c S



S
 


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.

g


    
 

14
Oxygen-15 N(d,n)15O 300mCi (12GBq)
16
Nitrogen-13 O(p,9)13N 100mCi (4GBq)
14
Carbon-11 N(p,9)11C 800mCi (32GBq)
18
Fluorine-18 O(p,n)18F 1000mCi (37GBq)

These positron emitters are explained in more detail below:

c 


Oxygen-15 is produced by deuteron bombardment of natural nitrogen through the

14
N(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.

c a 


Carbon-11 is produced by proton bombardment of natural nitrogen through the

14
N(p,9)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.
 c J


Nitrogen-13 is produced by proton bombardment of distilled water through the

16
O(p,9)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.

c 


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,9)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.

g
   
       
   

[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


 
[11C]AG957 BCR-abl receptors
[18F]nitroisatin caspase-3 inhibitor
[18F]mustard hypoxic tissue

g
    
 
 

15
O-labelled oxygen or carbon dioxide and 13N-labelled ammonia are directly produced out of
the target without further chemistry.
15
O-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 150jC. 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
11
CO2 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/>mol at the end of synthesis.