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Abstract
Radiopharmaceutical development has similar overall characteristics to any biomedical drug development requiring a compound's stability, aqueous solubility and selectivity to a specific disease site. However, organometallic complexes containing 188/186Re or 99mTc involve a d-block transition-metal radioactive isotope and therefore bring additional factors such as metal oxidation states, isotope purity and half life into play. This topical review is focused on the development of radiopharmaceuticals containing the radioisotopes of rhenium and technetium and, therefore, on the occurrence of these organometallic complexes in protein structures in the Worldwide Protein Data Bank (wwPDB). The purpose of incorporating the group 7 transition metals of rhenium/technetium in the protein and the reasons for study by protein crystallography are described, as certain PDB studies were not aimed at drug development. Technetium is used as a medical diagnostic agent and involves the 99mTc isotope which decays to release gamma radiation, thereby employed for its use in gamma imaging. Due to the periodic relationship among group 7 transition metals, the coordination chemistry of rhenium is similar (but not identical) to that of technetium. The types of reactions the potential model radiopharmaceutical would prefer to partake in, and by extension knowing which proteins and biomolecules the compound would react with in vivo, are needed. Crystallography studies, both small molecule and macromolecular, are a key aspect in understanding chemical coordination. Analyses of bonding modes, coordination to particular residues and crystallization conditions are presented. In our Forward look as a concluding summary of this topical review, the question we ask is: what is the best way for this field to progress?
Highlights
Drug development is a complex study involving multiple factors
This review focuses on protein structures found in the Protein Data Bank (PDB) that contain a rhenium or technetium metal centre
A list of amino-acid residues directly bound to the rhenium metal centre as well as weak interactions from the protein to the organic ligand of the organometallic complex are specified
Summary
Drug development is a complex study involving multiple factors. The development of one new medical product, from its discovery to the time it is made available for the treatment of patients, takes on average 10–15 years, with an average cost of $800 million to $1.6 billion to research and develop each successful drug. Given chemical complex is necessary to predict what types of reactions the potential model radiopharmaceutical would partake in and, by extension, know which amino acids in proteins and biomolecules the compound would react with in vivo. These structure–function–reactivity studies, both within small-molecule and macromolecular research fields, are a key aspect to predicting and/or optimizing chemical coordination. These properties are utilized in the field of fragment-based drug development and high-throughput screening (Erlanson, 2012; Murray et al, 2012; Joseph-McCarthy et al, 2014). CadCpd crystals transferred from mother liquor to 2.5M Li2SO4 to avoid the formation of metal–ammonia complexes. 30 mM K2ReCl6 and 1.7 M Li2SO4 cautiously added to the drop until final ReCl62À concentration reached 5 mM NS 20
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