Copper‐mediated radioiodination reaction through aryl boronic acid or ester precursor and its application to direct radiolabeling of a cyclic peptide

Abstract

A copper‐mediated radioiodination using aryl boronic precursors is attracting attention as a solution to oxidative iododestannylation and nickel‐mediated radioiodination drawbacks. The copper‐mediated radiolabeling method allows radioiodination at room temperature with stable aryl boronic precursors without preparing complex starting materials or reagents and can be performed in a reaction vessel exposed to air. This method has good potential in radiochemistry; however, studies on the scope of copper‐mediated radioiodination through boronic precursors are insufficient. In particular, few reports have demonstrated the effect of protecting groups on radiolabeling efficiency. Therefore, the effect of the protecting group of aryl boronic acids on the copper‐mediated radioiodination was investigated. In addition, this method, which does not require heating, is expected to be useful for direct radiolabeling of peptides. Thus, we attempted direct radioiodination of c(RGDyk) as an example. The resulting radioiodination method was well tolerated in various substrates and was unaffected by the pinacol ester‐type protecting group. Also, c(RGDyk) was labeled with 125I via copper‐mediated radioiodination using an aryl boronic acid precursor. The reaction time and yield were improved, compared with the indirect method. Furthermore, the large difference in polarity between the boronic acid precursor and the radiolabeled compound facilitated purification.

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

“…A copper-mediated radiolabeling reaction using a boronic precursor is well tolerated at the tracer level in both electron-rich and electron-poor substrates, including sterically crowded substrates. , However, in this study, using a mixture of solvents containing H 2 O/MeOH resulted in differences between positional isomers. These observations prompted us to investigate the effect of the substituents on labeling efficiency at the tracer level in a mixture solvent containing H 2 O/MeOH.…”

“…The target compounds ([ 125 I] 2 and [ 125 I] 4 ) were synthesized as shown in Figure . The radiolabeling protocol was prepared according to previously reported methods with some modifications. − In this study, Cu­(py) 4 (OTf) 2 (py = pyridine, OTf = trifluoromethanesulfonate) was used as it was reported as the optimal copper catalyst for this labeling reaction . A boronic precursor ( 1 or 3 ) and Cu­(py) 4 (OTf) 2 dissolved in a solvent, water (H 2 O), or an organic solvent to control the H 2 O content of the reaction solvent were added to a microtube in this precise order.…”

“…Copper-mediated nucleophilic reactions using a boronic precursor are promising radiosynthetic methods for labeling an aromatic ring with radioiodine. − Copper-mediated radioiododeboronation is performed in a reaction vessel exposed to air at room temperature, leading to the formation of the desired radiolabeled compound without the preparation of complex starting materials or reagents. In addition, copper-mediated radioiododeboronation can also be adapted for direct radiolabeling of peptide mimetics. , Thus, it solves the issues of classical direct radiolabeling of peptides using radioiododestannylation or electrophilic radioiodination of tyrosine residues, such as toxicity of the organotin precursor or formation of byproducts . However, information for optimizing reaction conditions for various peptides is ambiguous, as the method has scarcely been used for this type of compounds.…”

Merging the Versatile Functionalities of Boronic Acid with Peptides

“…Kondo et al reported an efficient methodology for the direct radiolabeling of a peptide side chain via copper-mediated radioiodination by using an aryl boronic acid precursor through a Chan–Evans–Lam cross-coupling reaction ( Figure 14 D) [ 85 ]. This approach allows for the avoidance of heavy metals, heating, oxidizing reagents, an inert condition, as well as the preparation of complex starting materials.…”

“…This approach allows for the avoidance of heavy metals, heating, oxidizing reagents, an inert condition, as well as the preparation of complex starting materials. In addition, it can be carried out at room temperature, and is easily separated due to the significantly different polarity between the boronic acid precursor and the iodine compound [ 85 ].…”