has been successfully used as to minimise in-target oxidation.

    • Fluorine-18

      Fluorine-18 is produced by proton bombardment of oxygen-18 enriched water through the 18O(p,n)18F nuclear reaction. Fluorine-18 is recovered as an aqueous solution of fluoride-18 (H2O/18F-), and can be easily extracted by ion-exchange chromatography. Ionic fluoride-18 can be transferred into an organic solvent and used for stereospecific nucleophilic substitutions. Routinely 800 mCi of fluorine-18 can be produced in one hour of irradiation. It is important to mention that fluorine-18 can also be produced as a radioactive gas through the 20Ne(d,a)18F nuclear reaction. This production method, which is useful for electrophilic substitution, requires the addition into the target of fluorine-19 gas as carrier, and is currently seen as a less attractive method.

  • The table below gives the list of the tracers/radiopharmaceuticals produced in our centre and an example of their biomedical applications.

    Radiotracers & radiopharmaceuticals Examples of biomedical applications

    [15O]oxygen oxygen metabolism
    [15O]carbon monoxide blood volume
    [15O]carbon dioxide blood flow
    [15O]water blood flow
    [13N]ammonia blood flow
    [18F]FDG glucose metabolism
    [18F]FMISO hypoxic tissue
    [18F]MPPF serotonin 5HT1A receptors
    [18F]A85380 nicotinic acetylcholine receptors
    [18F]FLT DNA proliferation
    [11C]SCH23390 dopamine DI receptor
    [11C]Ro151788 central benzodiazepine receptor
    [11C]PK11195 peripheral benzodiazepine receptor
    [11C]PIB amyloid plaque: Alzheimer's disease
    [11C]AG1478 EGF receptors
    [11C]choline biosynthesis of phospholipids
    under development:  
    [11C]AG957 BCR-abl receptors
    [18F]nitroisatin caspase-3 inhibitor
    [18F]mustard hypoxic tissue

    Radiopharmaceutical production in detail:

    15O-labelled oxygen or carbon dioxide and 13N-labelled ammonia are directly produced out of the target without further chemistry.

    15O-labelled water is produced on-line from 15O-oxygen after it is mixed with hydrogen, in a stoichiometric proportion, and passed over a palladium catalyst in an oven at 150°C. The radioactive water vapour diffuses across a semi-permeable membrane (cellulose acetate) into a sterile saline solution (0.9% NaCl). The saline solution is pumped continuously through the system with a medical infusion pump to generate a solution containing 15O-labelled water, which can be infused directly into the patient.
    System for on-line production of radioactive water.

    Radiofluorination, to produce 2-[18F]fluoro-2-deoxy-D-glucose (18FDG) and 1-(3-[18F]fluoro-2-hydroxypropyl)-2-nitroimidazole (18FMISO), requires a more sophisticated 2 step procedure shown below.

    Fluoro-radiosynthesier from IBA (Belgium).

    Labelling of both compounds is achieved using the nucleophilic substitution reaction of aminopolyether potassium complex [Kryotofix 2.2.2]18F- with the corresponding protected precursor. The trifluoromethansulfonyl analogue of mannopyranose and the tosyl analogue of misonidazole are used as the precursors for the preparation of 18FDG and 18FMISO respectively. The final de-protection step is achieved with either acid hydrolysis (14 min) or the faster base hydrolysis method (2 min). These methods give up to 600 mCi of 18FDG with a radiochemical yield close to 65% in a synthesis time of about 30 min from the end of bombardment. 18FMISO gives a lower yield (20% decay corrected) of up to 100 mCi after semi-preparative HPLC purification.

    For 11C-radiolabelling, currently the most commonly used method is through N-methylation using 11C-methyl iodide (11CH3I). The method of production of 11CH3I is via the reduction of 11CO2 using LiAlH4, followed by aqueous HI reaction. This method suffers from the major disadvantage of natural carbon dioxide (12CO2) contamination, resulting in a much lower specific activity of 11CH3I than the original 11CO2. The theoretical specific activity of 11CO2 produced could be as high as 10 Ci/pmol but could drop below 1 Ci/umol for the final labelled product. Theoretically, with 11C, any organic molecule could be labelled by isotopic substitution of 11C for natural carbon, retaining the full properties of the parent molecule. In reality the short half-life of this radioisotope imposes some constraints on labelling strategies. 11C-radiolabelling of both SCH23390 and flumazenil are achieved by 11C-methylation of the suitable precursor (desmethyl compound) using 11C-methyl iodide (see below). 11C-radiolabelling of both SCH23390 and flumazenil are achieved by 11C-methylation of the suitable precursors (desmethyl compound) using 11C-methyl iodide (see below).

    Due to the rapid radioactive decay of carbon-11 (t½=20 min), time is an important constraint and the multi-step radiosynthesis is performed in an automated chemistry module in 45 minutes including high performance liquid chromatography purification. In a typical experiment, over 100 mCi (4 GBq) of purified 11C-radiopharmaceutical is prepared (decay corrected yield >40%) with a specific activity higher than 1 Ci/mmol at the end of synthesis.

Facilities/Equipment    |    Basic Principle of PET
PET Radionuclides & Radiopharmaceuticals
Radiopharmacy    |    PET Nuclear Physics & Tomography
PET Principles of Tracer Modelling    |    Clinical Applications