Accelerating New Drug Development: The Role of Radioisotope Labeling

 

In drug development, Radioisotope labeling has become a powerful tool. It provides a means to track the fate of drugs in the body and helps researchers to better understand the metabolic processes and potential toxicity of new compounds. So, scientists can design more effective and safer drugs, reducing the risk of adverse effects and increasing the likelihood of success in clinical trials.

Isotopes are atoms of the same chemical element with different masses due to the presence of different neutron numbers in the nucleus, and there are light and heavy isotopes; based on physical properties, isotopes can also be classified into two forms: radioactive and stable. Radioisotope labeling technology is a very useful tool in the process of new drug development, and Medicilon offers radioisotope services.

Based on physical properties, isotopes can be classified into two forms: radioactive and stable. Radioactive isotopes (e.g. 3H, 14C) undergo their decay process and radiate radiation energy, are unstable, and have physical half-life; stable isotopes are non-radioactive, have stable physical properties, exist in nature in a certain proportion (abundance), are harmless to the human body, and can be labeled into drug molecules by chemical synthesis and tracked and detected by instruments such as gas and liquid quality.

 

1, The reason why radioisotopes are widely used.

Radioisotopes are widely used for active material tracing mainly depending on two most important characteristics:

(1) homogeneity with the material being traced, i.e., a high degree of consistency in chemical and biological behavior between the radionuclide and its non-radionuclides of the same element, without disturbing and disrupting the equilibrium of physiological processes in vivo and in vitro;

(2) Distinguishability with the traced material, where the nucleus of the radionuclide continuously decays and emits rays that can be detected by the radiosonde, thus enabling the quantification and localization of the marker.

In addition, radioisotope tracer technology has the advantages of high sensitivity, high specificity, wide applicability, and simple detection method, so it has been widely used in drug ADME research, and the U.S. FDA has long taken the pharmacokinetic data of radioisotope labeled drugs after administration as an important basis for the safety evaluation of new drugs, and has formulated relevant guidelines.

2, The direction of radioisotopes in drug development

In terms of quantitative sensitivity, radioisotope-labeled compounds are more sensitive than stable isotope markers, and the measurement of radioactivity is not affected by non-radioactive impurities and chemical states, thus making quantitative analysis easier and the results more accurate. In addition to solving analytical problems that cannot be solved by conventional analytical methods, radioisotope-labeled compounds can more importantly be used as tracers to study the distribution, metabolism, efficacy, and mechanism of action of drugs in vivo, providing an important basis for the pharmacokinetic study of drugs, and providing methods for the development of innovative drugs.

3, Choice of radioisotope labeling position

Before the preparation of labeled drugs, the first step is to select the appropriate isotope as the labeling element and decide on the labeling position. The labeled drug used for tracer study should make the labeled atoms represent the whole molecule of the drug in the organism as much as possible and should pay attention to the possible changes of the drug in the body. The structure of the drug molecule, the half-life of the isotope, the energy of the radiation, the ease of introducing the labeled atom, and the special requirements of the tracer test should be taken into account when choosing the isotope to be used as the labeled atom. The most commonly used isotopes are 14C, 3H, and 35S; sometimes 32P and 131I are also used.

As the most commonly used radionuclide, 14C is usually labeled on the skeleton structure of molecules, and its labeling sites are more stable; 3H is prone to exchange with 1H in the surrounding environment, resulting in a decrease in a specific activity, so it is less stable than 14C; in addition, 3H has a more obvious isotope effect compared with 14C, which also limits its application to some extent. However, in general, in tracer experiments, the errors caused by isotopic effects are often within the experimental allowable errors and can be neglected. In addition, considering that the synthesis of 3H markers is relatively simple, 3H markers are also often chosen as tracers when they can meet the experimental requirements.

In addition to the above, computer-assisted metabolite prediction (CAMP) techniques can be used in the selection of labeling sites to predict stable sites in the molecular structure of compounds. In general, labeling of C atoms on aromatic or alicyclic rings in the molecular structure should be considered first, while labeling at active sites such as carboxyl, hydroxyl, sulfhydryl, amino, and imino groups should be avoided as much as possible. This is because once these unstable groups are separated from the parent compound, the ability to trace the parent drug and major metabolites is lost. In addition, the labeling site should be far away from the chemical bond-break location to avoid the effect of isotope effect. If the parent compound generates 2 important metabolites simultaneously due to chemical bond breakage during metabolism, a dual-labeling technique can be considered for parent compound labeling.

Medicilon offers radioisotope analysis services for labeling experiments in the drug development process using radioisotopes such as 3H, 14C, 32P, 33P, 125I, and 35S.