Radiopharmaceuticals for imaging

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Chapter: Essentials of Inorganic Chemistry : Radioactive Compounds and Their Clinical Application

Radiopharmaceuticals are typically administered intravenously and then distributed to a particular organ. The molecule itself, and not the radiolabelling, will determine to which organ the radioactive molecule is transported.

Radiopharmaceuticals for imaging

Radiopharmaceuticals are typically administered intravenously and then distributed to a particular organ. The molecule itself, and not the radiolabelling, will determine to which organ the radioactive molecule is transported. γ-Radiation is detected externally by using a special scintillation detector, also known as a gamma camera. The camera captures the emitted radiation and forms a two-dimensional image. This diagnostic test is also called scintigraphy.

In contrast, PET produces a three-dimensional image of the functional processes in the human body. The method is based on the use of positron-emitting radionuclides and their indirectly emitted gamma rays. Radionuclides, the so-called tracers, are introduced to the body as parts of biologically active molecules. PET also uses gamma cameras to detect the internally applied radiation, but in modern scanners, three-dimensional images are often achieved with the aid of a CT X-ray scan performed at the same time as part of the same machine.

Diagnostic X-ray uses external radiation, which is sent through the body to produce a two-dimensional image, whereas scintography is based on the internal accumulation of radionuclides.


1. 99mTechnetium

Technetium has the chemical symbol Tc and atomic number 43. It is the lightest element that has no stable isotope. It is a silvery-grey transition metal (Figure 10.17).

99mTc (also referred to as technetium-99m) is the metastable isomer of 99Tc, which is a gamma-emitting nuclide routinely used in diagnostic medicine. It has a short half-life of around 6 h, which is ideal for diagnostic applications (but not for therapeutic applications) as it helps to keep the radiation exposure to the patient low. The use of a gamma camera allows detection of the radioactive tracer in the body and creates images of the area in question (Figure 10.18).

Figure 10.18 Scheme showing the use of a gamma camera on a patient treated with a 99mTc imaging agent  (Reprinted with permission from the Federation of American Scientists . )

One challenge of using a radioactive material is to safely manufacture the products and deliver them to the clinical setting. Radionuclides with long half-lives are usually prepared commercially using a nuclear reactor and supplied as the finished product. Products containing radionuclides with a short half-life cannot be delivered as the finished product because of their rapid decay. Therefore, they are delivered to the clinical setting as radionuclides with a long half-life and the desired radionuclide is then generated and formulated at the moment of use. 99mTc and its compounds are generated in situ for use as an imaging agent using a so-called 99mTc generator. The generator is loaded with molybdenum-99 (99Mo), which is often referred to as the commercially available transportable source of 99mTc. The general idea is that the generator contains a long-lasting ‘parent’ compound, which decays and produces the ‘daughter’ radionuclide. In the case of the 99mTc generator, it contains 99mMoO42− absorbed on an alumina column. 99mMoO42− decays to 99mTcO4, which can be removed as Na99mTcO4 when the column is washed with a NaCl solution. Hospitals tend to buy these generators on a regular basis to provide a continuous supply of 99mTcO4 (Figure 10.19).

Figure 10.19 (a–d) Illustration of a 99mTc generator  (Reproduced with permission from . Copyright © 2009, John Wiley & Sons, Ltd.)

Compounds containing 99mTc can be used for imaging a variety of functions and structures in the human body. The use of different molecules containing 99mTc determines to which part of the body the radionu-clide is transported and which structure can be imaged. There are a variety of different molecules, but, for example, 99mTc-aerosol can be used for the imaging of lung ventilation, whereas 99mTc-albumin is generally used for judging cardiac function. 99mTc-albumin is an injectable solution prepared by combining sodium pertechnetate (NaTcO4) and human albumin in the presence of a reducing agent such as a tin salt .

99mTc-medronate is used for skeletal imaging, and the succimer analogue is used for preparing images of the kidney. 99mTe succimer injection is prepared by reacting sodium pertechnetate (NaTcO4) with meso-2,3-dimercaptosuccinic acid in the presence of a reducing agent such as a stannous salt (Figure 10.20) .

Cardiolite is an organometallic compound based on 99mTc, which has become one of the most used nuclear imaging agents to visualise the heart muscle and abnormalities of the parathyroid. Cardiolite is the trade name of 99mTc-sestamibi, which is a coordination complex of 99mTc with six so-called MIBI ligands. MIBI stands for methoxyisobutylisonitrile. The full chemical name is (OC-6-11)-hexakis[1-(isocyano- C)-2-methoxy-2-methylpropane][99mTc]technetium(I) chloride. A typical solution for injection is prepared by heating a solution tetrakis[(2-methoxy-2-methylpropyl-1-isocyanide)copper(I)] tetrafluoroborate, which is a weak chelating agent, and sodium pertechnetate (NaTcO4) in the presence of a stannous salt (Figure 10.21) .

99mTc-exametazime is a 99mTc preparation that can be used to visualise damage to the brain, for example, in the evaluation and localisation of stroke damage, head trauma, dementia and cerebral function impairment (Figure 10.22 and Table 10.5) .

Each of these 99mTc-containing compounds is freshly prepared by the radiopharmacist strictly following a standard protocol issued by the supplier. Usually, all ingredients are supplied in closed vials, mostly characterised as reagent vials, buffer vials and, if applicable, a vial containing stabiliser. 

For illustration purposes, only the preparation of 99mTc-exametazime for injection (as supplied by GE Healthcare) is explained in the following. The nonstabilised formulation is prepared by adding 54 mCi of 99mTcO4 to a 5 ml reagent vial. The reagent vial contains the racemic mixtures of the ligand exametazime [(3RS,9RS)-4,8-diaza-3,6,6,9-tetramethylundecane-2,10-dione bisoxime] and stannous chloride dehydrate as reducing agent together with sodium chloride . The preparation should have a pH of 9.0–9.8 and should be used within 30 min .


2. 18Fluoride: PET scan

Fluorine has the chemical symbol F and atomic number 9 and is the most electronegative element. It belongs to group 17 of the periodic table, the so-called halogens. Fluorine typically exists as a diatomic molecule at room temperature.

There are 18 isotopes known of fluorine, but only 1 (19F) is stable. Most of the radioactive isotopes have a very short half-life, mostly <1 min. Only the radioisotope 18F has a longer half-life of around 110 min and is clinically used (Figure 10.23).

18F is a positron-emitting radioisotope and is used in radiopharmaceutical imaging such as PET scanning. Two compounds, namely fluorodeoxyglucose (18F-FDG) and derivatives of 18F choline, are under intense clinical investigation and/or use.

18F-FDG is a glucose derivative that contains a radiolabel (18F) at the 2 position replacing the hydroxyl group. 18F-FDG is administered intravenously and is used as an assessment of problems with glucose metabolism, especially in the brain, often associated with epilepsy and in cancer. Areas where an increased absorption of 18F-FDG are visible correlate to areas where an increased glucose metabolism is present. 18F-FDG is distributed around the body similar to glucose and is cleared renally. There are no known contraindications known to 18F-FDG (Figure 10.24).

18F-FDG is the main radioimaging agent used in PET scanning. Examples include studies of heart, where it is used to differentiate between dead and live tissue in order to assess the myocardium. In neurology, it can be used to diagnose dementia, seizure disorders or tumours of the brain. 18F-FDG is generally used to assess the extent of the tumour in a cancer patient. Cancerous tissue is characterised by increased cell proliferation, which requires energy, and therefore an increased amount of glucose. This leads to an accumulation of 18F-FDG in malignant tumours and allows judging the degree of metastasis formed. This information is important for any surgical procedure and also for the initial assessment of the cancer stage.

Unfortunately, there are limitations to the use of 18F-FDG, as its uptake is not very specific. As a result, other conditions can also cause an accumulation of 18F-FDG and can lead to misdiagnosis. These conditions include inflammation and healing of wounds, which also show increased glucose metabolism.

Therefore, a variety of other 18F-labelled compounds are under intense scrutiny as alternative PET scanning agents, mainly compounds with a more specific biological pathway. This includes 18F-choline. Choline is a compound incorporated into the cell membrane and therefore cells dividing at a fast rate have an increased need for this substance. Studies for a range of tumours were undertaken, but most studies focussed on prostate cancer. In comparison to 18F-FDG, 18F-choline showed less activity in the bladder and a prolonged elimination via the kidneys. Additionally, biological processes other than cancer also include rapid division of cells and can lead to misdiagnosis (Figure 10.25).


3. 67Gallium: PET

As previously mentioned (see Chapter 4), gallium consist of two stable isotopes (69Ga and 71Ga) and there are two radioisotopes (67Ga and 68Ga) that are commercially available. 67Ga has a half-life of 3.3 days, whereas 68Ga has an even shorter half-life of 68 min (Figure 10.26).

 67Ga decays via electron capture and subsequently emits γ-rays, which can be detected with a gamma camera. 68Ga is a positron-emitting isotope and is used for PET. Because of its short half-life, fresh 68Ga for clinical applications is obtained through generators. The generator is equipped with the parent compound 68Ge, which has a half-life of 271 days and decays via electron capture to form the ‘daughter’ 68Ga.

It has been reported that radioactive gallium-67 citrate accumulates in malignant cells when injected into animals that are infected with tumours. This has led to the development of 67Ga scans, which have been used over the past two decades mostly for the detection of residual cancer cells in patients with Hodgkin’s and non-Hodgkin’s lymphomas after chemo or radiotherapy. The level of 67Ga present in lymphoma cells correlates with their metabolic activity and directly with their proliferation rate. Therefore, a positive 67Ga scan (mostly undertaken after chemotherapy) indicates the survival of malignant cells and the need for further treatment (Figure 10.27).

As previously mentioned (see Chapter 4), Ga3+ is mainly transported by transferrin. In vitro studies have shown that the uptake of the radioactive gallium into the cancer cells was significantly increased when trans-ferrin was added to the medium .


4. 201Thallium

The element thallium belongs to the boron group, and has the chemical symbol Tl and atomic number 81.

Thallium is a soft grey metal, which cannot be found as the free metal in nature (Figure 10.28).

The common oxidation states for thallium are +3, which resembles the oxidation states of other group members, and +1, which is actually the far more dominant oxidation state for thallium ions. Thallium ions with the oxidation state +1 follow alkali metals in their chemical behaviour and are handled in biological systems similar to potassium (K+) ions.

Thallium and many of its compounds are toxic. In particular, the Tl+ cation displays good aqueous solubility and it can enter the body via the potassium-based uptake processes as its behaviour is similar to that of K+. Unfortunately, there are differences in the chemistry of both ions that affect, for example, their binding to sulfur-containing molecules and lead to the toxicity of thallium ions. Thallium-based compounds were used as rat poison, but their use is nowadays discontinued as their toxic properties are not very specific. Signs of thallium poisoning include hair loss, nerve damage and, ultimately, at high enough doses, sudden death.

The radioactive thallium isotope 201Tl was the main substance used for nuclear imaging in cardiology. It was used for the so-called thallium nuclear cardiac stress test, where a radiotracer such as 201TlCl (thallous chloride-201) is injected into a patient during exercise. After a short waiting period (in order to ensure good distribution of the radioactive substance), images of the heart are taken with a gamma camera and the blood flow within the heart muscle is evaluated. Nowadays, the radio isotope has been mostly replaced by 99mTc imaging. The radio isotope 201Tl has a half-life of 73 h and can be generated using a transportable thallium-201 generator. This generator uses 201Pb (lead-201) as the ‘parent’, which decays via electron capture to the ‘daughter’ 201Tl. 201Tl decays by electron capture and has good imaging characteristics .

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