Images from within

You might know someone who is going for or just had a ‘scan’ at the hospital. One common type of medical scan is ‘radiopharmaceutical imaging’. But what does such a scan involve and how can the images produced help physicians treat us?   

Radiopharmaceutical imaging 

This particular type of imaging technique uses very small amounts of radioactive materials (radiopharmaceuticals) which, when injected into the blood stream, accumulate in specific organs, tissues and bone. The radiopharmaceutical comprises an unstable form of an element, a radioisotope, attached to a molecule that has an affinity for particular tissues. The radioactive atoms decay into stable isotopes and in doing so emit   gamma radiation (photons) capable of passing through the body. An image of the distribution of this radioactivity in the body is taken by using   gamma cameras coupled to computers.   

While such images offer less detailed information on anatomical structure than those produced by a typical external x-ray examination, for example, they can identify different types of tissues, eg cancerous cells, and give a doctor insight into how organs are functioning. So long as a small amount of the radiopharmaceutical accumulates in any target tissue, the radioactivity can be detected and an image formed. Potential health problems can therefore be identified much earlier than with other diagnostic tests, thus allowing for earlier treatment. 

Making radiopharmaceuticals 

The first radiopharmaceutical approved by the US Food and Drugs Administration in 1951 was sodium [131I]iodide, which incorporates the 131I radioisotope (*t½ = eight days) and was used to diagnose thyroid disease. (The thyroid gland naturally absorbs iodine from the blood stream to synthesise thyroid hormones.) However, many of today’s radiopharmaceuticals are based on more complex chemicals found in the body (carrier molecules), to which the radioisotope is attached. UK-based GE Healthcare has for many years developed radiopharmaceuticals for diagnostic applications. ‘Identifying a medical need, such as wanting to see how blood flows through the heart, is the first step in developing a radiopharmaceutical’, says Dr Neil Rowley of GE Healthcare. ‘Chemists and pharmacists then collaborate to identify "lead candidate" molecules that have some propensity to enter the particular tissues to be studied. To attach a radioisotope to these carrier molecules chemists use ligand molecules. These form a stable complex (chelate) with the radioisotope which can then link to the carrier molecule. But modifying a molecule like this can affect its original pharmacological action so this needs to be checked before the potential imaging agent undergoes clinical trials’. 

The radioisotopes used can come from one of three sources:   

 irradiating a stable isotope with neutrons by placing a powdered sample in the core of a nuclear reactor. Neutrons released in the reactor interact with the nuclei of atoms in the sample to make the unstable radioisotope; 

 a cyclotron, a machine used to accelerate charged particles, eg protons and electrons, to high speeds which then hit a stable isotope (target sample). The atoms interact with the high energy particles to produce an unstable isotope;   

 the nuclear fission of uranium-235, a process which is used to produce the important isotope technetium-99m.   

‘These radioisotopes are produced in minute (picogram) quantities from grams of raw material’, explains Dr Steve Gill of GE Healthcare. ‘This presents chemists with the challenge of separating out the useful product. In addition, these products must be highly pure because any metallic impurities will compete for ligands, which will affect the efficacy of the final radiopharmaceutical. Chemists use separating techniques such as ion exchange columns to isolate the radioisotopes, and check the purity of the sample using inductively-coupled plasma mass spectrometry’.   

Technetium-99m 

The most widely used radioisotope is technetium-99m, 99mTc. This is a daughter product of the radioactive decay of molybdenum-99, which itself is a product of uranium-235 fission.   

The success of 99mTc is down to its chemistry and physics. Rowley explained, ‘Technetium-99m has a short half-life (t½ = six hours) and emits photons with suitable energy (140keV = 2.2 x 10–14J) 
to pass through the body. Being a transition metal, technetium has a varied aqueous chemistry, which allows chemists to use a plethora of ligand molecules to bind 99mTc to a variety of pharmacologically-active molecules found in the body. The physics of 99mTc production provides a convenient method for delivering 99mTc products to hospitals. GE Healthcare supplies hospitals with a technetium generator or "cow". This is a lead-lined generator containing a sample of the more stable molybdenum-99 (t½ of ca three days) adsorbed and retained on alumina, which is packed into a chromatographic column. The hospital is also supplied with an inactive form of the imaging agents. Hospital staff then "milk" the generator of the 99mTc produced during the molybdenum’s decay by washing it out from the column with sterile saline (salt solution). The 99mTc-containing eluate is collected in a vial containing the inactive pharmaceutical, and after mixing gently the 99mTc-labelled radiopharmaceutical is ready to administer to the patient’.   

Technetium-99m-labelled compounds are commonly used to assess abnormalities in bone (eg arthritic damage in joints). These compounds are 99mTc-labelled phosphate derivatives. Our bones comprise hydroxyapatite, a phosphorus-containing mineral, which is in a constant state of resorption and resynthesis in normal bone. However, at abnormal areas, eg sites of arthritic damage, the rate of bone mineral turnover is increased in an effort to repair the damage. As a result the 99mTc-phosphate derivatives are rapidly incorporated and concentrated at these sites, thus allowing the skeletal condition to be imaged. Table 1 shows the range of radioisotopes and drugs used and their applications. 

Images for the future 

Although successful diagnostic tools, the drugs shown in Table 1 only allow biological processes to be imaged on the macro level, ie in organs in the body. According to Gill, ‘The next goal for radiopharmaceutical imaging is to image biological processes occurring in cells, which could lead to finer levels of detail, greater diagnostic precision, lower patient doses and shorter imaging times’. But to get down to this molecular level requires smaller radioisotopes which are readily incorporated into the cell. One potential candidate is fluorine-18 (t½ = 110mins). GE Healthcare chemists are now working on the next generation of 18F-labelled compounds designed to produce images that will help provide a molecular understanding of specific diseases, and thus assist physicians to diagnose and treat disease earlier.   

James Berressem 

Table 1 Some common radioisotopes and their applications in radiopharmaceutical imaging