-
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.
|
 |
|
| 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.
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.
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.
|
|
