Radiolabelling small molecules with beta-emitters has been intensively explored in the last decades and novel concepts for the introduction of radionuclides continue to be reported regularly. New catalysts that induce carbon/hydrogen activation are able to incorporate isotopes such as deuterium or tritium into small molecules. However, these established labelling approaches have limited applicability for nucleic acid-based drugs, therapeutic antibodies, or peptides, which are typical of the molecules now being investigated as novel therapeutic modalities. These target molecules are usually larger (significantly >1 kDa), mostly multiply charged, and often poorly soluble in organic solvents. However, in preclinical research they often require radiolabelling in order to track and monitor drug candidates in metabolism, biotransformation, or pharmacokinetic studies. Currently, the most established approach to introduce a tritium atom into an oligonucleotide is based on a multistep synthesis, which leads to a low specific activity with a high level of waste and high costs. The most common way of tritiating peptides is using appropriate precursors. The conjugation of a radiolabelled prosthetic compound to a functional group within a protein sequence is a commonly applied way to introduce a radionuclide or a fluorescent tag into large molecules. This review highlights the state-of-the-art in different radiolabelling approaches for oligonucleotides, peptides, and proteins, as well as a critical assessment of the impact of the label on the properties of the modified molecules. Furthermore, applications of radiolabelled antibodies in biodistribution studies of immune complexes and imaging of brain targets are reported.
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