Method for synthesizing iodo- or astatoarenes using diaryliodonium salts
Inventors
GUERARD, François • Gestin, Jean-François • Brechbiel, Martin W. • Lee, Yong-Sok
Assignees
Centre National de la Recherche Scientifique CNRS • Universite dAngers • Universite de Nantes • Institut National de la Sante et de la Recherche Medicale INSERM • US Department of Health and Human Services
Publication Number
US-10703708-B2
Publication Date
2020-07-07
Expiration Date
2036-11-24
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Abstract
The present invention concerns a method of synthesizing a iodo- or astatoarene comprising the reaction of a diaryliodonium compound with a iodide or astatide salt, respectively. The invention also relates to said iodo- or astatoarene and diaryliodonium compound as such. The invention also concerns a method of synthesizing a iodo- or astatolabelled biomolecule and/or vector using said iodo- or astatoarene.
Core Innovation
The present invention concerns a method of synthesizing iodo- or astatoarenes by reacting diaryliodonium compounds with iodide or astatide salts, respectively. This method also relates to the iodo- or astatoarene compounds and diaryliodonium compounds themselves, as well as to methods for synthesizing iodo- or astato-labelled biomolecules and/or vectors using these iodo- or astatoarenes.
The background describes the challenges and limitations in synthesizing radioiodinated and astatinated aromatic compounds, which are valuable in nuclear medicine. Conventional methods such as nucleophilic substitution by halogen exchange and electrophilic substitution by halodemetallation often present issues including low radiochemical yields, low specific activity, and toxicity concerns related to tin-containing intermediates and side products. Additionally, controlling the oxidation state of astatine (+I state) is difficult, and mixtures of oxidation states are unstable due to radiolytic changes.
The invention addresses the need for new synthetic methods that achieve high and consistent yields, are easy to perform with efficient, fast, and low-cost purification, and are less toxic than previous iododestannylation and astatodestannylation methods. A particular aim is to achieve astatoarenes using astatine in the (−I) oxidation state. The inventors discovered that reacting diaryliodonium compounds with iodide(−I) or astatide(−I) salts can produce iodo- or astatoarenes with high efficiency, especially with astatide, and that purification by solvent extraction (e.g., diethylether) is simpler and less wasteful than traditional HPLC procedures.
Claims Coverage
The patent contains multiple independent claims focusing on methods for synthesizing astatoarenes and related compounds, reactions involving diaryliodonium salts and halide salts, and methods for synthesizing astato-labelled biomolecules and vectors. The inventive features encompass the chemical structures employed, reaction conditions, purification methods, and precursor compositions.
Method of synthesizing an astatoarene from diaryliodonium compound and astatide salt
A method comprising reacting a diaryliodonium compound of specified formula (II) with an astatide salt to produce an astatoarene.
Use of diaryliodonium compounds with specific substituents and counter-ions
Diaryliodonium compounds are defined with detailed aryl and heteroaryl groups substituted with functional groups including alkyl, alkynyl, halogen, nitro, azide, succinimidyl, maleimidyl, and others, and associated monovalent anions such as CF3COO, TsO, MsO, NsO, TfO, NO3, Br, Cl, SO4, and BF4.
Astatoarene products with radioactive astatine
The astatoarene products of formula (I) wherein X is astatine, including radioactive isotopes such as 211At.
Reaction conditions involving solvents and purification
The reaction is conducted in solvents like acetonitrile, alcohols (especially methanol), dimethylformamide, water, or their mixtures, and includes a purification step extracting the astatoarene with solvents in which the salt and diaryliodonium salt are insoluble but the astatoarene is soluble.
Reduction of astatine prior to reaction
The method includes a prior reduction step of astatine to generate astatide salts before reaction with the diaryliodonium compound.
Method of synthesizing an astatolabeled biomolecule or vector
A method involving first synthesizing an astatoarene as defined and then reacting it with a biomolecule or vector carrying a functional group reactive with the astatoarene.
The claims cover synthesizing astatoarenes using diaryliodonium compounds and astatide salts with specified chemical structures and conditions, purification methods avoiding chromatography, pre-reaction reduction of astatine, and use of the astatoarenes for radiolabeling biomolecules or vectors.
Stated Advantages
Higher and consistent yields in synthesizing iodo- or astatoarenes, including radioiodo- or radioastatoarenes.
Ease of performance with efficient, fast, and low-cost purification steps compared to conventional HPLC.
Reduced toxicity by avoiding tin-containing intermediates and side products present in iododestannylation and astatodestannylation methods.
Use of astatine in the (−I) oxidation state, improving stability and control over the oxidation state.
Unexpectedly higher reactivity of astatide compared to iodide leading to efficient astatination under milder conditions.
Documented Applications
Radiolabeling of biomolecules and vectors with radioactive isotopes of iodine or astatine for use in nuclear medicine.
Conjugation of radioiodo- or radioastatoarenes to biomolecules such as antibodies, recombinant proteins, and synthetic peptides for tumor treatment and localization.
Use of radiolabeled biomolecules or vectors in the imaging or therapy of tumors, leveraging isotopes like 123I, 124I, 125I, 131I, and 211At.
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