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

Abstract

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.

Bifunctional aryliodonium salts for highly efficient radioiodination and astatination of antibodies

“…Three aryl rich (hetero)arenes (Ar b ) were chosen for comparison of their ability to induce this regioselectivity: (i) the 4-anisyl group previously reported as providing good to excellent selectivity of radioiodination and astatination, 19 (ii) the 4-isopropoxyphenyl group as an electron richer analogue of anisyl and (iii) the 2-thienyl group that has been reported as providing excellent regioselectivity of radiofluorination but which use has not yet been reported for radioiodination or astatination. 20 …”

“…19 However, partial hydrolysis of the activated ester was observed, resulting in an inseparable mixture of iodonium species (Scheme 2). This hydrolysis was attributed to the presence of water introduced in the reaction via the tosylic acid which is available in the monohydrated form, the electrophilicity of the carbonyl center of the activated ester being greatly enhanced by the electron withdrawing effect of the iodonium group.…”

“…Although the counter ion associated to the iodonium salt can dramatically impact reactivity, this change was not expected to provide any marked difference since we observed previously that using either tosylate or triflate had no detectable impact on radioiodination and astatination results. 19 …”

“…We have also previously observed that reaction kinetics were sensibly improved in methanol in the case of astatination (but not for radioiodination). 19 However our initial radiolabeling attempts with precursor 4a indicated that the activated ester in the iodonium precursor was extensively transesterified by methanol only a few minutes after dissolution in this solvent, which was attributed to the strong electron withdrawing effect of the iodonium function on the aryl and the carbonyl center, making methanol incompatible for [ 211 At]SAB synthesis. Acetonitrile was thus kept for both radioiodination and astatination.…”

“…16,17 In radiochemistry, aryliodonium salts have been increasingly used for radiofluorination reactions over the past ten years, 18 and we have recently shown that these precursors could also be radioiodinated and astatinated with an unexpected high efficiency on a series of model compounds. 19 We observed that radioiodination and especially astatination could be performed at much lower temperature than radiofluorination (which generally requires high temperatures in the absence of a catalyst), making these precursors potentially applicable to the radioiodination and astatination of more complex structures bearing heat sensitive functional groups.…”