What are radiopharmaceuticals? – Basics of nuclear medicine

What are radiopharmaceuticals?

What are radiopharmaceuticals? Radiopharmaceuticals consist of a radionuclide connected to a targeting agent with an affinity to the target. For example, a tumor. Depending on the coupled radionuclide, the type of radiation allows for imaging and/or treatment. The targeting agent is used for its carrier and binding properties. Biodistribution and binding-specificity are based on the targeting agent. Many types of substances can be used as a targeting agent. Think of glucose which can be radiolabeled with fluor-18 to track glucose metabolism. There are some exceptions where the radionuclide itself binds to the targets, without the use of a targeting agent. These radionuclides are indicated as organ seekers. For example, iodine is naturally taken up by the thyroid gland, or radium and fluorine accumulate in bone.

Radiodiagnostics and -therapeutics

Radiopharmaceuticals can be injected, infused, inhaled, ingested, or delivered topically. Once in the body, gamma radiation can be picked up by cameras for imaging. When used as therapeutics, the damaging effect of beta or alpha radiation can be used to destroy the targeted cells. You now know the basics of nuclear medicine, let’s take a closer look at the various radionuclides used and how they differ.

Not all radionuclides are equal

Not all radionuclides are equal. Radionuclides differ by type of decay and emissions they produce. Common categorizations for types of decay are alpha, beta, and gamma. Good to know: a single radionuclide can decay via alpha or beta decay but can also release a gamma photon. For example, iodine-131 is both a beta and gamma emitter.
Emission can be energy in the form of electromagnetic waves, as in gamma and X-ray, or particles as in neutrons, protons, positrons, and electrons. The energy transferred to the traversed medium (e.g. tissue) by these emissions differs. This is expressed in Linear Energy Transfer (LET). LET is measured in units of energy per unit distance, typically in kilo electron volts per micrometer (keV/μm). It represents the amount of energy transferred per unit length of the path of the radiation.

Table: Alpha vs beta vs gamma

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* Exact values depend on individual radionuclides and type of tissue. You may find different values in literature.

** Most radionuclides emit multiple types of radiation. They are classified here based on their main type. E.g. many radionuclides that emit beta or alpha particles also emit gamma rays after the main type of decay.

Gamma rays

Beta and alpha emitters are used for therapeutic purposes. The emitted particles contain both energy and mass. Contrary to gamma photons, which only exist as energy and have no mass. Gamma rays can be transmitted directly as a form of decay or as a result of the decay of alpha and beta-emitting radioisotopes. Positron decay indirectly produces two gamma photons when the emitted positron collides with an electron in the body. The suitability of a radionuclide for (quantitative) imaging depends on its gamma rays and their energy.

How does nuclear medicine work

Nuclear medicine uses radionuclides for diagnosis and treatment. For imaging, different gamma-emitting radionuclides can be used. For treatment, the damage caused by beta and alpha emitters is intentionally used. Alpha particles are the heaviest and travel a short distance before losing too much energy. All of their energy can be released in the proximity of a few cells, causing greater cell damage in a targeted region compared to other radiation. Since gamma electromagnetic waves don’t have mass, they travel more easily through matter and can be picked up by gamma cameras outside the body.

Types of decay: comparison of alpha, beta-minus, beta-plus, and gamma decay

In the figure below are the different types of decay visually explained.

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Gamma radiation is not fully included in this table. The energy state of an element stabilizes by emitting gamma photons, this may happen after a process called electron capture or after other types of decay. A gamma photon can be released to get rid of excess energy, moving the nucleus from an excited energy state to a ground state. The auger effect, a possible result of decay, is excluded from this table but is hereby mentioned for completeness.

Radionuclide vs radioisotope vs radiopharmaceutical

The terms radionuclide and radioisotope are used interchangeably for radioactive substances. They indicate exactly the same but differ in the context in which they are used.

• The term “radionuclide” can be used for all atoms that emit nuclear radiation.
• The term “isotope” is used to indicate different versions of a specific element, all having the same number of protons but a different number of neutrons.
• The term “radioisotope” is used when such an isotope emits nuclear radiation — because of this, the term radionuclide may also be used.
• The term radiopharmaceutical is used when a radionuclide is used as (part of) a drug.

Element vs isotope vs radioisotope

For a better understanding, let’s look at the difference between elements, isotopes, and radioisotopes. The name of an element and its atomic number — as known from the periodic table — are defined by the number of protons in its nucleus. Alpha, beta, and in some cases, gamma decay will change the number of protons and/or neutrons.

• When the number of protons changes, it becomes a different element.
• When only the number of neutrons changes (neutron emission), it becomes a different isotope of the same element.
• When the ratio of neutrons vs protons (n/p ratio) is near to 1:1 the element is stable.
• When the ratio of neutrons and protons deviates too much, the element becomes unstable and emits radiation to decay to a stable state, therefore it is named radioisotope or radionuclide.

Example: carbon

For example, carbon has the atomic number six because it has six protons. Carbon has 14 different isotopes (carbon-8 to 20 and carbon-22). All have 6 protons but a different number of neutrons. The number of neutrons can be calculated by:

Good to know:

• Carbon 12 is stable, since 12-6=6 (proton-neutron ratio 1:1).
• Carbon-13 is also stable; the nucleus has enough energy to stay bound together.
• All other versions of carbon are unstable.

Making radiopharmaceuticals from radionuclides, example: carbon-11

Let’s look at the molecular answer to “What are Radiopharmaceuticals?” Carbon-11 can be used as a radiotracer for labeling compounds for imaging studies in, for example, oncology or neurology. One of the benefits of carbon-11 is that it can be incorporated into the compound when the compound already includes carbon. Therefore, the structure of the initial compound will not be altered. The stable carbon isotope will be replaced by the unstable isotope, making the compound suitable for imaging. A disadvantage of carbon-11 is the short half-life of only 20 minutes. The short half-life only allows visualization of the biodistribution of compounds with a fast uptake in the target tissue and fast excretion from non-target tissues. It also brings logistic challenges for the clinical trial.

Chelator and linker to build radiopharmaceuticals

In addition to building the radionuclide into the molecular structure, chelators and linkers can be used to bind a radionuclide to a targeting agent. The chelator or linker forms a bridge between a radionuclide and the targeting agent. The chelator makes labeling possible and prevents the radionuclide from moving freely in the body with the risk of increased off-target accumulation. Common chelators are DOTA, NOTA, NOTP, HBED, THP, TRAP, and DATA. The linker can act as a spacer between the radionuclide and chelator and targeting agent. Because both the chelator and linker can be of pharmacokinetic influence, especially for smaller molecules, seek advice from a specialist such as TRACER.

Interested in the labeling of your drug? TRACER can advise you and provide the production and logistics.

Basics of radiopharmaceuticals FAQ

Below we’ve listed frequently asked questions and the corresponding answers. You may already be able to answer some of these based on the knowledge you have gained from this article.