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
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-9611215-B2
Publication Date
2017-04-04
Expiration Date
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 concerns a precursor compound having a defined formula and substituent architecture. The precursor includes a spacer R0 and a protective monovalent group R10 associated with a carboxylic function. R0 is selected from spacer radicals including hydrocarbon-containing spacers, and R2 and R3 are defined as structural substituent portions of the precursor, with R2 corresponding to hydrogen or to an alkyl, cyclo-alkyl, aryl, arylalkyl, alkylaryl, acyl, alkenyl, alkynyl radical, or combinations thereof, and R3 corresponding to a hydrocarbon moiety.
A key aspect of the precursor structure is the protective monovalent group R10. R10 avoids any side reaction on the carboxylic function and is defined as corresponding to an alkyl, a cyclo-alkyl, or hydrogen, or selected among radicals R1, wherein R1 is an activating group of the oxygen atom of the ester function. The functional units COOR10 are nucleophile-reactive with different nucleophilic reactivity between functional units, and their nucleophilic reactivity is less than the nucleophilic reactivity of the comparison functional unit.
The disclosed platform relates to radiolabeling and labeling using nucleophile-reactive sulfonated prosthetic groups formed from sultone-based precursors by nucleophile-induced ring opening. The described labeled compounds include a radionuclide- or NIR-bearing nucleophilic radical R* and an activated ester functionality R1, and the precursor structures are linked to hydrophilicity and radiolabeling/bioconjugation use cases. After formation of the sulfonated nucleophile-reactive species, carboxyl activation is described as enabling installation of the activated ester functionality R1, followed by conjugation to (bio)molecules to produce the labeled compounds.
Claims Coverage
The consolidated claim coverage centers on one precursor compound architecture and its dependent refinements. The independent claim focus combines the spacer and substituent definitions with the protective monovalent group R10 and the nucleophile-reactive COOR10 functional units, and the dependent claims further constrain R3 as a repeating radical and narrow the repeating-unit substituents.
Defined precursor compound with spacer and substituents
A precursor compound characterized by a formula wherein R0 is a spacer selected from spacer radicals, R2 corresponds to hydrogen or to an alkyl, a cyclo-alkyl, an aryl, an arylalkyl, an alkylaryl, an acyl, an alkenyl, an alkynyl radical or a combination of these radicals, and R3 corresponds to a hydrocarbon moiety.
Protective monovalent group avoiding side reaction on carboxylic function
R10 is a protective monovalent group that avoids any side reaction on the carboxylic function and corresponds to an alkyl, a cyclo-alkyl, or hydrogen, or selected among radicals R1, wherein R1 is an activating group of the oxygen atom of the ester function.
Differential nucleophile-reactive functional units COOR10
The functional units of formula COOR10 being nucleophile-reactive, the nucleophilic reactivity of these functional units being different, and COOR10's nucleophilic reactivity being less than the nucleophilic reactivity of the comparison functional unit shown in the claim text.
Repeating-unit definition for hydrocarbon moiety R3
A compound wherein R3 corresponds to a hydrocarbon moiety defined as a repeating radical (CR4R5)n.
Restrained repeating-unit substituents within R3
The compound of the repeating-unit definition wherein R4 and R5 are both hydrogen.
The claim set is directed to a precursor compound with a protective monovalent group R10 that avoids side reaction on the carboxylic function, and nucleophile-reactive COOR10 functional units with nucleophilic reactivity different from and less than a comparison functional unit. Dependent claims then specify the repeating-unit structure for R3 and further narrow R4 and R5 to hydrogen.
Stated Advantages
Increased hydrophilicity for conjugation/radiolabeling/bioconjugation purposes.
High yields at room temperature.
Short reaction times.
No by-products.
Automation suitability.
Water-compatible coupling.
Documented Applications
Provision of labeled prosthetic compounds for radiolabeling/bioconjugation.
Labeling of fragile (bio)molecules including peptides, proteins, antibodies, and oligonucleotides using radiolabeling and labeling via nucleophile-reactive sulfonated prosthetic groups.
Nuclear imaging contexts indicated through radionuclides and nuclear medicine use, including PET/SPECT and therapy/tracers.
Near-infrared (NIR) labeling use indicated through inclusion of an NIR-bearing nucleophilic radical R*.
Interested in licensing this patent?