Effect of Water on Direct Radioiodination of Small Molecules/Peptides Using Copper-Mediated Iododeboronation in Water–Alcohol Solvent

Abstract

Direct radioiodination of peptides using copper-mediated iododeboronation is a promising radiosynthetic method for solving issues of classical direct radiolabeling, such as toxicity of the organotin precursor (iododestannylation) or formation of radio byproducts (by electrophilic iodination of a tyrosine residue). However, the parameters for optimizing the reaction conditions for various peptides are not completely understood. In particular, considering peptide solubility, the effects of water-containing solvents on labeling efficiency should be thoroughly investigated. Herein, we describe the effect of water on copper-mediated radioiododeboronation and the key factors for ensuring the successful radiolabeling of small molecules and peptides in water–organic solvents. 125I-labeled substrates containing peptides ([125I]m/p-IBTA) were obtained with high radiochemical conversions (RCCs: >95%) using an alcohol solvent, and a decrease in these RCCs was observed with increasing water content in the methanol solvent. Additionally, when using water–methanol solvents, a difference in RCC due to the substituent effect was also observed. However, the RCCs can be improved without the use of other additives by adjusting the copper catalyst and time of the labeling reaction or by utilizing substituent effects. This study contributes to the improvement of the design of boronic peptide precursors and radiolabeling protocols using copper-mediated iododeboronation.

Mechanism of Cu-Catalyzed Iododeboronation: A Description of Ligand-Enabled Transmetalation, Disproportionation, and Turnover in Cu-Mediated Oxidative Coupling Reactions

“…Very limited mechanistic information is available on the halodeboronation reaction in general, with a tentative mechanistic description of the iododeboronation largely based on the framework of the Chan–Lam reaction (Scheme b). ,− This proposed mechanism involves transmetalation of the arylorganoboron compound to Cu(II), giving a Cu(II)(aryl) species, followed by disproportionation to Cu(III) and anion exchange/reductive elimination to give the aryl iodide product and Cu(I). Aerobic reoxidation of Cu(I) to Cu(II) closes the cycle.…”

One-pot two-step radioiodination based on copper-mediated iododeboronation and azide–alkyne cycloaddition reaction

“…Prior research has proposed direct radiolabeling strategies for peptides via copper-mediated radioiododeboronation (CuRIB) reactions. [13][14][15] CuRIB is a radiochemical reaction that facilitates the radioiodine-labeling of an aromatic ring [13][14][15][16][17][18] and is modulated by a Cu(I)/Cu(II)/Cu(III) catalytic cycle. 15,19 The CuRIB reactions allow efficient radioiodination in the presence of a copper catalyst under mild conditions.…”

“…[13][14][15] CuRIB is a radiochemical reaction that facilitates the radioiodine-labeling of an aromatic ring [13][14][15][16][17][18] and is modulated by a Cu(I)/Cu(II)/Cu(III) catalytic cycle. 15,19 The CuRIB reactions allow efficient radioiodination in the presence of a copper catalyst under mild conditions. [13][14][15][16] Additionally, CuRIB does not require oxidative reagents, such as hydrogen peroxide, peracetic acid, chloramine-T, and N-halosuccinimides, which is beneficial owing to the nucleophilic nature of radioiodine anions.…”

“…15,19 The CuRIB reactions allow efficient radioiodination in the presence of a copper catalyst under mild conditions. [13][14][15][16] Additionally, CuRIB does not require oxidative reagents, such as hydrogen peroxide, peracetic acid, chloramine-T, and N-halosuccinimides, which is beneficial owing to the nucleophilic nature of radioiodine anions. Consequently, a Laboratory of Analytical and Bioinorganic Chemistry, Division of Analytical and Physical Sciences, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan.…”

“…In further investigation, Cu(py) 4 (OTf) 2 was used as the copper catalyst for ease of comparison with previous reports related to CuRIB. [13][14][15][16] The effect of solvents on the one-pot two-step radioiodination reaction was examined. In this study, the five solvents documented in Table 2 were selected based on the suitability of this reaction to the radiolabeling of peptides.…”