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Cyclotron

A cyclotron is an accelerator for atomic and sub-atomic charged particles. As the particles are accelerated, they gain energy. The cyclotron accelerates these particles using spiral motion through a series of steps, so that a small amount of energy is gained per rotation. The spiral motion is caused by powerful magnets which are many times stronger than the earth’s magnetic field. The energy for acceleration is provided through a voltage very similar to that found in larger televisions. The acceleration of these particles occurs under vacuum to minimise collisions with air and other gases.

Once the particles gain sufficient energy (about 18 million volts) they are stripped of their electrons to reveal protons (or in some cases deuterons) that are then fired into a target of special atomic composition. Those nuclei of the target that absorb a proton become radioactive and are known as “radioisotopes”. The choice of target determines the type of radioisotope produced. Most PET images utilise the radioisotope “Fluorine-18”.

The WA PET Centre cyclotron is capable of accelerating hydrogen negative ions (made up of one proton and 2 electrons) and deuterium negative ions (made up of a proton, a neutron and two electrons). The cyclotron is used for the production of a range of PET isotopes and a limited but useful range of other products for physics and radiochemistry research.

Although there are a number of different models, all cyclotrons are essentially made up of the following components:

A brief description of the listed components is provided.

Ion Source and Injection System

The H- ions used for acceleration are obtained from Hydrogen gas. The gas is pumped into a chamber where it is heated by passing a large current of electrons through it. On passing through the chamber, the electrons collide with the Hydrogen gas, producing a large number of H- ions. The H- ions are then injected into the vacuum chamber by the application of another voltage. A large collection of ions injected into the accelerating chamber forms an ion beam, otherwise known as the cyclotron beam.

Accelerating Radiofrequency Assembly

One of nature’s fundamental properties is that a when a positively or negatively charged particle moves into a magnetic field it will be deflected and begin to undergo a spiral motion. This is most likely to occur when the magnetic field is at right angles to the direction of the particle movement. The speed and hence energy of the particle remains unaffected. In order to gain energy, the particle needs to be accelerated. A high voltage (typically 30,000V) is applied at a right angle to the magnetic field, between two electrodes known as dees. A dee is a hollow copper electrode made of low resistivity copper to maximise transfer of the accelerating voltage. The large voltage attracts and hence accelerates the particle. By rapidly alternating the voltage, acceleration occurs many times in small steps. Each successive acceleration causes the ions to spiral outwards so that once sufficiently accelerated, the beam can be injected into a target material.

Vacuum System

The dees are evacuated using high vacuum pumps in order to minimise energy losses resulting from collisions between the ion beam and air molecules. The low levels of pressure are generated to prevent the ion beam from bombarding gases inside the cyclotron chamber. Contaminant gases act as poor quality targets, which cause the beam to become splattered onto the chamber wall, and resulting in reducing the beam intensity. A number of pumps are typically used, though oil diffusion pumps are by far most commonly used in this pressure range.

Target Assembly

Cyclotrons use highly energetic particles which form a beam that is focused or bombarded onto a target material. In the case of the WA PET Centre cyclotron, the targets contain particular types of Oxygen (O), Nitrogen (N) and Neon (Ne). When a bombarding particle is absorbed in the target material, a number of reactions occur at a sub-atomic level, resulting in the formation of a compound nucleus. The compound nucleus subsequently decays and in the process gives off energy in the form of radiation.

The continual production of compound nuclei produces a great amount of heat, which needs to be rapidly removed. A combination of cooling gases and chilled water are used to effectively cool the target assembly.

Safety Systems

There are a number of safety systems controlling the cyclotron in addition to a large number dedicated systems for the monitoring of services such as gases, ventilation, air-conditioning, cooling, radiation monitoring and personnel safety. Monitors log and display the status levels of each of the systems over a 24 hour period.

During production of the radioisotopes, which takes approximately 90 minutes, the cyclotron produces radiation. This radiation is effectively contained in the cyclotron enclosure, known as a cyclotron vault. The vault is made of concrete up to 2.0 metres thick. Once the cyclotron is switched off, the cyclotron no longer produces any radiation.

Access to the facility is limited with operation of the equipment performed by highly trained and skilled personnel.

The cyclotron developed in 1934 by E.O. Laurence and M.S. Livingston used the above principles to accelerate charged particles to very high energies. The WA PET Centre cyclotron uses the same principles to bombard target materials of Oxygen, Nitrogen and Neon to produce radioisotopes used in the diagnosis and treatment of disease, for the benefit of patients in Western Australia.

PET Radiopharmaceutical production

Positron emission tomography (PET) is a non-invasive imaging procedure used to look at the function of tissues and organs within a patient. To achieve this, a pharmaceutical is administered to a patient, by injection. The pharmaceutical contains a small amount of radioisotope. The most common radioisotope used in PET is Fluorine-18 or 18F. 18F has a half-life of just 110 minutes and can be joined with or added to a number of pharmaceuticals to make a radiopharmaceutical. The radiopharmaceutical is organ or tissue specific so that once injected, it will find its way to the specific organ or tissue, where it is detected due to the presence of a small quantity of radioisotope.

A radiopharmaceutical is made up of two parts, namely the radioisotope and the pharmaceutical which are joined together, in a process known as labelling. A cyclotron located at the Hospital makes the radioisotope. Once the radioisotope is made, it is transferred to a laboratory where it is joined to a pharmaceutical, creating the radiopharmaceutical.

Automated FDG production apparatus

The most common radiopharmaceutical used in PET is 18F-labelled fluorodeoxyglucose or FDG. This radiopharmaceutical is used extensively in tumour, brain and heart imaging studies.

Much of the process of FDG production is automated, however manual preparation of a number of separate components is required just prior to the production, because of a very short shelf-life of some of the mixed components. Once the individual components are prepared, typically in small glass containers, they are connected to FDG production apparatus to undergo a sequencial process of chemistry in a carefully controlled environment. FDG production requires a starting product that undergoes mixing, heating, gassing, evaporation and filtering. To ensure that the final product is sterile and pyrogen free, the production must take place in a “clean room” laboratory, which must be approved by the Australian Therapeutic Goods Administration.

Clean Room Laboratory

The laboratory at Sir Charles Gairdner Hospital has been constructed and equipped in a way such that microbes or any other contaminants are either removed or significantly reduced. Staff who operate the apparatus are also required to adhere to strict procedures of cleanliness.

The final product is subjected to quality control tests required for a conventional drug, which include simple visual inspections such as pH and colour of the final product as well as more complicated tests to ensure that no residual chemicals remain in the final product. The final product of FDG is essentially a man-made sugar molecule with one 18F attached to each molecule.

18F-FDG is the most widely used radiopharmaceutical for PET imaging in oncology (90%±). However, in some types of malignancies 18F-FDG is not a highly specific tracer since glucose is utilised by many benign cell types. In complement of 18F-FDG, we have developed in our laboratory the automated synthesis of three additional 18F tracers now available for clinical applications: namely 18F-FMISO (18F-Fluoromisonidazole), 18F-FLT (18F-Fluorodeoxythymidine) and 18F-FCH (18F-Fluorocholine). These tracers undergo a very similar synthetic process to the one of 18F-FDG and are subjected to careful quality control before release.