Development of Peptide and Protein Based Radiopharmaceuticals
Evelien Wynendaele, Nathalie Bracke, Sofie Stalmans and Bart De Spiegeleer
Affiliation: Drug Quality and Registration (DruQuaR) group, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, B-9000, Belgium.
Radiolabelled peptides and proteins have recently gained great interest as theranostics, due to their numerous and considerable
advantages over small (organic) molecules. Developmental procedures of these radiolabelled biomolecules start with the radiolabelling
process, greatly defined by the amino acid composition of the molecule and the radionuclide used. Depending on the radionuclide selection,
radiolabelling starting materials are whether or not essential for efficient radiolabelling, resulting in direct or indirect radioiodination,
radiometal-chelate coupling, indirect radiofluorination or 3H/14C-labelling. Before preclinical investigations are performed, quality
control analyses of the synthesized radiopharmaceutical are recommended to eliminate false positive or negative functionality results, e.g.
changed receptor binding properties due to (radiolabelled) impurities. Therefore, radionuclidic, radiochemical and chemical purity are investigated,
next to the general peptide attributes as described in the European and the United States Pharmacopeia. Moreover, in vitro and
in vivo stability characteristics of the peptides and proteins also need to be explored, seen their strong sensitivity to proteinases and peptidases,
together with radiolysis and trans-chelation phenomena of the radiopharmaceuticals. In vitro biomedical characterization of the radiolabelled
peptides and proteins is performed by saturation, kinetic and competition binding assays, analyzing KD, Bmax, kon, koff and internalization
properties, taking into account the chemical and metabolic stability and adsorption events inherent to peptides and proteins.
In vivo biodistribution can be adapted by linker, chelate or radionuclide modifications, minimizing normal tissue (e.g. kidney and liver)
radiation, and resulting in favorable dosimetry analyses. Finally, clinical trials are initiated, eventually leading to the marketing of radiolabelled
peptides and proteins for PET/SPECT-imaging and therapy of different clinical diseases.
Keywords: Radiolabelling procedures, peptide, protein, quality control, drug development process.
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