Wide range of radioisotopes is used in nuclear medicine for diagnostic and therapeutic applications. In recent years, a number of metal radioisotopes have been considered as they enable nuclear medicine utilizations in exact accordance to patient needs as defined by principles of “personalized medicine”; for such utilizations, the term “theranostics” is also used. These radioisotopes cannot be applied in free form as, in such form, they are non- specifically deposited in tissues. Therefore, the metal radioisotopes have to be bound by suitable organic compounds (“ligands”, or “chelators”) to form a stable complex which is not decomposed in body.
The presented cyclam based ligands combined with copper radioisotopes can be used for visualization of the biodistribution of many biologically active compounds using PET imaging. By leveraging this novel theranostic approach, our compounds allow the determination of dose during the diagnostic stage with Copper-64 and deliver the right amount of radiation to the tumor for therapy with Copper-67.
Technology Features, Specifications and Advantages
Copper-64 is an emerging PET radioisotope with a half-life of ~12 h and soft positron emission. Cyclam based ligands (= chelators), as highly selective chelators for copper over metallic impurities (e.g. nickel and zinc), were modified with a highly hydrophilic bis(phosphinate) pendant arm. The group is responsible for a fast and efficient radiolabelling of the chelators with copper radioisotopes. Bifunctional chelators containing carboxylic, amine, isothiocyanate, azide or cyclooctyne groups were synthesized and conjugated to various substrates and biologically active targeting molecules (oligopeptides, antibodies or their fragments , folic acid, bis-phosphonates etc.). The chelators and their conjugates incorporate 64-Cu very efficiently even at room temperature and with very low chelator excess, producing radiopharmaceuticals with very high specific activities. The 64-Cu-labelled molecules are stable in-vivo with no non-specific deposition of the radiometal and are easily excreted from body. The chelators represents a novel and unique family of ligands which has the best labelling efficiency among published copper chelators.
Group of Prof. Petr Hermann (Department of Inorganic Chemistry, Faculty of Science, Charles University) designed, synthesized and tested the copper bifunctional chelators and their conjugation reactions. The team has a long-time experience with chemistry of macrocycles and organophosphorus chemistry.
The presented cyclam based ligands combined with copper radioisotopes can be used for visualization of the biodistribution of many biologically active compounds using PET imaging. By leveraging this novel theranostic approach, our compounds allow the determination of dose during the diagnostic stage with Copper-64 and delivers the right amount of radiation to the tumor for therapy with Copper-67.
- Reactive groups for conjugations are located far away from the metal binding site and the efficient radiolabelling is not altered by conjugation.
- Conjugations are possible with unprotected chelators (protection-deprotection strategy is not necessary).
- Chelators are suitable for conjugations with sensitive biomolecules.
- Modular design for easy introduction of new bifunctional reactive group(s).
- Radiolabelling with 64-Cu is very fast even at room temperature and with small chelator/conjugate excess.
- The complexes are highly hydrophilic and easily excreted from the body.
- The radiopharmaceuticals are stable in-vivo.