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Bifunctional ligands for efficient 64-Cu labelling

PET imaging is common diagnostic modality mostly using 18F having some disadvantages (price, short half-life). Other Beta+ emitters can be more convenient and such radionuclides are metal elements requiring complexation by organic ligands. Ligands must be bifunctional (having reactive side group) to be conjugated to targeting biological vector.

64-Cu is a radioisotope having long half-life (12 h) matching biological circulation/accumulation time of antibodies/antibody fragments or large molecules, and soft positron emission (high resolution in PET). As metal element, it requires chelation to be safely (no unspecific accumulation) used in vivo. Chelator must be bifunctional to be conjugated to biologically active molecule and has to bind 64-Cu very effectively to reach high specific activity. Conjugate body distribution is controled by targeting molecule. New ligands are based on cyclam (cyclic tetraamine) skeleton having high selectivity for Cu2+. It is modified with phosphorus acid groups accelerating complexation of very diluted radioisotope. Groups for conjugation involve -NH2, -CO2H, -N3, tetrazine, -NCS, alkyne etc.

Ligands bind 64-Cu with the best efficiency among ligand classes suggested/used for the utilization and published in scholary literature. It leads to very high specific activity (activity per amount of conjugate) potentially decreasing injected dose to get good diagnostic image and/or decreasing necessary amount of expensive targeting group. Possibility to be used in theranostic combinations. Phosphonic/inic acid group(s) accelerate labelling, increases hydrophilicity and solubility - it probably will increase kidney elimination. They are orthogonal to some conjugation reactions. Syntheses are based on unique know-how in our laboratory based on work with this class of compounds for years.

Final ligands syntheses on 0.1-5 gram scale, oligopeptide conjugations and excellent labelling with 64-Cu confirmed.

Tomáš David, Petr Hermann, Vojtěch Kubíček: Czech Patent Application (PV 2015-825) "Sloučeniny na bázi cyklamu, jejich konjugáty, cílící konjugáty, koordinační sloučeniny, farmaceutický přípravek je obsahující, způsob jejich přípravy a jejich použití" ("Compounds based on cyclam, their conjugates, targeting conjugates, coordination compounds, pharmaceuticals containing the compounds, their syntheses and utilizations")

Patent application submitted to Czech Industrial Property Office on November 20, 2015; No. PV 2015-825.

Charles University in Prague (Faculty of Science), Ovocny trh 3-5, Prague 1, Czech Republic