I5

Bifunctional cyclam based ligands for conjugations with targeting vectors and their 64-Cu radiopharmaceuticals for PET imaging

Prof. Petr Hermann, Charles University

IOCB Tech


Challenge

The presented cyclam based ligands combined with copper radioisotopes can be used for the visualization of bio-distribution of many biologically active compounds used in Positron Emission Tomography (PET) imaging. By leveraging this novel theranostic approach, our compounds allow the determination of the radioactive dose during the diagnostic stage with Copper-64 (64-CU) and therefore deliver the right amount of radiation to the tumor for therapy with Copper-67.


Technology

64-Cu is an emerging PET radioisotope with a half-life of ~12 h and a soft positron emission. Cyclam based ligands (= chelators) are highly selective chelators for copper over metallic impurities (e.g. nickel and zinc) and were modified with a highly hydrophilic bis(phosphinate) pendant arm. Bi-functional 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 radio-pharmaceuticals with high specific activities. The 64-Cu-labelled molecules are stable in-vivo without non-specific deposition of the radio-metal and are easily excreted from body. The chelators represent a novel and unique family of ligands which have the best labeling efficiency among published copper chelators.


Commercial Opportunity

Metal radioisotopes are emerging tracers for PET, e.g. 68-Ga is now widely clinically used. Copper-64 offers convenient logistics from production sites, extended PET imaging window, a high image resolution.


Development Status

Available for demonstration. The synthetic procedures for bifunctional ligands are known and conjugations were tested. 64-Cu radiolabeling was tested. In-vivo stability/bio-distributions of labelled molecules have been tested in rodents. Selected samples for labelling/in-vitro/in-vivo tests are available. Some chelators designed in the group have been already successfully tested in patients (>200 patients) for PET imaging (with 68-Ga) and/or treatment (with 177-Lu) of bone metastases. These ligands are based on macrocycles (as radiometal-binding moiety) conjugated to bis-phosphonates (as bone-targeting groups).

We are able to prepare the bifunctional chelators up to a gram scale or to design/synthesize chelators tailored for a particular utilization. Samples for radiolabeling tests are available on demand.


Patent Situation

International Patent Application published under PCT on May 26, 2017.


Further Reading

www.cuni.cz/UK-8684-version1-kip___bifunctional_cyclam_base.pdf


 

Bifunctional cyclam based ligands for conjugations with targeting vectors and their 64-Cu radiopharmaceuticals for PET imaging
Bifunctional cyclam based ligands for conjugations with targeting vectors and their 64-Cu radiopharmaceuticals for PET imaging