Ionic liquid supported organotin reagents to prepare molecular imaging and therapy agents

Baidoo

et al. 2016

Chemistry A European J

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Aryliodonium salts have become precursors of choice for the synthesis of 18F-labelled tracers for nuclear imaging. However little is known on the reactivity of these precursors with heavy halogenides, i.e. radioiodide and astatide at the radiotracer scale. Herein, we report the first comparative study of radiohalogenation of aryliodonium salts with [125I]-iodide and [211At]-astatide. Initial experiments on a model compound highlight a higher reactivity of astatide compared to iodide that could not be anticipated from the trends previously observed within the halogen series. Kinetic studies indicate a significant difference in activation energy (Ea = 23.5 and 17.1 kcal/mol with 125I− and 211At−, respectively). Quantum chemical calculations support the hypothesis of a monomeric iodonium-astatide intermediate whereas radio-iodination occurs in a dimeric environment. The good to excellent regioselectivity of halogenation and high yields achieved with diversely substituted aryliodonium salts indicates that this class of compounds is a promising alternative to the stannane chemistry currently used for radiohalogen labeling of tracers in nuclear medicine.

Section: Introductionsupporting

confidence: 77%

Unexpected Behavior of the Heaviest Halogen Astatine in the Nucleophilic Substitution of Aryliodonium Salts

Baidoo

et al. 2016

Chemistry A European J

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“…Accordingly, improvements have recently been proposed to facilitate these purifications with the use of supported tin precursors that avoid the need of an HPLC step and which could facilitate the transfer to automated radiosynthesis. 10,11 …”

Section: Introductionmentioning

confidence: 99%

Bifunctional aryliodonium salts for highly efficient radioiodination and astatination of antibodies

Navarro

Bioorganic & Medicinal Chemistry

et al. 2017

In this report we describe the development of an alternative approach to arylstannane chemistry for radiolabeling antibodies with radioiodine or astatine based on aryliodonium salts precursors. Bifunctional aryliodonium salts were designed and tested for the synthesis of 125I and 211At labeled prosthetic groups for bioconjugation. The nature of the electron rich aryl group was varied and its impact on the regioselectivity of radiohalogenation was evaluated. Unexpectedly, whereas the 2-thienyl group provided the best regioselectivity towards the radioiodination of the aryl moiety of interest (98:2), it was less selective for astatination (87:13); the anisyl group providing the best regioselectivity of astatination (94:6). Under optimized conditions, both radioiodination and astatination could be performed very efficiently in mild conditions (radiochemical yields > 85%). The ionic nature of the precursors was exploited to develop an efficient purification approach: the HPLC step that is usually necessary in conventionnal approaches to optimize removal of organotin toxic precursors and side products was replaced by a filtration through a silica cartridge with a significantly reduced loss of radiolabeled product. The purified radioiodinated and astatinated prosthetic groups were then conjugated efficiently to an anti-CD138 monoclonal antibody (75–80% conjugation yield). By using this novel and simple radiohalogenation procedure, higher overall radiochemical yields of astatination were obtained in comparison with the use of an arylstannane precursor and procedures of the litterature for labeling the same antibody. Overall, due to their simplicity of use and high robustness, these new precursors should simplify the labeling of proteins of interest with iodine and astatine radioisotopes for imaging and therapeutic applications.

“…[16,21,22] Latest advances in astatination methodologies show that electrophilic substitution of arylstannane remains the preferred method because of the RCYs generally obtained under smooth conditions. [23,24] However, since astatine can potentially exist in several oxidation states (−I, +I, +III, +V and +VII), obtaining pure At + for electrophilic reactions is difficult to control, and partial over-oxidation to unwanted species can be difficult to avoid. This difficulty is mostly due to the extremely high dilution of 211 At (cyclotron produced and distilled from a bismuth target) available in solution (generally available at picomolar or subpicomolar concentrations), with tiny traces of impurity being able to perturb its reactivity and lead to side reactions and inconsistent reaction yields.…”

Section: Introductionmentioning

confidence: 99%

Unexpected Behavior of the Heaviest Halogen Astatine in the Nucleophilic Substitution of Aryliodonium Salts

Baidoo

et al. 2016

Chemistry A European J

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What is the most significant result of this study?Astatine is definitely ah alogen apart and it was demonstrated again in this study.B ecause it is too rare to observe and analyze by conventional approaches, chemists have tried for decades to anticipate its reactivity by extrapolation from its closest neighbor, iodine, but experiments frequently proved these predictions wrong. In this study,w ei nitially anticipated the nucleophilic substitution of astatide on aryliodonium salts to occur similarly to iodide. However,w eobserved ar eactivity that was much higher.Quantum chemical calculations were then utilized to propose mechanisms for this reactivity since astatine is "invisible"; it is available only at the nanogram scale at best. These observations make diaryliodonium salts much more useful than expected to synthesize astatinated compounds, especially with the radioisotope