Nucleophile-reactive sulfonated compounds for the (radio)labelling of (bio)molecules; precursors and conjugates thereof

Inventors

Priem, Thomas • Bouteiller, Cedric • Camporese, Davide • Romieu, Anthony • Renard, Pierre-Yves

Assignees

Advanced Accelerator Applications SA

Abstract

Nucleophile-reactive sulfonated compounds used as precursors to (radio)labelled (bio)molecules are produced by pre-introduction of a nucleophilic compound R* through an unusual nucleophile-induced ring-opening reaction of the sultone moiety of the precursor. The precursors and compounds conform to respective formulae (Ip) and (I): Also disclosed are methods for producing these precursors and compounds, as well as for conjugation of these compounds with (bio)molecules, and to the drugs obtained by this method.

Core Innovation

The invention provides compounds of formula (I) or pharmaceutically acceptable salts, together with corresponding sultone-type precursor compounds of formula (Ip). The approach uses nucleophile-induced ring opening of the sultone moiety to form sulphonate-bearing intermediates that are conjugatable to water-soluble biomolecules, including amino-containing peptides, proteins, and oligonucleotides.

The compounds include a bi-functional spacer R0, defined substituent selections for R1, R2 and R2′, and a bi-functional group moiety (CR4R5)n, where R4 and R5 are selected from the listed groups and n is an integer between 1 and 3. R* is a (radio)nuclide, and the disclosed structures include nonradioactive and radiofluorinated precursors, including 18F, with reference also to fluorine-18 and 19F.

The precursors are described with a protecting labile carboxyl function (COOR10) to enable orthogonal nucleophilic reactivity. The disclosed prosthetic groups and precursors are configured for coupling in aqueous conditions and improved (radio)labelling performance, with therapeutic and diagnostic nuclear imaging (PET/SPECT) and NIRF uses explicitly stated.

Claims Coverage

The claim coverage centers on a compound of formula (I) or a pharmaceutically acceptable salt, with inventive coverage grounded in the defined spacer R0, defined activating or terminal group R1, defined substituent sets R2/R2′/R3, and the (radio)nuclide-bearing feature R*. Dependent scope further specifies alternative structural representations and a formulation context with a pharmaceutically acceptable carrier.

Overall, the claim coverage centers on a formula (I) compound where the spacer R0, reactive group R1, substituent selections R2 and R2′, and the (CR4R5)n moiety parameters are constrained to defined sets, while R* is a (radio)nuclide. Dependent claims refine the structure via formulas (II) and (III) and add a drug or diagnostic product formulation context including a pharmaceutically acceptable carrier.

Stated Advantages

Documented Applications