Bracco Imaging S.p.a.

Bracco Suisse Sa

Bracco Suisse

Federico Crivellin

Federico Maisano

Federica Buonsanti

Lorena Pizzuto

Laura Orio

Philippe Bussat

Roberta Napolitano

Samir Cherkaoui

Thierry Bettinger

Giovanni Valbusa

Andrea Ferraris

Christian Koller

Adrian Lobito

Francesco Blasi

Luciano Lattuada

Fulvio Ferretti

The present invention relates to the field of optical imaging. More particularly, it relates to compounds of the cyanine family with near-infrared emission characterized by improved physico-chemical and biological properties and to conjugates with biological ligands thereof. The invention also relates to the use of these compounds as optical diagnostic agents in imaging or therapy of solid tumors, to the methods for their preparation and to the compositions comprising them.

Near-infrared cyanine dyes and conjugates thereof

The invention discloses a recombinant protein (P-selectin glycoprotein ligand-1 and Neural Retina-specific Leucine Zipper) PSGL-1-NRL chimeric protein comprising a Selectin Binding domain and a non-covalent dimerization domain, which is a leucine zipper and is more preferably the leucine zipper domain of the human or mouse Neural Retina-specific Leucine Zipper. The chimeric protein further comprises a covalent dimerization domain with at least one cysteine suitable to form a disulfide bridge with another chimeric protein to form a homodimer. In the chimeric protein, the PSGL-1 domain corresponds to the extracellular region of Human PSGL-1 and is more preferably the selectin binding region of the mature protein. The chimeric protein is correctly post-translationally modified and is efficiently expressed in a mammalian system. It is sulfated, O-linked glycosylated and sialylated and binds P, E and L selectin, allowing in vivo and in vitro targeting for diagnostic or therapeutic purposes.

Recombinant chimeric protein for selectins targeting

The present invention relates to the field of optical imaging. More particularly, it relates to compounds of the cyanine family with near-infrared emission characterized by improved physico-chemical and biological properties and to conjugates with biological ligands thereof. The invention also relates to the use of these compounds as optical diagnostic agents in imaging or therapy of solid tumors, to the methods for their preparation and to the compositions comprising them. The compounds have formula (I), formula (I), wherein X is direct bond or —O—; Y is a group selected from linear or branched C1-C6 alkyl, C3-C7 cycloalkyl and heterocyclyl, substituted by at least two hydroxyl groups; R1 and R2 are each independently a linear or branched C1-C6 alkyl substituted by a group selected from —SO3H, —COOH, —CONH2 and —COO—C1-C6 alkyl; and R3 is hydrogen, —SO3H or a linear or branched C1-C6 alkyl substituted by —COOH or —CONH—Y, wherein Y is a group selected from linear or branched C1-C6 alkyl, C3-C7 cycloalkyl and heterocyclyl, substituted by at least two hydroxyl groups.

The application relates to a process for the synthesis of a Near Infra-Red (NIR) fluorescent probe which is a cRGD-Cy5.5 conjugate of formula (I) known as DA364 comprising an aza-bicycloalkane based cyclic peptide labelled with a Cy5.5 dye moiety and used in the guided surgery of tumors and pathologic regions. 

Synthesis of NIR fluorescent probe

The present invention generally relies on a process for the preparation of chelated compounds, comprising the selective interaction between a solid matrix and a chelating agent. In more details, the present invention enables the preparation of chelated compounds useful as diagnostic agents, in high yields and in a reliable way.

Process for the preparation of chelated compounds

Process for the preparation of chelated compound

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Caselle Torinese, Italy

Federico Crivellin