Year 13 BTEC trip to Northwick Park Hospital

How radiopharmaceuticals are used in medicine

The BTEC students need to know about how radiopharmaceuticals are used in diagnostic imaging but this article also looks at how they can be used in the treatment of disease.

http://en.wikipedia.org/wiki/Nuclear_medicine

Nuclear medicine is a medical specialty involving the application of radioactive substances (radioactive isotopes or radioisotopes) in the diagnosis and treatment of disease. It is used to image and investigate the function of the body.

Nuclear medicine scans are usually conducted by Radiographers. Nuclear medicine, in a sense, is “radiology done inside out” or “endoradiology” because it records radiation emitting from within the body rather than radiation that is generated by external sources like X-rays.

X-ray images show only the structure of the body, so they can be used to see things like broken bones and some tumours. Unlike x-ray images, nuclear medicine can show the function of the body. It follows what happens to certain chemicals so it can be used to see if an organ is doing its job properly. The chemicals, called tracers, are ‘labelled’ with a radioactive isotope and their path followed through the body.

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Labelling chemicals with the radioactive isotopes

http://en.wikipedia.org/wiki/Radiopharmacology

Radiopharmacology or medicinal radiochemistry is radiochemistry applied to medicine and thus the pharmacology of radiopharmaceuticals (medicinal radiocompounds, that is, pharmaceutical drugs that are radioactive). Radiopharmaceuticals are used in the field of nuclear medicine as radioactive tracers in medical imaging and in therapy for many diseases (for example, brachytherapy). Many radiopharmaceuticals use technetium-99m (Tc-99m) which has many useful properties as a gamma-emitting tracer nuclide. In the book Technetium a total of 31 different radiopharmaceuticals based on Tc-99m are listed for imaging and functional studies of the brain, myocardium, thyroid, lungs, liver, gallbladder, kidneys, skeleton, blood and tumours.

In nuclear medicine imaging, radiopharmaceuticals are taken internally, for example, intravenously or orally. Then, external detectors (gamma cameras) capture and form images from the radiation emitted by the radiopharmaceuticals. This process is unlike a diagnostic X-ray, where external radiation is passed through the body to form an image.

There are several techniques of diagnostic nuclear medicine.

3D: SPECT is a 3D tomographic technique that uses gamma camera data from many projections and can be reconstructed in different planes. Positron emission tomography (PET) uses coincidence detection to image functional processes.

Radioactive tracers can be used to see how well organs in your body are working or to find areas of disease e.g. radioisotopes of iodine or technetium.

Often these are mixed with a drug that collects in a particular organ in the body.

If the drug is injected into the body you can examine the organ by detecting the radiation coming from that organ.

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Gamma camera

http://en.wikipedia.org/wiki/Gamma_camera

A gamma camera, also called a scintillation camera or Anger camera, is a device used to image gamma radiation emitting radioisotopes, a technique known as scintigraphy. The applications of scintigraphy include early drug development and nuclear medical imaging to view and analyse images of the human body or the distribution of medically injected, inhaled, or ingested radionuclides emitting gamma rays.

A gamma camera consists of one or more flat crystal planes (or detectors) optically coupled to an array of photomultiplier tubes in an assembly known as a “head”, mounted on a gantry. The gantry is connected to a computer system that both controls the operation of the camera as well as acquisition and storage of acquired images. The construction of a gamma camera is sometimes known as a compartmental radiation construction.

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The system accumulates events, or counts, of gamma photons that are absorbed by the crystal in the camera. Usually a large flat crystal of sodium iodide with thallium doping in a light-sealed housing is used.

The crystal scintillates in response to incident gamma radiation. When a gamma photon leaves the patient (who has been injected with a radioactive pharmaceutical), it knocks an electron loose from an iodine atom in the crystal, and a faint flash of light is produced when the dislocated electron again finds a minimal energy state.

After the flash of light is produced, it is detected. Photomultiplier tubes (PMTs) behind the crystal detect the fluorescent flashes (events) and a computer sums the counts. The computer reconstructs and displays a two dimensional image of the relative spatial count density on a monitor. This reconstructed image reflects the distribution and relative concentration of radioactive tracer elements present in the organs and tissues imaged.

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The above right image shows examples of lung scintigraphy examination

Gamma-rays are uncharged so they can’t be deflected using electric or magnetic fields. You need to use a collimator to attenuate the gamma-rays via absorption or scatter.

A Parallel hole collimator provides direct projection of activity distribution onto a crystal without any magnification or reduction in size.

Other collimation schemes magnify or reduce the image to allow better visualisation of small organs or to allow large organs to be imaged with relatively small detector.

Magnification of the image and sensitivity changes as a function of distance from collimator.

Large hole diameters and short hole lengths gives the best sensitivity.

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Collimators’ geometry is chosen for differing clinical applications. They accept radiation only from a narrow cylinder defined by geometry

The cylinder defines the Line of Response (LoR). The line of response is the straight line of coincidence that allows the source of two 511 keV gamma photons, being emitted at almost 180 degrees to each other, to be identified.

In practice, the LOR has a non-zero width as the emitted photons are not exactly 180 degrees apart if the resolving time of the detectors is less than 500 picoseconds rather than about 10 nanoseconds.

Gamma‐ray detectors are a key component of all nuclear imaging systems, including the gamma camera.

Detectors must measure energy accurately and efficiently, with good timing resolution. Scintillator detectors are most common.

http://en.wikipedia.org/wiki/Gamma_spectroscopy

The equipment used in gamma spectroscopy includes an energy-sensitive radiation detector, electronics to process detector signals produced by the detector, such as a pulse sorter (i.e., multichannel analyser), and associated amplifiers and data readout devices to generate, display, and store the spectrum.

A scintillator uses a photomultiplier tube to multiply the current produced by incident radiation by as much as 100 million times (i.e., 160 dB), in multiple dynode stages, enabling (for example) individual photons to be detected when the incident flux is very low.

http://en.wikipedia.org/wiki/Gamma_spectroscopy

http://en.wikipedia.org/wiki/Photomultiplier

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Radionuclide generators

http://en.wikipedia.org/wiki/Radionuclide

http://www.nucmedtutorials.com/dwgenerator/gen2.html

The radioisotopes are produced in generators where isotopes with long half-lives (e.g. molybdenum-99, half-life 67 hours) decay to isotopes with shorter lives (e.g. technetium-99m, half-life 6 hours). The shorter half-lives are necessary so that the radioactivity of the patient does not remain much above its normal background level for longer than necessary.

A generator is a self-contained system housing a parent/daughter mixture in equilibrium. There must be a method of removing the daughter and leaving the parent behind to regenerate more daughter activity. It is designed to produce the daughter for some purpose separate from the parent. Generators produce certain short-lived radioisotopes on-site which cannot be shipped by commercial sources. To be useful, the parent’s half-life must be long compared to the travel time required to transport the generator to recipient. The typical shelf-life of a Mo/Tc generator is 2 weeks, as is the expiration date (molybdenum-99, half-life 67 hours to technetium-99m, half-life 6 hours). The process of removing the daughter from the generator is referred to as elution; the solution used to remove the daughter is called the eluent; and the solution collected from the generator containing the daughter radioisotope is called the eluate.

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http://www.lightsource.ca/operations/medicalisotopes/

http://www.bbc.co.uk/schools/gcsebitesize/science/add_ocr_gateway/radiation/treatmentrev2.shtml

Using the radiopharmaceuticals

The isotope (Technetium-99m) with the shorter half-life is drawn out of the generator in a solution and can be made into a range of different drugs (radiopharmaceuticals) that are absorbed by different parts of the body. The radiopharmaceutical is drawn up into a syringe shielded with lead and its dose checked before it is injected into the patient.

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Properties of an ideal generator:

1) If intended for clinical use, output of the generator must be sterile (you don’t want the patient to pick up any diseases) and pyrogen-free (i.e.it must not induce a fever)

2) The chemical properties of the daughter must be different than those of the parent to permit separation of daughter from parent. Separations are usually performed by affinity or ion exchange chromatography.

3) Generator should be eluted with 0.9% saline solution and should involve no violent chemical reactions. Human intervention should be minimal to minimize radiation dose. Eluents other than 0.9% NaCl may require tedious pH adjustment, associated with a significant radiation dose, and are therefore undesirable. Saline is used because it can then be injected into a person; if you inject water into a vein it will cause haemolysis and possibly death.

4) Daughter isotope for diagnostic studies should be short-lived gamma-emitting nuclide (tphys = hrs-days). Beta particles are undesirable as they confer a high radiation dose and are not imageable.

5) Physical half-life of parent should be short enough so daughter in-growth after elution is rapid, but long enough for practicality. The Mo/Tc generator is a perfect example- in-growth of Tc-99m is very rapid, but the shelf-life of the generator is two weeks.

6) Daughter chemistry should be amenable to the preparation of a wide variety of compounds, especially those in kit form. In the case of the Mo/Tc generator, there are cold kits for imaging essentially any organ or system in the human body.

7) Very long-lived or stable granddaughter so no radiation dose is conferred to patient by decay of subsequent generations. In the case of Tc-99 ground state, the granddaughter of Mo-99, the half-life of 220,000 yr guarantees a minimal radiation dose to the patient, regardless of the effective half-life.

8) Inexpensive, effective shielding of generator, minimizing radiation dose to those using it. This is easy to accomplish since lead is very dense and therefore a good attenuator of radiation. In addition, it is a very inexpensive metal and can be easily moulded into almost any shape desired.

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Even the syringe is lead lined

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Preparing the tracer – The lead glass is used to shield the face of the medical physicist. Lead can absorb all types of radiation, even gamma rays.

9) Generator is easily recharged (Mo/Tc generators are not easily recharged as the radiation dose associated with this procedure would be excessive). After their useful life is over, they are stored in a decay area until a background reading is obtained at the surface of the generator.

http://www.slideshare.net/lonevidya/radiopharmaceuticals

The gamma rays given off by the radioisotope are detected by a gamma-camera (a detector that takes images with gamma rays) which is connected to a computer and gives an image of where the isotope is in the patient. The image shows where the drug is absorbed.

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If several pictures are taken over a period of time with the gamma camera it can also show how quickly the isotope is absorbed.

These three images above show the build-up of a tracer in the kidneys over time (the right kidneys are on the left of each image). We can tell that the left kidney is blocked, as the tracer hasn’t been able to reach it.

Computer software enables us to look at the kidney from all directions.

The gamma camera displays the position of each gamma ray that it detects.

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Images from Jeff Jones

A ventilation/perfusion scan involves two tests which may be done together or separately. The patient is injected with a radioactive drug which remains in the bloodstream around the lungs. An image of the distribution of this drug (in brown) shows the blood perfusion in the lungs. This should be uniform. A light area may show a blockage where the blood is not adequately perfusing the lung. The second test is a ventilation scan, where the patient breathes radioactive xenon or krypton gas. This image (in green) shows those parts of the lungs which are adequately ventilated. Combining both scans allows a doctor to work out whether the lung is functioning properly, and allows operations to be designed so as to reduce long-term damage.

Below is a whole-body bone scan made using a radiopharmaceutical labelled with technetium-99m. The images show where the drug is absorbed (collects in the bones), and if several pictures are taken over a period of time it can also show how quickly the isotope is absorbed.

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The thyroid is a gland in the neck which can be overactive, underactive, or can develop a cancer. The thyroid is the only organ which processes iodine, so an injection of radioactive iodine (obtained from the pot shown, and injected using lead-lined syringes) can indicate the activity of the thyroid (as shown in the image on the left). A larger dose of radioactive iodine can destroy a thyroid tumour.

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http://en.wikipedia.org/wiki/Fludeoxyglucose_%2818F%29

Fludeoxyglucose (18F) (INN), or fludeoxyglucose F 18 (USAN and USP), also commonly called fluorodeoxyglucose and abbreviated [18F]FDG, 18F-FDG or FDG, is a radiopharmaceutical used in the medical imaging modality positron emission tomography (PET). Chemically, it is 2-deoxy-2-(18F)fluoro-D-glucose, a glucose analogue, with the positron-emitting radioactive isotope fluorine-18 substituted for the normal hydroxyl group at the 2′ position in the glucose molecule.

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The uptake of 18F-FDG by tissues is a marker for the tissue uptake of glucose, which in turn is closely correlated with certain types of tissue metabolism. After 18F-FDG is injected into a patient, a PET scanner can form two-dimensional or three-dimensional images of the distribution of 18F-FDG within the body.

http://en.wikipedia.org/wiki/Radioactive_tracer

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Some radiopharmaceuticals can be produced by bombarding a target material with high speed charged particles produced in particle accelerators such as a cyclotron.

http://en.wikipedia.org/wiki/Cyclotron

They can be produced by a long-lived parent radionuclide decaying to the desired short-lived daughter radionuclide. This daughter radionuclide is then separated from the mother radionuclide by using column chromatography, solvent extraction or sublimation.

http://www.slideshare.net/aartidubey1987/radionuclide-imaging-aarti-dubey

https://books.google.co.uk/books?id=xfbKH9epiZgC&pg=PA70&lpg=PA70&dq=advantages+and+disadvantages+of+radionuclide+imaging&source=bl&ots=O3X0pqOBjy&sig=g6G-76gho9XpDUNd3HNohjtWJ_c&hl=en&sa=X&ei=DqMIVZ_XOcOv7AbuwYCIDw&ved=0CCgQ6AEwAQ#v=onepage&q=advantages%20and%20disadvantages%20of%20radionuclide%20imaging&f=false

The advantages and disadvantages of radionuclide imaging:

1) Assesses body functions, uptake tests and monitoring flow rates

2) Identify skeletal problems

3) Monitors body behaviour following treatment

4) Measures body composition

5) Whole body scanning to assess disease and detect tumours

6) Poor resolution compared with other imaging techniques

7) Radiation risk (although comparable to x-rays)

8) Can be invasive as injections may be required

9) Disposal of radioactive waste

10) Relatively high costs

Therapeutic Radiopharmaceuticals

http://www.world-nuclear.org/info/Non-Power-Nuclear-Applications/Radioisotopes/Radioisotopes-in-Medicine/

For some medical conditions cells that are not functioning properly are destroyed using radiation. The radioisotope that generates the radiation can be localised in the required organ in the same way it is used for diagnosis – through a radioactive element following its usual biological path, or through the element being attached to a suitable biological compound. In most cases, it is beta radiation which causes the destruction of the damaged cells. This is radionuclide therapy (RNT) or radiotherapy. Short-range radiotherapy is known as brachytherapy, and this is becoming the main means of treatment.

Although radiotherapy is less common than diagnostic use of radioactive material in medicine, it is nevertheless widespread, important and growing. An ideal therapeutic radioisotope is a strong beta emitter with just enough gamma to enable imaging, eg lutetium-177. This is prepared from ytterbium-176 which is irradiated to become Yb-177 which decays rapidly to Lu-177. Yttrium-90 is used for treatment of cancer, particularly non-Hodgkin’s lymphoma and liver cancer, and it is being used more widely, including for arthritis treatment. Lu-177 and Y-90 are becoming the main RNT agents.

Iodine-131, samarium-153 and phosphorus-32 are also used for therapy. Iodine-131 is used to treat the thyroid for cancers and other abnormal conditions such as hyperthyroidism (over-active thyroid). In a disease called Polycythemia vera, an excess of red blood cells is produced in the bone marrow. Phosphorus-32 is used to control this excess.

A new and still experimental procedure uses boron-10, which concentrates in the tumour. The patient is then irradiated with neutrons which are strongly absorbed by the boron, to produce high-energy alpha particles which kill the cancer.

For targeted alpha therapy (TAT), actinium-225 is readily available, from which the daughter bismuth-213 can be obtained (via 3 alpha decays) to label targeting molecules. The bismuth is obtained by elution from an Ac-225/Bi-213 generator similar to the Mo-99/Tc-99 one. Bi-213 has a 46-minute half-life. The actinium-225 (half-life 10 days) is formed from radioactive decay of radium-225, the decay product of long-lived thorium-229, which is obtained from decay of uranium-233, which is formed from Th-232 by neutron capture in a nuclear reactor.

Another radionuclide recovered from thorium-232 is lead-212, with half-life of 10.6 hours, which can be attached to monoclonal antibodies for cancer treatment by TAT. A Ra-224/Pb-212 generator system similar to the Mo-99/Tc-99 one is used to provide lead-212 from radium-224 (via Rn-220 and Po-216). Pb-212 has a half-life of 10.6 hours, and beta decays to bismuth-212, then most beta decays to polonium-212. The alpha decays of Bi-212 and Po-212 are the active ones destroying cancer cells over a couple of hours. Stable Pb-208 results, via thallium-208 for the bismuth decay.

Considerable medical research is being conducted worldwide into the use of radionuclides attached to highly specific biological chemicals such as immunoglobulin molecules (monoclonal antibodies). The eventual tagging of these cells with a therapeutic dose of radiation may lead to the regression – or even cure – of some diseases.

Isotopes used in Medicine

As mentioned earlier many radioisotopes are made in nuclear reactors, some in cyclotrons. Generally neutron-rich ones and those resulting from nuclear fission need to be made in reactors, neutron-depleted ones are made in cyclotrons. There are about 40 activation product radioisotopes and five fission product ones made in reactors.

Reactor Radioisotopes (half-life indicated)

Bismuth-213 (46 min): Used for targeted alpha therapy (TAT), especially cancers, as it has a high energy (8.4 MeV).

Caesium-137 (30 yr): Used for low-intensity sterilisation of blood.

Chromium-51 (28 d): Used to label red blood cells and quantify gastro-intestinal protein loss.

Cobalt-60 (5.27 yr): Formerly used for external beam radiotherapy, now almost universally used for sterilising.

Dysprosium-165 (2 h): Used as an aggregated hydroxide for synovectomy treatment of arthritis.

Erbium-169 (9.4 d): Use for relieving arthritis pain in synovial joints.

Holmium-166 (26 h): Being developed for diagnosis and treatment of liver tumours.

Iodine-125 (60 d): Used in cancer brachytherapy (prostate and brain), also diagnostically to evaluate the filtration rate of kidneys and to diagnose deep vein thrombosis in the leg. It is also widely used in radioimmuno-assays to show the presence of hormones in tiny quantities.

Iodine-131 (8 d)*: Widely used in treating thyroid cancer and in imaging the thyroid; also in diagnosis of abnormal liver function, renal (kidney) blood flow and urinary tract obstruction. A strong gamma emitter, but used for beta therapy.

Iridium-192 (74 d): Supplied in wire form for use as an internal radiotherapy source for cancer treatment (used then removed). Beta emitter.

Iron-59 (46 d): Used in studies of iron metabolism in the spleen.

Lead-212 (10.6 h): Used in TAT for cancers or alpha radioimmunotherapy, with decay products Bi-212 and Po-212 delivering the alpha particles. Used especially for melanoma, breast cancer and ovarian cancer.

Lutetium-177 (6.7 d): Lu-177 is increasingly important as it emits just enough gamma for imaging while the beta radiation does the therapy on small (eg endocrine) tumours. Its half-life is long enough to allow sophisticated preparation for use. It is usually produced by neutron activation of natural or enriched lutetium-176 targets.

Molybdenum-99 (66 h)*: Used as the ‘parent’ in a generator to produce technetium-99m.

Palladium-103 (17 d): Used to make brachytherapy permanent implant seeds for early stage prostate cancer.

Phosphorus-32 (14 d): Used in the treatment of polycythemia vera (excess red blood cells). Beta emitter.

Potassium-42 (12 h): Used for the determination of exchangeable potassium in coronary blood flow.

Rhenium-186 (3.8 d): Used for pain relief in bone cancer. Beta emitter with weak gamma for imaging.

Rhenium-188 (17 h): Used to beta irradiate coronary arteries from an angioplasty balloon.

Samarium-153 (47 h): Sm-153 is very effective in relieving the pain of secondary cancers lodged in the bone, sold as Quadramet. Also very effective for prostate and breast cancer. Beta emitter.

Selenium-75 (120 d): Used in the form of seleno-methionine to study the production of digestive enzymes.

Sodium-24 (15 h): For studies of electrolytes within the body.

Strontium-89 (50 d)*: Very effective in reducing the pain of prostate and bone cancer. Beta emitter.

Technetium-99m (6 h): Used in to image the skeleton and heart muscle in particular, but also for brain, thyroid, lungs (perfusion and ventilation), liver, spleen, kidney (structure and filtration rate), gall bladder, bone marrow, salivary and lacrimal glands, heart blood pool, infection and numerous specialised medical studies. Produced from Mo-99 in a generator.

Xenon-133 (5 d)*: Used for pulmonary (lung) ventilation studies.

Ytterbium-169 (32 d): Used for cerebrospinal fluid studies in the brain.

Ytterbium-177 (1.9 h): Progenitor of Lu-177.

Yttrium-90 (64 h)*: Used for cancer brachytherapy and as silicate colloid for the relieving the pain of arthritis in larger synovial joints. Pure beta emitter and of growing significance in therapy, especially liver cancer.

Radioisotopes of caesium, gold and ruthenium are also used in brachytherapy.

* fission product

Cyclotron Radioisotopes

Carbon-11, Nitrogen-13, Oxygen-15, Fluorine-18: These are positron emitters used in PET for studying brain physiology and pathology, in particular for localising epileptic focus, and in dementia, psychiatry and neuropharmacology studies. They also have a significant role in cardiology. F-18 in FDG (fluorodeoxyglucose) has become very important in detection of cancers and the monitoring of progress in their treatment, using PET.

Cobalt-57 (272 d): Used as a marker to estimate organ size and for in-vitro diagnostic kits.

Copper-64 (13 h): Used to study genetic diseases affecting copper metabolism, such as Wilson’s and Menke’s diseases, and for PET imaging of tumours, and therapy.

Copper-67 (2.6 d): Beta emitter, used in therapy.

Fluorine-18 as FLT (fluorothymidine), F-miso (fluoromisonidazole), 18F-choline: tracer.

Gallium-67 (78 h): Used for tumour imaging and localisation of inflammatory lesions (infections).

Gallium-68 (68 min): Positron emitter used in PET and PET-CT units. Derived from germanium-68 in a generator.

Germanium-68 (271 d): Used as the ‘parent’ in a generator to produce Ga-68.

Indium-111 (2.8 d): Used for specialist diagnostic studies, eg brain studies, infection and colon transit studies.

Iodine-123 (13 h): Increasingly used for diagnosis of thyroid function, it is a gamma emitter without the beta radiation of I-131.

Iodine-124: tracer.

Krypton-81m (13 sec) from Rubidium-81 (4.6 h): Kr-81m gas can yield functional images of pulmonary ventilation, e.g. in asthmatic patients, and for the early diagnosis of lung diseases and function.

Rubidium-82 (1.26 min): Convenient PET agent in myocardial perfusion imaging.

Strontium-82 (25 d): Used as the ‘parent’ in a generator to produce Rb-82.

Thallium-201 (73 h): Used for diagnosis of coronary artery disease other heart conditions such as heart muscle death and for location of low-grade lymphomas. It is the most commonly used substitute for technetium-99 in cardiac-stress tests.

References:

OECD/NEA 2012, A Supply & Demand Update of the Mo-99 Market

IAEA 2015, Feasibility of Producing Molybdenum-99 on a Small Scale Using Fission of Low Enriched Uranium or Neutron Activation of Natural Molybdenum, Technical reports series #478

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